Concentrations of trimethoprim and sulphadoxine in tissues from goats and a cow

Energy Technology Data Exchange (ETDEWEB)

Nielsen, P; Rasmussen, F [Kongelige Veterinaer- og Landbohoejskole, Copenhagen (Denmark)

1975-01-01

The concentration of trimethoprim and sulphadoxine in plasma and tissue from goats and a cow have been determined after a single intravenous injection. Furthermore, the concentration of the two drugs and their metabolites in plasma and tissues have been determined after continuous intravenous infusion for 2 1/2 - 3 hrs. Trimethoprim was present in all tissues but brain at higher concentrations than in plasma while the concentration of sulphadoxine in the different tissues were lower than in plasma. The highest concentration of the 2 drugs and their metabolites was found in the kidney. The distribution pattern of trimethoprim and sulphadoxine was similar in cow and goats.

Concentrations of trimethoprim and sulphadoxine in tissues from goats and a cow

International Nuclear Information System (INIS)

Nielsen, P.; Rasmussen, F.

1975-01-01

The concentration of trimethoprim and sulphadoxine in plasma and tissue from goats and a cow have been determined after a single intravenous injection. Furthermore, the concentration of the two drugs and their metabolites in plasma and tissues have been determined after continuous intravenous infusion for 2 1/2 - 3 hrs. Trimethoprim was present in all tissues but brain at higher concentrations than in plasma while the concentration of sulphadoxine in the different tissues were lower than in plasma. The highest concentration of the 2 drugs and their metabolites was found in the kidney. The distribution pattern of trimethoprim and sulphadoxine was similar in cow and goats. (author)

An introduction to predictive modelling of drug concentration in anaesthesia monitors.

Science.gov (United States)

DeCou, J; Johnson, K

2017-01-01

A significant amount of anaesthetists' work involves the prediction of drug effects and interactions to produce a smooth general anaesthetic that minimises drug side effects and promotes rapid emergence. Successfully managing this process requires a basic understanding of drug effects, experience and inevitably some guesswork, since it is difficult (and in some cases impossible) to anticipate all relevant patient and surgical factors. Although data are generally available to allow calculation of plasma drug and effect site concentrations, this is often difficult to apply in complex clinical contexts, particularly when multiple drug types are used. In recent years, manufacturers have developed and incorporated into anaesthetic workstations technologies that use drug pharmacodynamic and pharmacokinetic data to predict drug effects and interactions. Such systems can predict the duration and effects of drugs during anaesthesia and assist the anaesthetist to understand complex drug interactions. With this information available, different drug types, doses and combinations may be tailored in a scientific way to maximise useful effects whilst minimising overdose and side-effects, particularly in high-risk patients. Examples are used to illustrate how such systems can be used in practice, and how drug effects and interactions can be simulated to "rehearse" an anaesthetic before any drugs are actually administered. At present only a small number of anaesthetic workstations use this technology, and as yet they are not able to manage all drugs used in anaesthetic practice. However, such systems have the potential to help anaesthetists manage the complexity of their work, and to provide information on predicted drug effects in a way that is useful and relevant to both experienced anaesthetists and trainees. © 2017 The Association of Anaesthetists of Great Britain and Ireland.

Trace elements in natural drugs determined by INAA

International Nuclear Information System (INIS)

Chen Kehshaw; Tseng Chialiang; Lin Tehsien

1993-01-01

Natural drugs are widely used for diuretic, phlegm elimination and stomach invigoration purposes. Seventy-five of the most common remedies used by Chinese people have been subjected to trace element survey analysis by instrumental neutron activation. Within this large number of different natural products, fourteen trace elements (K, Sc, Cr, Fe, Co, Zn, Br, Rb, Cs, La, Sm, Eu, Au and Th) are commonly detected. Among these elements, Fe had the highest concentration followed by Zn, and Rb, Sm, Eu and Au were found to have the lowest concentrations. Although the three groups of natural drugs exhibit a widely different therapeutic action, the concentration ranges of the fourteen elements were very similar. While this suggests no apparent specific role for the trace elements in the drug function, parallels are drawn between the known drug related functions of Rb, Zn, Br, Fe, Co and K and the levels of elements found in the natural drugs. It is concluded that the various natural drugs also provide human benefits through supplements of essential elements such as Fe, Zn, Cr, Sc, Rb and Co. (author) 13 refs.; 5 tabs

Occurrence of illicit drugs and selected pharmaceuticals in Slovak municipal wastewater.

Science.gov (United States)

Bodík, Igor; Mackuľak, Tomáš; Fáberová, Milota; Ivanová, Lucia

2016-10-01

We analyzed illicit drugs and their metabolites and pharmaceuticals in wastewater from 15 selected wastewater treatment plants (WWTPs) in Slovakia. Our results indicate that methamphetamine is one of the most commonly used illegal drugs in all the regions of Slovakia monitored in this study. Compared with the international results, the Slovak cities of Dunajská Streda (479 mg/day/1000inh) and Trnava (354 mg/day/1000inh) are among the cities with the largest numbers of methamphetamine users in Europe. These results indicate an increase in the incidence of drugs in big cities and in the satellite cities (Trnava and Dunajská Streda) near Bratislava. These results also confirm the police statistics about production and use of illicit drugs in Slovakia. The highest specific loads of cocaine were found in Bratislava (112 mg/day/1000inh), followed by Petržalka (74 mg/day/1000inh). Compared with other European cities, Bratislava and the other Slovak cities in this study have a relatively low number of COC consumers. The ecstasy load in wastewater from larger cities also significantly increased over the weekend and during music festivals. The highest 2-year mean concentrations of THC-COOH, a cannabis biomarker, were observed in the sewage from BA-Petržalka and BA-Central (191 and 171 ng/L, respectively). A first complex monitoring of pharmaceuticals in all therapeutic groups was also realized in selected Slovak WWTPs. Occurrence of wide spectrum of pharmaceuticals with very high concentrations as well as consumptions were observed mainly in small Slovak cities. Considering all 120 monitored pharmaceuticals, Valsartan had the highest concentrations: 6000 ng/L, on average.

High affinity capture and concentration of quinacrine in polymorphonuclear neutrophils via vacuolar ATPase-mediated ion trapping: Comparison with other peripheral blood leukocytes and implications for the distribution of cationic drugs

Energy Technology Data Exchange (ETDEWEB)

Roy, Caroline; Gagné, Valérie; Fernandes, Maria J.G.; Marceau, François, E-mail: francois.marceau@crchul.ulaval.ca

2013-07-15

Many cationic drugs are concentrated in acidic cell compartments due to low retro-diffusion of the protonated molecule (ion trapping), with an ensuing vacuolar and autophagic cytopathology. In solid tissues, there is evidence that phagocytic cells, e.g., histiocytes, preferentially concentrate cationic drugs. We hypothesized that peripheral blood leukocytes could differentially take up a fluorescent model cation, quinacrine, depending on their phagocytic competence. Quinacrine transport parameters were determined in purified or total leukocyte suspensions at 37 °C. Purified polymorphonuclear leukocytes (PMNLs, essentially neutrophils) exhibited a quinacrine uptake velocity inferior to that of lymphocytes, but a consistently higher affinity (apparent K{sub M} 1.1 vs. 6.3 μM, respectively). However, the vacuolar (V)-ATPase inhibitor bafilomycin A1 prevented quinacrine transport or initiated its release in either cell type. PMNLs capture most of the quinacrine added at low concentrations to fresh peripheral blood leukocytes compared with lymphocytes and monocytes (cytofluorometry). Accumulation of the autophagy marker LC3-II occurred rapidly and at low drug concentrations in quinacrine-treated PMNLs (significant at ≥ 2.5 μM, ≥ 2 h). Lymphocytes contained more LAMP1 than PMNLs, suggesting that the mass of lysosomes and late endosomes is a determinant of quinacrine uptake V{sub max}. PMNLs, however, exhibited the highest capacity for pinocytosis (uptake of fluorescent dextran into endosomes). The selectivity of quinacrine distribution in peripheral blood leukocytes may be determined by the collaboration of a non-concentrating plasma membrane transport mechanism, tentatively identified as pinocytosis in PMNLs, with V-ATPase-mediated concentration. Intracellular reservoirs of cationic drugs are a potential source of toxicity (e.g., loss of lysosomal function in phagocytes). - Highlights: • Quinacrine is concentrated in acidic organelles via V-ATPase-mediated ion

High affinity capture and concentration of quinacrine in polymorphonuclear neutrophils via vacuolar ATPase-mediated ion trapping: Comparison with other peripheral blood leukocytes and implications for the distribution of cationic drugs

International Nuclear Information System (INIS)

Roy, Caroline; Gagné, Valérie; Fernandes, Maria J.G.; Marceau, François

2013-01-01

Many cationic drugs are concentrated in acidic cell compartments due to low retro-diffusion of the protonated molecule (ion trapping), with an ensuing vacuolar and autophagic cytopathology. In solid tissues, there is evidence that phagocytic cells, e.g., histiocytes, preferentially concentrate cationic drugs. We hypothesized that peripheral blood leukocytes could differentially take up a fluorescent model cation, quinacrine, depending on their phagocytic competence. Quinacrine transport parameters were determined in purified or total leukocyte suspensions at 37 °C. Purified polymorphonuclear leukocytes (PMNLs, essentially neutrophils) exhibited a quinacrine uptake velocity inferior to that of lymphocytes, but a consistently higher affinity (apparent K M 1.1 vs. 6.3 μM, respectively). However, the vacuolar (V)-ATPase inhibitor bafilomycin A1 prevented quinacrine transport or initiated its release in either cell type. PMNLs capture most of the quinacrine added at low concentrations to fresh peripheral blood leukocytes compared with lymphocytes and monocytes (cytofluorometry). Accumulation of the autophagy marker LC3-II occurred rapidly and at low drug concentrations in quinacrine-treated PMNLs (significant at ≥ 2.5 μM, ≥ 2 h). Lymphocytes contained more LAMP1 than PMNLs, suggesting that the mass of lysosomes and late endosomes is a determinant of quinacrine uptake V max . PMNLs, however, exhibited the highest capacity for pinocytosis (uptake of fluorescent dextran into endosomes). The selectivity of quinacrine distribution in peripheral blood leukocytes may be determined by the collaboration of a non-concentrating plasma membrane transport mechanism, tentatively identified as pinocytosis in PMNLs, with V-ATPase-mediated concentration. Intracellular reservoirs of cationic drugs are a potential source of toxicity (e.g., loss of lysosomal function in phagocytes). - Highlights: • Quinacrine is concentrated in acidic organelles via V-ATPase-mediated ion trapping

The frequency of drugs among Danish drivers before and after the introduction of fixed concentration limits

DEFF Research Database (Denmark)

Steentoft, Anni; Simonsen, Kirsten Wiese; Linnet, Kristian

2010-01-01

Until July 2007, the driving under the influence of drugs (DUID) legislation in Denmark was based on impairment, evaluated on the basis of a clinical investigation and toxicological analyses, but in 2007 fixed concentration limits were introduced into the Danish traffic legislation. The objective...... for this study was to investigate the prevalence of medication and illicit drugs among Danish drivers before and after 2007.......Until July 2007, the driving under the influence of drugs (DUID) legislation in Denmark was based on impairment, evaluated on the basis of a clinical investigation and toxicological analyses, but in 2007 fixed concentration limits were introduced into the Danish traffic legislation. The objective...

A case-control study estimating accident risk for alcohol, medicines and illegal drugs.

Directory of Open Access Journals (Sweden)

Kim Paula Colette Kuypers

Full Text Available The aim of the present study was to assess the risk of having a traffic accident after using alcohol, single drugs, or a combination, and to determine the concentrations at which this risk is significantly increased.A population-based case-control study was carried out, collecting whole blood samples of both cases and controls, in which a number of drugs were detected. The risk of having an accident when under the influence of drugs was estimated using logistic regression adjusting for gender, age and time period of accident (cases/sampling (controls. The main outcome measures were odds ratio (OR for accident risk associated with single and multiple drug use. In total, 337 cases (negative: 176; positive: 161 and 2726 controls (negative: 2425; positive: 301 were included in the study.Main findings were that 1 alcohol in general (all the concentrations together caused an elevated crash risk; 2 cannabis in general also caused an increase in accident risk; at a cut-off of 2 ng/mL THC the risk of having an accident was four times the risk associated with the lowest THC concentrations; 3 when ranking the adjusted OR from lowest to highest risk, alcohol alone or in combination with other drugs was related to a very elevated crash risk, with the highest risk for stimulants combined with sedatives.The study demonstrated a concentration-dependent crash risk for THC positive drivers. Alcohol and alcohol-drug combinations are by far the most prevalent substances in drivers and subsequently pose the largest risk in traffic, both in terms of risk and scope.

The Impact of Serum Drug Concentration on the Efficacy of Imipramine, Pregabalin and their Combination in Painful Polyneuropathy

DEFF Research Database (Denmark)

Sindrup, Søren Hein; Holbech, Jakob Vormstrup; Bach, Flemming W

2017-01-01

OBJECTIVE: The serum concentration-effect relation was explored for first line drugs in neuropathic pain and aimed to determine if efficacy could be increased. METHODS: Data from a randomized, placebo-controlled, cross-over trial on imipramine, pregabalin and their combination in painful...... polyneuropathy were used. Treatment periods were of 4 weeks' duration, outcome was the weekly median of daily pain rated by a 0-10 numeric scale, and drug concentrations were determined by high-performance liquid chromatography. RESULTS: In 47 patients pain was reduced -1.0 (95% CI -1.5:-0.6) by imipramine, -0.......178). There was no correlation between drug concentration and pain reduction for imipramine (r= 0.17, P=0.247), whereas there was a marginally, positive correlation for pregabalin (r=0.28, P=0.057). There was no interaction between treatment and concentration classes (imipramine

Stereocomplex-Reinforced PEGylated Polylactide Micelle for Optimized Drug Delivery

Directory of Open Access Journals (Sweden)

Chunsheng Feng

2016-04-01

Full Text Available The instability of PEGylated polylactide micelles is a challenge for drug delivery. Stereocomplex interaction between racemic polylactide chains with different configurations provides an effective strategy to enhance the stability of micelles as the nanocarriers of drugs. In this work, a stereocomplex micelle (SCM self-assembled from the amphiphilic triblock copolymers comprising poly(ethylene glycol (PEG, and dextrorotatory and levorotatory polylactides (PDLA and PLLA was applied for efficient drug delivery. The spherical SCM showed the smallest scale and the lowest critical micelle concentration (CMC than the micelles with single components attributed to the stereocomplex interaction between PDLA and PLLA. 10-Hydroxycamptothecin (HCPT as a model antitumor drug was loaded into micelles. Compared with the loading micelles from individual PDLA and PLLA, the HCPT-loaded SCM exhibited the highest drug loading efficiency (DLE and the slowest drug release in phosphate-buffered saline (PBS at pH 7.4, indicating its enhanced stability in circulation. More fascinatingly, the laden SCM was demonstrated to have the highest cellular uptake of HCPT and suppress malignant cells most effectively in comparison to the HCPT-loaded micelles from single copolymer. In summary, the stereocomplex-enhanced PLA–PEG–PLA micelle may be promising for optimized drug delivery in the clinic.

Flexing the PECs: Predicting environmental concentrations of veterinary drugs in Canadian agricultural soils.

Science.gov (United States)

Kullik, Sigrun A; Belknap, Andrew M

2017-03-01

Veterinary drugs administered to food animals primarily enter ecosystems through the application of livestock waste to agricultural land. Although veterinary drugs are essential for protecting animal health, their entry into the environment may pose a risk for nontarget organisms. A means to predict environmental concentrations of new veterinary drug ingredients in soil is required to assess their environmental fate, distribution, and potential effects. The Canadian predicted environmental concentrations in soil (PECsoil) for new veterinary drug ingredients for use in intensively reared animals is based on the approach currently used by the European Medicines Agency for VICH Phase I environmental assessments. The calculation for the European Medicines Agency PECsoil can be adapted to account for regional animal husbandry and land use practices. Canadian agricultural practices for intensively reared cattle, pigs, and poultry differ substantially from those in the European Union. The development of PECsoil default values and livestock categories representative of typical Canadian animal production methods and nutrient management practices culminates several years of research and an extensive survey and analysis of the scientific literature, Canadian agricultural statistics, national and provincial management recommendations, veterinary product databases, and producers. A PECsoil can be used to rapidly identify new veterinary drugs intended for intensive livestock production that should undergo targeted ecotoxicity and fate testing. The Canadian PECsoil model is readily available, transparent, and requires minimal inputs to generate a screening level environmental assessment for veterinary drugs that can be refined if additional data are available. PECsoil values for a hypothetical veterinary drug dosage regimen are presented and discussed in an international context. Integr Environ Assess Manag 2017;13:331-341. © 2016 Her Majesty the Queen in Right of Canada

Biochemistry of drugs. XXVII

International Nuclear Information System (INIS)

Raz, K.; Smolik, S.; Vinarova, M.; Janda, J.; Franc, Z.

1979-01-01

The erythro- and threoform of p-hydroxynorephedrine belong to the group of drugs affecting the course of hypertensive disease. For pharmacological studies both forms were labelled with 3 H radionuclide on the benzene ring. 90% of radioactivity was concentrated in the ortho positions with regard to the hydroxyl, 10% in the meta position. After the administration of the labelled drug to rats, rapid absorption occurs and radioactivity is eliminated from the organism, especially in the urine. Three radioactive substances were found in the urine of experimental animals. A substance with properties corresponding to those of the administered drug prevailed. The highest levels of radioactivity in the tissues were found after intravenous administration as early as after 5 minutes after administration, 15 minutes after subcutaneous administration. It was found that p-hydroxynorephedrine significantly restricted the detainment of labelled noradrenaline-7- 3 H in the tissues of premedicated animals. (author)

Citalopram and escitalopram plasma drug and metabolite concentrations: genome-wide associations.

Science.gov (United States)

Ji, Yuan; Schaid, Daniel J; Desta, Zeruesenay; Kubo, Michiaki; Batzler, Anthony J; Snyder, Karen; Mushiroda, Taisei; Kamatani, Naoyuki; Ogburn, Evan; Hall-Flavin, Daniel; Flockhart, David; Nakamura, Yusuke; Mrazek, David A; Weinshilboum, Richard M

2014-08-01

Citalopram (CT) and escitalopram (S-CT) are among the most widely prescribed selective serotonin reuptake inhibitors used to treat major depressive disorder (MDD). We applied a genome-wide association study to identify genetic factors that contribute to variation in plasma concentrations of CT or S-CT and their metabolites in MDD patients treated with CT or S-CT. Our genome-wide association study was performed using samples from 435 MDD patients. Linear mixed models were used to account for within-subject correlations of longitudinal measures of plasma drug/metabolite concentrations (4 and 8 weeks after the initiation of drug therapy), and single-nucleotide polymorphisms (SNPs) were modelled as additive allelic effects. Genome-wide significant associations were observed for S-CT concentration with SNPs in or near the CYP2C19 gene on chromosome 10 (rs1074145, P = 4.1 × 10(-9) ) and with S-didesmethylcitalopram concentration for SNPs near the CYP2D6 locus on chromosome 22 (rs1065852, P = 2.0 × 10(-16) ), supporting the important role of these cytochrome P450 (CYP) enzymes in biotransformation of citalopram. After adjustment for the effect of CYP2C19 functional alleles, the analyses also identified novel loci that will require future replication and functional validation. In vitro and in vivo studies have suggested that the biotransformation of CT to monodesmethylcitalopram and didesmethylcitalopram is mediated by CYP isozymes. The results of our genome-wide association study performed in MDD patients treated with CT or S-CT have confirmed those observations but also identified novel genomic loci that might play a role in variation in plasma levels of CT or its metabolites during the treatment of MDD patients with these selective serotonin reuptake inhibitors. © 2014 The British Pharmacological Society.

Impaired psychomotor function and plasma methadone and levo-alpha-acetylmethadol (LAAM) concentrations in opioid-substitution patients.

Science.gov (United States)

Newcombe, David A L; Somogyi, Andrew A; Bochner, Felix; White, Jason M

2017-06-01

Tolerance to the psychomotor impairing effects of opioid drugs is expected to develop with repeated dosing, but may be incomplete. The relationship between plasma opioid concentration and psychomotor function in opioid-dependent patients was examined to determine whether impairment was more likely at the time of highest plasma drug concentration. Sixteen patients participating in a cross-over trial comparing methadone and LAAM completed a tracking task (OSPAT) 11 times over the dosing-interval for methadone (24-hrs) and LAAM (48-hrs). Venous blood was collected for the quantification of plasma (R)-(-)-methadone, LAAM, and nor-LAAM concentrations. The Digit Symbol Substitution Test (DSST) and Trail-Making Test were administered at the time of peak plasma concentration. Ten healthy controls (HCs) also participated. OSPAT scores (obtained for 15 patients) fluctuated significantly across the dosing-interval for both drugs and were lower in patients than HCs at the times of peak concentrations of (R)-(-)-methadone (1 hr: (mean difference; 95% CI) (2.13; 0.18-4.08); 2 hrs: (2.38; 0.48-4.28) postdosing) and LAAM (2 hrs: (1.81; 0.09-3.53), and 4 hrs (1.90: 0.9-3.71) postdosing). Within-participant analysis of the peak-change from baseline for OSPAT scores found that 10 of the 15 patients could be categorized as impaired on methadone and 9 on LAAM. No HCs were impaired. Patients performed worse on the DSST and Trails-A than HCs, but not on Trails-B. Results suggest that some patients receiving opioids long term may exhibit impairment at the time of highest plasma drug concentration. These patients should be made aware that their ability to undertake complex tasks may be affected. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

Illicit drugs in Canadian municipal wastewater and estimates of community drug use

Energy Technology Data Exchange (ETDEWEB)

Metcalfe, Chris, E-mail: cmetcalfe@trentu.c [Worsfold Water Quality Centre, Trent University, 1600 West Bank Drive Peterborough, ON, K9J 7B8 (Canada); Tindale, Kathryn [Worsfold Water Quality Centre, Trent University, 1600 West Bank Drive Peterborough, ON, K9J 7B8 (Canada); Li, Hongxia, E-mail: lihongxia@trentu.c [Worsfold Water Quality Centre, Trent University, 1600 West Bank Drive Peterborough, ON, K9J 7B8 (Canada); Rodayan, Angela [Department of Chemical Engineering, McGill University, 3610 University St., Montreal, QC, H3A 2B2 (Canada); Yargeau, Viviane, E-mail: viviane.yargeau@mcgill.c [Department of Chemical Engineering, McGill University, 3610 University St., Montreal, QC, H3A 2B2 (Canada)

2010-10-15

In this study of wastewater treatment plants in three Canadian cities, selected illicit drugs, including cocaine and its major metabolite, benzoylecgonine (BE), amphetamine, methamphetamine and ecstasy (i.e. MDMA) were detected in untreated wastewater. Cocaine was the most widely used illicit drug at a median level for the 3 cities of 15.7 doses per day per 1000 people. For the other drugs, the median doses per day per 1000 people were 1.8 for amphetamine, 4.5 for methamphetamine and 0.4 for ecstasy. Methamphetamine use was highest in the largest city and cocaine use was lowest in the smallest city. Removal of the illicit drugs by wastewater treatment was generally >50%, except in a WWTP that uses primary treatment. The community consumption estimate for ecstasy in the present study is far below published estimates of the prevalence of ecstasy use among the Canadian population, which may be due to only occasional use of ecstasy. - Cocaine and amphetamines were detected in untreated and treated sewage in the wastewater treatment plants of three Canadian cities, and community consumption patterns estimated from the concentrations of the drugs in untreated wastewater were consistent with estimates of the use of illicit drugs in Canada.

Illicit drugs in Canadian municipal wastewater and estimates of community drug use

International Nuclear Information System (INIS)

Metcalfe, Chris; Tindale, Kathryn; Li, Hongxia; Rodayan, Angela; Yargeau, Viviane

2010-01-01

In this study of wastewater treatment plants in three Canadian cities, selected illicit drugs, including cocaine and its major metabolite, benzoylecgonine (BE), amphetamine, methamphetamine and ecstasy (i.e. MDMA) were detected in untreated wastewater. Cocaine was the most widely used illicit drug at a median level for the 3 cities of 15.7 doses per day per 1000 people. For the other drugs, the median doses per day per 1000 people were 1.8 for amphetamine, 4.5 for methamphetamine and 0.4 for ecstasy. Methamphetamine use was highest in the largest city and cocaine use was lowest in the smallest city. Removal of the illicit drugs by wastewater treatment was generally >50%, except in a WWTP that uses primary treatment. The community consumption estimate for ecstasy in the present study is far below published estimates of the prevalence of ecstasy use among the Canadian population, which may be due to only occasional use of ecstasy. - Cocaine and amphetamines were detected in untreated and treated sewage in the wastewater treatment plants of three Canadian cities, and community consumption patterns estimated from the concentrations of the drugs in untreated wastewater were consistent with estimates of the use of illicit drugs in Canada.

Suboptimal Antituberculosis Drug Concentrations and Outcomes in Small and HIV-Coinfected Children in India: Recommendations for Dose Modifications.

Science.gov (United States)

Guiastrennec, Benjamin; Ramachandran, Geetha; Karlsson, Mats O; Kumar, A K Hemanth; Bhavani, Perumal Kannabiran; Gangadevi, N Poorana; Swaminathan, Soumya; Gupta, Amita; Dooley, Kelly E; Savic, Radojka M

2017-12-16

This work aimed to evaluate the once-daily antituberculosis treatment as recommended by the new Indian pediatric guidelines. Isoniazid, rifampin, and pyrazinamide concentration-time profiles and treatment outcome were obtained from 161 Indian children with drug-sensitive tuberculosis undergoing thrice-weekly dosing as per previous Indian pediatric guidelines. The exposure-response relationships were established using a population pharmacokinetic-pharmacodynamic approach. Rifampin exposure was identified as the unique predictor of treatment outcome. Consequently, children with low body weight (4-7 kg) and/or HIV infection, who displayed the lowest rifampin exposure, were associated with the highest probability of unfavorable treatment (therapy failure, death) outcome (P unfavorable ). Model-based simulation of optimized (P unfavorable ≤ 5%) rifampin once-daily doses were suggested per treatment weight band and HIV coinfection status (33% and 190% dose increase, respectively, from the new Indian guidelines). The established dose-exposure-response relationship could be pivotal in the development of future pediatric tuberculosis treatment guidelines. © 2017, The Authors Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

Comparison of Drug Concentrations in Human Aqueous Humor after the Administration of 0.3% Gatifloxacin Ophthalmic Gel, 0.3% Gatifloxacin and 0.5% Levofloxacin Ophthalmic Solutions.

Science.gov (United States)

Ding, Wenting; Ni, Weiling; Chen, Huilian; Yuan, Jingqun; Huang, Xiaodan; Zhang, Zheng; Wang, Yao; Yu, Yibo; Yao, Ke

2015-01-01

To investigate the penetration of 0.3% gatifloxacin ophthalmic gel, 0.3% gatifloxacin ophthalmic solution and 0.5% levofloxacin ophthalmic solution into aqueous humor after topical application. Age-related cataract patients (150 eyes in 150 cases) receiving phacoemulsification were randomly divided into three groups: a 0.3% gatifloxacin gel group (n=50), a 0.3% gatifloxacin solution group (n=50), and a 0.5% levofloxacin solution group (n=50). Each group was administered one drop of gel or solution every 15 minutes for four doses. Aqueous samples were collected at different time points after the last drop. High pressure liquid chromatography (HPLC) was applied to determine the concentrations. The one-way ANOVA analysis was performed. Our data indicated that the concentration of the gatifloxacin gel group was higher than that of the gatifloxacin solution group at all time points (P solution group at 120.0 min and 180.0 min (Psolutions reached their peak values at 60.0 min. 0.3% gatifloxacin ophthalmic gel application produced highest aqueous humor drug concentration, maintained the longest time, had the best penetration and bioavailability.

Study on interaction of gastrointestinal agents in the presence of cytoprotective drugs. Part III. In vitro study on the adsorption of selected prokinetic drugs on sucralfate.

Science.gov (United States)

Grimling, Bozena; Pluta, Janusz

2005-01-01

Adsorbance of certain prokinetic drugs, regulating the motility of the digestive tract, on a cytoprotective drug--sucralfate was investigated. The evaluation of adsorbance capability was carried out by means of a statistical method in in vitro conditions, taking into account environmental pH, concentration of the investigated drugs as well as the form of sucralfate. Obtained results prove that the analyzed active agents are adsorbed on sucralfate at all the investigated pH ranges and the capability of sucralfate binding depends on its form and environmental pH. The highest binding capability was revealed by samples with pH = 3.6 in the presence of sucralfate in the form of suspension, while the lowest binding capability was observed at pH = 1.5 in the presence of sucralfate in the form of paste. The adsorbance capacity of sucralfate (k) at pH = 3.6 is the highest for cisaprid (k = 8.5) and it is significantly lower for metoclopramide (k = 1.5)

Considerations for effect site pharmacokinetics to estimate drug exposure: concentrations of antibiotics in the lung.

Science.gov (United States)

Rodvold, Keith A; Hope, William W; Boyd, Sara E

2017-10-01

Bronchoalveolar lavage (BAL) and microdialysis have become the most reliable and relevant methods for measuring lung concentrations of antibiotics, with the majority of BAL studies involving either healthy adult subjects or patients undergoing diagnostic bronchoscopy. Emphasis on the amount of drug that reaches the site of infection is increasingly recognized as necessary to determine whether a dose selection will translate to good clinical outcomes in the treatment of patients with pneumonia. Observed concentrations and/or parameters of exposure (e.g. area-under-the-curve) need to be incorporated with pharmacokinetic-pharmacodynamic indices so that rational dose selection can be identified for specific pathogens and types of pneumonic infection (community-acquired vs hospital-acquired bacterial pneumonia, including ventilator-associated bacterial pneumonia). Although having measured plasma or lung concentration-time data from critically ill patients to incorporate into pharmacokinetic-pharmacodynamic models is very unlikely during drug development, it is essential that altered distribution, augmented renal clearance, and renal or hepatic dysfunction should be considered. Notably, the number of published studies involving microdialysis and intrapulmonary penetration of antibiotics has been limited and mainly involve beta-lactam agents, levofloxacin, and fosfomycin. Opportunities to measure in high-resolution effect site spatial pharmacokinetics (e.g. with MALDI-MSI or PET imaging) and in vivo continuous drug concentrations (e.g. with aptamer-based probes) now exist. Going forward these studies could be incorporated into antibiotic development programs for pneumonia in order to further increase the probability of candidate success. Copyright © 2017 Elsevier Ltd. All rights reserved.

Lowest cost due to highest productivity and highest quality

Science.gov (United States)

Wenk, Daniel

2003-03-01

Since global purchasing in the automotive industry has been taken up all around the world there is one main key factor that makes a TB-supplier today successful: Producing highest quality at lowest cost. The fact that Tailored Blanks, which today may reach up to 1/3 of a car body weight, are purchased on the free market but from different steel suppliers, especially in Europe and NAFTA, the philosophy on OEM side has been changing gradually towards tough evaluation criteria. "No risk at the stamping side" calls for top quality Tailored- or Tubular Blank products. Outsourcing Tailored Blanks has been starting in Japan but up to now without any quality request from the OEM side like ISO 13919-1B (welding quality standard in Europe and USA). Increased competition will automatically push the quality level and the ongoing approach to combine high strength steel with Tailored- and Tubular Blanks will ask for even more reliable system concepts which enables to weld narrow seams at highest speed. Beside producing quality, which is the key to reduce one of the most important cost driver "material scrap," in-line quality systems with true and reliable evaluation is going to be a "must" on all weld systems. Traceability of all process related data submitted to interfaces according to customer request in combination with ghost-shift-operation of TB systems are tomorrow's state-of-the-art solutions of Tailored Blank-facilities.

Prevalence of alcohol and drugs among car and van drivers killed in road accidents in Norway: an overview from 2001 to 2010.

Science.gov (United States)

Christophersen, Asbjørg S; Gjerde, Hallvard

2014-01-01

To examine the prevalence of alcohol and drugs in blood samples collected from car and van drivers killed in traffic accidents in Norway during the time period from 2001 to 2010. Blood samples (n = 676, 63% of all killed drivers) were analyzed for alcohol, psychoactive medications, and illicit drugs. The cutoff limits for positive results were set according to the new legislative limits under the Norwegian Road Traffic Act. The results were assessed in relation to sex and age, time of day and day of week, and single- versus multiple-vehicle and all investigated vehicle accidents. Alcohol or one or more drugs was detected in samples from 40.2 percent of all investigated drivers, with 28.7 percent showing blood concentrations of at least 5 times the legislative limits. For the investigated female drivers, the total prevalence was 24.0 percent. Among the single-vehicle accidents, alcohol or drugs was found in 63.8 percent of the cases, with 49.1 percent showing blood concentrations of at least 5 times the legislative limits. Alcohol was detected in 25.3 and 49.1 percent of samples from all investigated drivers and among drivers killed in single-vehicle accidents, respectively. Psychoactive medications were found in 14.4 and 17.7 percent and illicit drugs in 14.1 and 19.2 percent, respectively. The most commonly detected group of medications was benzodiazepines, and amphetamines and tetrahydrocannabinol were the most commonly detected illicit drugs. The prevalence of alcohol alone was highest among drivers under the age of 25, and the combination of alcohol with other drugs was highest among drivers under the age of 35. Drivers between the ages of 25 and 54 showed the highest prevalence of medications and/or illicit drugs without the presence of alcohol. The highest prevalence of alcohol or drugs was found among drivers killed in single-vehicle accidents on weeknights (83.8%) and on weekend nights (89.3%). The findings confirm that a large number of fatally injured

Serum concentrations of psychotropic drugs in neonates as a PROgnOstic Factor for admission to the neonatology ward and withdrawal symptoms: PROOF-1.

Science.gov (United States)

Sparla, Shirley C A; Coppens, Hans; Evers, Inge M; Stramrood, Claire A I; Pasker-de Jong, Pieternel C M; van der Westerlaken, Monique M L; Hogeman, Paul H G; Malingré, Mirte M

2017-05-01

The aim is to determine whether serum drug concentrations obtained from the neonate's umbilical cord can be used as a prognostic factor for admission to the neonatology ward and the occurrence of withdrawal symptoms. A retrospective observational monocenter cohort study was carried out among pregnant women using psychotropic drugs and their baby. Binary logistic regression was used for the multivariate analysis. Of the 186 neonates included, 22.6% (n=42) were admitted to the neonatology ward, 6.5% (n=12) because of withdrawal. Among women with therapeutic concentrations of psychotropic medication, 22.0% (n=5) of the neonates had withdrawal symptoms. When comparing neonates with therapeutic versus undetectable drug concentrations, an odds ratio of 3.1 (95% confidence interval: 1.1-8.6) was found for admission to the neonatology ward and an odds ratio of 20.5 (95% confidence interval: 2.2-186.1) for the occurrence of withdrawal symptoms. Therapeutic concentrations of psychotropic drugs in neonates' umbilical cord blood correspond with higher odds for admission to the neonatology ward and the occurrence of withdrawal symptoms compared with neonates with undetectable drug concentrations. The measurement of drug concentrations in the neonate may contribute toward the general clinical assessment of the physician to predict the necessity of admission to the neonatology ward and the risk of withdrawal symptoms.

Optimization of a model of red blood cells for the study of anti-oxidant drugs, in terms of concentration of oxidant and phosphate buffer.

Science.gov (United States)

Bureau, A; Lahet, J-J; Lenfant, F; Bouyer, F; Petitjean, M; Chaillot, B; Freysz, M

2005-08-01

The aggression of erythrocytes by an oxidative stress induces hemolysis. This paper aims to valid a model of erythrocytes in terms of composition of the phosphate buffer solution and of concentration of a well-known oxidant, AAPH. Three compositions of phosphate buffer solution are mixed with three concentrations of oxidant. The influence of these two parameters on hemolysis is independently studied by a variance analysis and a Kruskal-Wallis test when ANOVA is not available. The hemolysis rate increases with time at fixed oxidant concentration, but is not influenced by the composition of the buffer solution. The highest hemolysis rate, 90%, was only measured within 2 h with the highest oxidant concentration. If we retain this concentration of oxidant, the lower concentration of the buffer can by eliminated by a significant less hemolysis and the highest concentration of the buffer can by chosen in regard of the better precision for a similar hemolysis compared to the mean buffer. We hope to study the effect of anti-oxidant agent with such a model of erythrocytes.

An inert 3D emulsification device for individual precipitation and concentration of amorphous drug nanoparticles.

Science.gov (United States)

Lorenz, T; Bojko, S; Bunjes, H; Dietzel, A

2018-02-13

Nanosizing increases the specific surface of drug particles, leading to faster dissolution inside the organism and improving the bioavailability of poorly water-soluble drugs. A novel approach for the preparation of drug nanoparticles in water using chemically inert microfluidic emulsification devices is presented in this paper. A lithographic fabrication sequence was established, allowing fabrication of intersecting and coaxial channels of different depths in glass as is required for 3D flow-focusing. Fenofibrate was used as a model for active pharmaceutical ingredients with very low water solubility in the experiments. It was dissolved in ethyl acetate and emulsified in water, as allowed by the 3D flow-focusing geometry. In the thread formation regime, the drug solution turned into monodisperse droplets of sizes down to below 1 μm. Fast supersaturation occurs individually in each droplet, as the disperse phase solvent progressively diffuses into the surrounding water. Liquid antisolvent precipitation results in highly monodisperse and amorphous nanoparticles of sizes down to 128 nm which can be precisely controlled by the continuous and disperse phase pressure. By comparing optically measured droplet sizes with particle sizes by dynamic light scattering, we could confirm that exactly one particle forms in every droplet. Furthermore, a downstream on-chip concentration allowed withdrawal of major volumes of only the continuous phase fluid which enabled an increase of particle concentration by up to 250 times.

Drug Concentration Thresholds Predictive of Therapy Failure and Death in Children With Tuberculosis: Bread Crumb Trails in Random Forests.

Science.gov (United States)

Swaminathan, Soumya; Pasipanodya, Jotam G; Ramachandran, Geetha; Hemanth Kumar, A K; Srivastava, Shashikant; Deshpande, Devyani; Nuermberger, Eric; Gumbo, Tawanda

2016-11-01

 The role of drug concentrations in clinical outcomes in children with tuberculosis is unclear. Target concentrations for dose optimization are unknown.  Plasma drug concentrations measured in Indian children with tuberculosis were modeled using compartmental pharmacokinetic analyses. The children were followed until end of therapy to ascertain therapy failure or death. An ensemble of artificial intelligence algorithms, including random forests, was used to identify predictors of clinical outcome from among 30 clinical, laboratory, and pharmacokinetic variables.  Among the 143 children with known outcomes, there was high between-child variability of isoniazid, rifampin, and pyrazinamide concentrations: 110 (77%) completed therapy, 24 (17%) failed therapy, and 9 (6%) died. The main predictors of therapy failure or death were a pyrazinamide peak concentration <38.10 mg/L and rifampin peak concentration <3.01 mg/L. The relative risk of these poor outcomes below these peak concentration thresholds was 3.64 (95% confidence interval [CI], 2.28-5.83). Isoniazid had concentration-dependent antagonism with rifampin and pyrazinamide, with an adjusted odds ratio for therapy failure of 3.00 (95% CI, 2.08-4.33) in antagonism concentration range. In regard to death alone as an outcome, the same drug concentrations, plus z scores (indicators of malnutrition), and age <3 years, were highly ranked predictors. In children <3 years old, isoniazid 0- to 24-hour area under the concentration-time curve <11.95 mg/L × hour and/or rifampin peak <3.10 mg/L were the best predictors of therapy failure, with relative risk of 3.43 (95% CI, .99-11.82).  We have identified new antibiotic target concentrations, which are potential biomarkers associated with treatment failure and death in children with tuberculosis. © The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America.

Prevalence and sunlight photolysis of controlled and chemotherapeutic drugs in aqueous environments

International Nuclear Information System (INIS)

Lin, Angela Yu-Chen; Lin, Yen-Ching; Lee, Wan-Ning

2014-01-01

This study addresses the occurrences and natural fates of chemotherapeutics and controlled drugs when found together in hospital effluents and surface waters. The results revealed the presence of 11 out of 16 drugs in hospital effluents, and the maximum detected concentrations were at the μg L −1 level in the hospital effluents and the ng L −1 level in surface waters. The highest concentrations corresponded to meperidine, morphine, 5-fluorouracil and cyclophosphamide. The sunlight photolysis of the target compounds was investigated, and the results indicated that morphine and codeine can be significantly attenuated, with half-lives of 0.27 and 2.5 h, respectively, in natural waters. Photolysis can lower the detected environmental concentrations, also lowering the estimated environmental risks of the target drugs to human health. Nevertheless, 5-fluorouracil and codeine were found to have a high risk quotient (RQ), demonstrating the high risks of directly releasing hospital wastewater into the environment. - Highlights: • High occurrence of chemotherapeutics and controlled substances in aqueous systems. • Photolysis lowers the detected concentrations of morphine and codeine. • 5-fluorouracil and codeine in hospital effluents have high risk quotients. - Chemotherapeutics and controlled drugs occur at significant levels in hospital effluents and surface waters. Natural sunlight photolysis reduces their environmental occurrence

Efavirenz Has the Highest Anti-Proliferative Effect of Non-Nucleoside Reverse Transcriptase Inhibitors against Pancreatic Cancer Cells.

Directory of Open Access Journals (Sweden)

Markus Hecht

Full Text Available Cancer prevention and therapy in HIV-1-infected patients will play an important role in future. The non-nucleoside reverse transcriptase inhibitors (NNRTI Efavirenz and Nevirapine are cytotoxic against cancer cells in vitro. As other NNRTIs have not been studied so far, all clinically used NNRTIs were tested and the in vitro toxic concentrations were compared to drug levels in patients to predict possible anti-cancer effects in vivo.Cytotoxicity was studied by Annexin-V-APC/7AAD staining and flow cytometry in the pancreatic cancer cell lines BxPC-3 and Panc-1 and confirmed by colony formation assays. The 50% effective cytotoxic concentrations (EC50 were calculated and compared to the blood levels in our patients and published data.The in vitro EC50 of the different drugs in the BxPC-3 pancreatic cancer cells were: Efavirenz 31.5 μmol/l (= 9944 ng/ml, Nevirapine 239 μmol/l (= 63,786 ng/ml, Etravirine 89.0 μmol/l (= 38,740 ng/ml, Lersivirine 543 μmol/l (= 168,523 ng/ml, Delavirdine 171 μmol/l (= 78,072 ng/ml, Rilpivirine 24.4 μmol/l (= 8941 ng/ml. As Efavirenz and Rilpivirine had the highest cytotoxic potential and Nevirapine is frequently used in HIV-1 positive patients, the results of these three drugs were further studied in Panc-1 pancreatic cancer cells and confirmed with colony formation assays. 205 patient blood levels of Efavirenz, 127 of Rilpivirine and 31 of Nevirapine were analyzed. The mean blood level of Efavirenz was 3587 ng/ml (range 162-15,363 ng/ml, of Rilpivirine 144 ng/ml (range 0-572 ng/ml and of Nevirapine 4955 ng/ml (range 1856-8697 ng/ml. Blood levels from our patients and from published data had comparable Efavirenz levels to the in vitro toxic EC50 in about 1 to 5% of all patients.All studied NNRTIs were toxic against cancer cells. A low percentage of patients taking Efavirenz reached in vitro cytotoxic blood levels. It can be speculated that in HIV-1 positive patients having high Efavirenz blood levels pancreatic

A Generic Multi-Compartmental CNS Distribution Model Structure for 9 Drugs Allows Prediction of Human Brain Target Site Concentrations

NARCIS (Netherlands)

Yamamoto, Yumi; Valitalo, Pyry A.; van den Berg, Dirk-Jan; Hartman, Robin; van den Brink, Willem; Wong, Yin Cheong; Huntjens, Dymphy R.; Proost, Johannes H.; Vermeulen, An; Krauwinkel, Walter; Bakshi, Suruchi; Aranzana-Climent, Vincent; Marchand, Sandrine; Dahyot-Fizelier, Claire; Couet, William; Danhof, Meindert; van Hasselt, Johan G. C.; de lange, Elizabeth C. M.

Purpose Predicting target site drug concentration in the brain is of key importance for the successful development of drugs acting on the central nervous system. We propose a generic mathematical model to describe the pharmacokinetics in brain compartments, and apply this model to predict human

Drug affordability-potential tool for comparing illicit drug markets.

Science.gov (United States)

Groshkova, Teodora; Cunningham, Andrew; Royuela, Luis; Singleton, Nicola; Saggers, Tony; Sedefov, Roumen

2018-06-01

The importance of illicit drug price data and making appropriate adjustments for purity has been repeatedly highlighted for understanding illicit drug markets. The European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) has been collecting retail price data for a number of drug types alongside drug-specific purity information for over 15 years. While these data are useful for a number of monitoring and analytical purposes, they are not without their limitations and there are circumstances where additional adjustment needs to be considered. This paper reviews some conceptual issues and measurement challenges relevant to the interpretation of price data. It also highlights the issues with between-country comparisons of drug prices and introduces the concept of affordability of drugs, going beyond purity-adjustment to account for varying national economies. Based on a 2015 European data set of price and purity data across the heroin and cocaine retail markets, the paper demonstrates a new model for drug market comparative analysis; calculation of drug affordability is achieved by applying to purity-adjusted prices 2015 Price Level Indices (PLI, Eurostat). Available data allowed retail heroin and cocaine market comparison for 27 European countries. The lowest and highest unadjusted prices per gram were observed for heroin: in Estonia, Belgium, Greece and Bulgaria (lowest) and Finland, Ireland, Sweden and Latvia (highest); for cocaine: the Netherlands, Belgium and the United Kingdom (lowest) and Turkey, Finland, Estonia and Romania (highest). The affordability per gram of heroin and cocaine when taking into account adjustment for both purity and economy demonstrates different patterns. It is argued that purity-adjusted price alone provides an incomplete comparison of retail price across countries. The proposed new method takes account of the differing economic conditions within European countries, thus providing a more sophisticated tool for cross

Effects of drugs in subtoxic concentrations on the metabolic fluxes in human hepatoma cell line Hep G2

International Nuclear Information System (INIS)

Niklas, Jens; Noor, Fozia; Heinzle, Elmar

2009-01-01

Commonly used cytotoxicity assays assess the toxicity of a compound by measuring certain parameters which directly or indirectly correlate to the viability of the cells. However, the effects of a given compound at concentrations considerably below EC 50 values are usually not evaluated. These subtoxic effects are difficult to identify but may eventually cause severe and costly long term problems such as idiosyncratic hepatotoxicity. We determined the toxicity of three hepatotoxic compounds, namely amiodarone, diclofenac and tacrine on the human hepatoma cell line Hep G2 using an online kinetic respiration assay and analysed the effects of subtoxic concentrations of these drugs on the cellular metabolism by using metabolic flux analysis. Several changes in the metabolism could be detected upon exposure to subtoxic concentrations of the test compounds. Upon exposure to diclofenac and tacrine an increase in the TCA-cycle activity was observed which could be a signature of an uncoupling of the oxidative phosphorylation. The results indicate that metabolic flux analysis could serve as an invaluable novel tool for the investigation of the effects of drugs. The described methodology enables tracking the toxicity of compounds dynamically using the respiration assay in a range of concentrations and the metabolic flux analysis permits interesting insights into the changes in the central metabolism of the cell upon exposure to drugs.

Comparison of Active Drug Concentrations in the Pulmonary Epithelial Lining Fluid and Interstitial Fluid of Calves Injected with Enrofloxacin, Florfenicol, Ceftiofur, or Tulathromycin

Science.gov (United States)

Foster, Derek M.; Martin, Luke G.; Papich, Mark G.

2016-01-01

Bacterial pneumonia is the most common reason for parenteral antimicrobial administration to beef cattle in the United States. Yet there is little information describing the antimicrobial concentrations at the site of action. The objective of this study was to compare the active drug concentrations in the pulmonary epithelial lining fluid and interstitial fluid of four antimicrobials commonly used in cattle. After injection, plasma, interstitial fluid, and pulmonary epithelial lining fluid concentrations and protein binding were measured to determine the plasma pharmacokinetics of each drug. A cross-over design with six calves per drug was used. Following sample collection and drug analysis, pharmacokinetic calculations were performed. For enrofloxacin and metabolite ciprofloxacin, the interstitial fluid concentration was 52% and 78% of the plasma concentration, while pulmonary fluid concentrations was 24% and 40% of the plasma concentration, respectively. The pulmonary concentrations (enrofloxacin + ciprofloxacin combined) exceeded the MIC90 of 0.06 μg/mL at 48 hours after administration. For florfenicol, the interstitial fluid concentration was almost 98% of the plasma concentration, and the pulmonary concentrations were over 200% of the plasma concentrations, exceeding the breakpoint (≤ 2 μg/mL), and the MIC90 for Mannheimia haemolytica (1.0 μg/mL) for the duration of the study. For ceftiofur, penetration to the interstitial fluid was only 5% of the plasma concentration. Pulmonary epithelial lining fluid concentration represented 40% of the plasma concentration. Airway concentrations exceeded the MIC breakpoint for susceptible respiratory pathogens (≤ 2 μg/mL) for a short time at 48 hours after administration. The plasma and interstitial fluid concentrations of tulathromcyin were lower than the concentrations in pulmonary fluid throughout the study. The bronchial concentrations were higher than the plasma or interstitial concentrations, with over 900

Comparison of Active Drug Concentrations in the Pulmonary Epithelial Lining Fluid and Interstitial Fluid of Calves Injected with Enrofloxacin, Florfenicol, Ceftiofur, or Tulathromycin.

Directory of Open Access Journals (Sweden)

Derek M Foster

Full Text Available Bacterial pneumonia is the most common reason for parenteral antimicrobial administration to beef cattle in the United States. Yet there is little information describing the antimicrobial concentrations at the site of action. The objective of this study was to compare the active drug concentrations in the pulmonary epithelial lining fluid and interstitial fluid of four antimicrobials commonly used in cattle. After injection, plasma, interstitial fluid, and pulmonary epithelial lining fluid concentrations and protein binding were measured to determine the plasma pharmacokinetics of each drug. A cross-over design with six calves per drug was used. Following sample collection and drug analysis, pharmacokinetic calculations were performed. For enrofloxacin and metabolite ciprofloxacin, the interstitial fluid concentration was 52% and 78% of the plasma concentration, while pulmonary fluid concentrations was 24% and 40% of the plasma concentration, respectively. The pulmonary concentrations (enrofloxacin + ciprofloxacin combined exceeded the MIC90 of 0.06 μg/mL at 48 hours after administration. For florfenicol, the interstitial fluid concentration was almost 98% of the plasma concentration, and the pulmonary concentrations were over 200% of the plasma concentrations, exceeding the breakpoint (≤ 2 μg/mL, and the MIC90 for Mannheimia haemolytica (1.0 μg/mL for the duration of the study. For ceftiofur, penetration to the interstitial fluid was only 5% of the plasma concentration. Pulmonary epithelial lining fluid concentration represented 40% of the plasma concentration. Airway concentrations exceeded the MIC breakpoint for susceptible respiratory pathogens (≤ 2 μg/mL for a short time at 48 hours after administration. The plasma and interstitial fluid concentrations of tulathromcyin were lower than the concentrations in pulmonary fluid throughout the study. The bronchial concentrations were higher than the plasma or interstitial concentrations

Dominant psychoactive drugs in the Central European region: A wastewater study.

Science.gov (United States)

Mackuľak, Tomáš; Bodík, Igor; Hasan, Jamal; Grabic, Roman; Golovko, Oksana; Vojs-Staňová, Andrea; Gál, Miroslav; Naumowicz, Monika; Tichý, Jozef; Brandeburová, Paula; Híveš, Ján

2016-10-01

The aim of this study was to analyze 26 various illicit drugs, psychopharmaceuticals and metabolites thereof in sewer from 17 selected wastewater treatment plants (WWTPs) in the Slovak and Czech Republics. Urinary bio-markers used were analyzed using liquid chromatography coupled with the tandem mass spectrometry (LC-MS/MS). We then compared our results with data obtained in other parts of Europe and the world. The present study shows that the Slovak and Czech Republics have one of the highest methamphetamine consumption rates in Europe. Within Slovakia, the highest level of methamphetamine consumption was found in Dunajská Streda with the mean specific load of the drug in sewage being up to 479mg/day/1000 inhabitants; the next highest load was detected in Trnava (354mg/day/1000 inhabitants). The methamphetamine, ecstasy and cannabis consumptions in our study were comparable to those found in other European cities, whereas cocaine consumption was lower. Among all of the studied psychopharmaceuticals, tramadol and venlafaxine were represented in the highest concentrations. The highest mean specific load of tramadol was detected in the spa town of Piešťany (371mg/day/1000 inhabitants) and Košice (372mg/day/1000 inhabitants), while the highest mean loads of venlafaxine were recorded for the towns of Trenčín (230mg/day/1000 inhabitants) and Piešťany (108mg/day/1000 inhabitants). Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Solid lipid nanoparticles as anti-inflammatory drug delivery system in a human inflammatory bowel disease whole-blood model.

Science.gov (United States)

Serpe, Loredana; Canaparo, Roberto; Daperno, Marco; Sostegni, Raffaello; Martinasso, Germana; Muntoni, Elisabetta; Ippolito, Laura; Vivenza, Nicoletta; Pera, Angelo; Eandi, Mario; Gasco, Maria Rosa; Zara, Gian Paolo

2010-03-18

Standard treatment for inflammatory bowel diseases (IBD) necessitates frequent intake of anti-inflammatory and/or immunosuppressive drugs, leading to significant adverse events. To evaluate the role solid lipid nanoparticles (SLN) play as drug delivery system in enhancing anti-inflammatory activity for drugs such as dexamethasone and butyrate in a human inflammatory bowel diseases whole-blood model. ELISA assay and the peripheral blood mononuclear cell (PBMC) cytokine mRNA expression levels were evaluated by quantitative SYBR Green real-time RT-PCR to determine the IL-1beta, TNF-alpha, IFN-gamma and IL-10 secretion in inflammatory bowel diseases patients' PBMC culture supernatants. There was a significant decrease in IL-1beta (p<0.01) and TNF-alpha (p<0.001) secretion, whilst IL-10 (p<0.05) secretion significantly increased after cholesteryl butyrate administration, compared to that of butyrate alone at the highest concentration tested (100 microM), at 24h exposure. There was a significant decrease in IL-1beta (p<0.01), TNF-alpha (p<0.001) and IL-10 (p<0.001) secretion after dexamethasone loaded SLN administration, compared to dexamethasone alone at the highest concentration tested (250 nM) at 24h exposure. No IFN-gamma was detected under any conditions and no cytotoxic effects observed even at the highest concentration tested. The incorporation of butyrate and dexamethasone into SLN has a significant positive anti-inflammatory effect in the human inflammatory bowel disease whole-blood model. Copyright 2010 Elsevier B.V. All rights reserved.

Parallel monitoring of plasma and intraluminal drug concentrations in man after oral administration of fosamprenavir in the fasted and fed state.

Science.gov (United States)

Brouwers, Joachim; Tack, Jan; Augustijns, Patrick

2007-10-01

The purpose of this study was to explore the feasibility of linking the pharmacokinetic profile of a drug with its gastrointestinal behavior by simultaneously monitoring plasma and intraluminal drug concentrations. Fosamprenavir, a phosphate ester prodrug of the poorly water-soluble HIV-inhibitor amprenavir, was selected as model compound. A single tablet of fosamprenavir (Telzir) was administered to 5 volunteers in the fasted and fed state (simulated by intake of a nutritional drink). Gastric and duodenal fluids were aspirated in function of time and characterized with respect to the concentration of (fos)amprenavir, inorganic phosphate and pH. In parallel, blood samples were collected and analyzed for amprenavir. The observed plasma concentration-time profiles suggested a food-induced delay in the absorption of amprenavir: in the fed state, mean tmax increased by more than 150 min compared to the fasted state. A similar delay was seen in the duodenal appearance of fosamprenavir (concentrations in mM-range) and, after dephosphorylation, amprenavir (concentrations below 160 microM). This observation could be related to the behavior of fosamprenavir in the stomach. In the fasted state, gastric dissolution of fosamprenavir started immediately, resulting in a Cmax of 4 +/- 2 mM after 43 +/- 15 min; however, in the fed state, the fosamprenavir concentration remained below 20 microM for the first 90 min after drug intake. The postponed gastric dissolution may be attributed to a food-induced delay in tablet disintegration. For the first time, the pharmacokinetic profile of a drug was monitored in parallel with its gastrointestinal concentrations. The observed food effect in the plasma concentration-time profile of amprenavir after intake of its phosphate ester prodrug could be related to a food-induced delay in gastric dissolution of fosamprenavir.

Diclofenac affects kidney histology in the three-spined stickleback (Gasterosteus aculeatus) at low μg/L concentrations.

Science.gov (United States)

Näslund, Johanna; Fick, Jerker; Asker, Noomi; Ekman, Elisabet; Larsson, D G Joakim; Norrgren, Leif

2017-08-01

Diclofenac, a commonly used non-steroidal anti-inflammatory drug, is considered for regulation under the European water framework directive. This is because effects on fish have been reported at concentrations around those regularly found in treated sewage effluents (∼1μg/L). However, a recent publication reports no effects on fish at 320μg/L. In this study, three-spined sticklebacks (Gasterosteus aculeatus) were exposed to 0, 4.6, 22, 82 and 271μg/L diclofenac in flow-through systems for 28days using triplicate aquaria per concentration. At the highest concentration, significant mortalities were observed already after 21days (no mortalities found up to 22μg/L). Histological analysis revealed a significant increase in the proportion of renal hematopoietic tissue (renal hematopoietic hyperplasia) after 28days at the lowest concentration and at all higher concentrations, following a clear dose-response pattern. Skin ulcerations of the jaw were noted by macroscopic observations, primarily at the two highest concentrations. No histological changes were observed in the liver. There was an increase in the relative hepatic mRNA levels of c7 (complement component 7), a gene involved in the innate immune system, at 22μg/L and at all higher concentrations, again following a clear dose-response. The bioconcentration factor was stable across concentrations, but lower than reported for rainbow trout, suggesting lower internal exposure to the drug in the stickleback. In conclusion, this study demonstrates that diclofenac causes histological changes in the three-spined stickleback at low μg/L concentrations, which cause concern for fish populations exposed to treated sewage effluents. Copyright © 2017 Elsevier B.V. All rights reserved.

Impact of concentration and rate of intraluminal drug delivery on absorption and gut wall metabolism of verapamil in humans.

Science.gov (United States)

Glaeser, Hartmut; Drescher, Siegfried; Hofmann, Ute; Heinkele, Georg; Somogyi, Andrew A; Eichelbaum, Michel; Fromm, Martin F

2004-09-01

In humans gut wall metabolism can be quantitatively as important as hepatic drug metabolism in limiting the systemic exposure to drugs after oral administration. However, it has been proposed that the role of gut wall metabolism might be overemphasized, because high luminal drug concentrations would lead to a saturation of gut wall metabolism. Therefore we investigated the impact of concentration and rate of intraluminal drug delivery on absorption (F(abs)) and gastrointestinal extraction (E(GI)) of a luminally administered cytochrome P450 (CYP) 3A4 substrate (verapamil) using a multilumen perfusion catheter in combination with a stable isotope technique. Two 20-cm-long, adjacent jejunal segments were isolated with the multilumen perfusion catheter in 7 subjects. In this study 80 mg of unlabeled verapamil (d0-verapamil 15 min) was infused into one segment over a 15-minute period, 80 mg of 3-fold deuterated verapamil (d3-verapamil 240 min) was administered over a 240-minute period into the other segment, and simultaneously, 5 mg of 7-fold deuterated verapamil (d7-verapamil) was injected intravenously over a 15-minute period. The rate of intraluminal drug delivery had only a modest effect on bioavailability of the verapamil isotopes (after correction for F abs ) (F/F abs d3-verapamil 240 min versus d0-verapamil 15 min, 0.24 +/- 0.10 versus 0.20 +/- 0.09; P d3-verapamil 240 min was 0.50 +/- 0.18 compared with 0.59 +/- 0.14 for d0 -verapamil 15 min ( P d0-verapamil 15 min ) correlated strongly with E GI (d3-verapamil 240 min ) (r = 0.94, P d0-verapamil 15 min /d3-verapamil 240 min (r = 0.62, P =.03). Substantial gut wall metabolism of verapamil occurs in humans and can be predicted from ex vivo data by use of shed enterocytes. The different intraluminal concentrations and rates of intraluminal drug delivery did not lead to a pronounced saturation of intestinal drug metabolism.

Usefulness of saliva for measurement of 3,4-methylenedioxymethamphetamine and its metabolites: correlation with plasma drug concentrations and effect of salivary pH.

Science.gov (United States)

Navarro, M; Pichini, S; Farré, M; Ortuño, J; Roset, P N; Segura, J; de la Torre, R

2001-10-01

Saliva is an alternative biologic matrix for drugs-of-abuse testing that offers the advantages of noninvasive, rapid, and easy sampling. We studied the excretion profile of 3,4-methylenedioxymethamphetamine (MDMA) and its metabolites in both saliva and plasma, as well the effect of the drug on salivary pH. Saliva and plasma samples were obtained from eight healthy MDMA consumers after ingestion of a single 100-mg dose of the drug. Concentrations of MDMA and its main metabolites, 3,4-methylenedioxyamphetamine (MDA) and 4-hydroxy-3-methoxymethamphetamine (HMMA), in saliva and plasma were measured by gas chromatography-mass spectrometry. Apparent pharmacokinetic parameters for MDMA in saliva were estimated, and the saliva-to-plasma ratio at each time interval was calculated and correlated with salivary pH. MDMA, MDA, and HMMA were detected in saliva. Salivary concentrations of MDMA were 1728.9-6510.6 microg/L and peaked at 1.5 h after drug intake. This was followed by a progressive decrease, with a mean concentration of 126.2 microg/L at 24 h. The saliva-to-plasma ratio was 32.3-1.2, with a peak of 18.1 at 1.5 h after drug administration. Salivary pH seemed to be affected by MDMA administration; pH values decreased by 0.6 units (mean pH values of 6.9 and 6.8 at 1.5 and 4 h after drug administration vs predose pH of 7.4). Measurement of MDMA in saliva is a valuable alternative to determination of plasma drug concentrations in both clinical and toxicologic studies. On-site testing is also facilitated by noninvasive and rapid collection of salivary specimens.

Catching the Highest Energy Neutrinos

Energy Technology Data Exchange (ETDEWEB)

Stanev, Todor [Bartol Research Institute and Department of Physics and Astronomy, University of Delaware, Newark, DE 19716 (United States)

2011-08-15

We briefly discuss the possible sources of ultrahigh energy neutrinos and the methods for their detection. Then we present the results obtained by different experiments for detection of the highest energy neutrinos.

Hydrogel-Forming Microneedle Arrays Allow Detection of Drugs and Glucose In Vivo: Potential for Use in Diagnosis and Therapeutic Drug Monitoring.

Directory of Open Access Journals (Sweden)

Ester Caffarel-Salvador

Full Text Available We describe, for the first time the use of hydrogel-forming microneedle (MN arrays for minimally-invasive extraction and quantification of drug substances and glucose from skin in vitro and in vivo. MN prepared from aqueous blends of hydrolysed poly(methyl-vinylether-co-maleic anhydride (11.1% w/w and poly(ethyleneglycol 10,000 daltons (5.6% w/w and crosslinked by esterification swelled upon skin insertion by uptake of fluid. Post-removal, theophylline and caffeine were extracted from MN and determined using HPLC, with glucose quantified using a proprietary kit. In vitro studies using excised neonatal porcine skin bathed on the underside by physiologically-relevant analyte concentrations showed rapid (5 min analyte uptake. For example, mean concentrations of 0.16 μg/mL and 0.85 μg/mL, respectively, were detected for the lowest (5 μg/mL and highest (35 μg/mL Franz cell concentrations of theophylline after 5 min insertion. A mean concentration of 0.10 μg/mL was obtained by extraction of MN inserted for 5 min into skin bathed with 5 μg/mL caffeine, while the mean concentration obtained by extraction of MN inserted into skin bathed with 15 μg/mL caffeine was 0.33 μg/mL. The mean detected glucose concentration after 5 min insertion into skin bathed with 4 mmol/L was 19.46 nmol/L. The highest theophylline concentration detected following extraction from a hydrogel-forming MN inserted for 1 h into the skin of a rat dosed orally with 10 mg/kg was of 0.363 μg/mL, whilst a maximum concentration of 0.063 μg/mL was detected following extraction from a MN inserted for 1 h into the skin of a rat dosed with 5 mg/kg theophylline. In human volunteers, the highest mean concentration of caffeine detected using MN was 91.31 μg/mL over the period from 1 to 2 h post-consumption of 100 mg Proplus® tablets. The highest mean blood glucose level was 7.89 nmol/L detected 1 h following ingestion of 75 g of glucose, while the highest mean glucose concentration

Prevalence of alcohol and other drugs and the concentrations in blood of drivers killed in road traffic crashes in Sweden.

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Ahlner, Johan; Holmgren, Anita; Jones, Alan Wayne

2014-03-01

Drunk or drug-impaired drivers represent a major public health and societal problem worldwide. Because over 95% of drivers killed on the roads in Sweden are autopsied, reliable information is available about the use of alcohol and/or other drug before the crash. This retrospective 4-year study (2008-2011) used a forensic toxicology database (TOXBASE) to evaluate the concentrations of alcohol and other drugs in blood samples from drivers killed in road-traffic crashes. The mean age of all victims (N = 895) was 48 ± 20 years, and the majority were male (86%). In 504 drivers (56%), the results of toxicological analysis were negative and these victims were older; mean age (± SD) 47 ± 20 years, than alcohol positive cases (35 ± 14 years) and illicit drug users (34 ± 15 years). In 21% of fatalities, blood-alcohol concentration (BAC) was above the statutory limit for driving (0.2 g/L), although the median BAC was appreciably higher (1.72 g/L). Illicit drugs (mainly amphetamine and cannabis) were identified in ~7% of victims, either alone (2.5%), together with alcohol (1.8%) or a prescription drug (2%). The psychoactive prescription drugs identified were mainly benzodiazepines, z-hypnotics and tramadol, which were found in the blood of 7.6% of crash victims. The high median BAC in fatally-injured drivers speaks strongly towards alcohol-induced impairment as being responsible for the crash. Compared with alcohol, the prevalence of illicit and psychoactive prescription drugs was fairly low despite a dramatic increase in the number of drug-impaired drivers arrested by the police after a zero-tolerance law was introduced in 1999.

Parenteral formulation of an antileishmanial drug candidate--tackling poor solubility, chemical instability, and polymorphism.

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Kupetz, Eva; Preu, Lutz; Kunick, Conrad; Bunjes, Heike

2013-11-01

The paullon chalcone derivative KuRei300 is active against Leishmania donovani, the protozoans causing visceral leishmaniasis. The aim of this study was the development of a parenteral formulation of the virtually water insoluble compound in order to enable future studies in mice. Mixed lecithin/bile salt micelles, liposomes, supercooled smectic cholesterol myristate nanoparticles, cubic phase nanoparticles and a triglyceride emulsion were screened for their solubilizing properties. Due to the limited available amount of KuRei300 a passive loading approach with pre-formulated carriers that were incubated with drug substance deposited onto the walls of glass vials was used. The loading capacities of the nanocarriers, the influence of the solid state properties of the drug and its deposits on the loading results and chemical stability aspects of KuRei300 were investigated. Employed methods included HPLC, UV spectroscopy, (1)H NMR, XRPD, and DSC. All nanocarriers substantially improved the solubility of KuRei300; the mixed micelles exhibited the highest drug load. Related to the lipid matrix, however, the smectic nanoparticles solubilized the significantly highest amount of drug. Loading from physically altered drug deposits improved the obtainable concentration to the threefold compared with untreated drug powder. Formulations with KuRei300 must be stored excluded from light under a nitrogen atmosphere as the substance is susceptible to photoisomerization and decomposition. Copyright © 2013 Elsevier B.V. All rights reserved.

Adequate plasma drug concentrations suggest that amoxicillin can be administered by continuous infusion using elastomeric pumps.

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Arensdorff, Lyne; Boillat-Blanco, Noémie; Decosterd, Laurent; Buclin, Thierry; de Vallière, Serge

2017-09-01

Elastomeric pumps can be useful for the administration of antibiotics in the outpatient setting. To determine amoxicillin degradation in elastomeric pumps, as well as the effectiveness of amoxicillin treatment administered by elastomeric pumps. Antibiotic degradation was measured in elastomeric pumps filled with 6 g of amoxicillin in 240 mL of NaCl 0.9% by drawing samples at 12 h intervals when stored in the fridge for 48 h and when worn around the waist for 24 h. Subsequently nine patients were treated with continuous infusions of 8 or 12 g of amoxicillin per day. Plasma amoxicillin concentrations were measured on each visit to the outpatient parenteral antibiotic therapy unit. Clinical outcome was verified 3 months after the end of treatment. Amoxicillin degradation in elastomeric pumps reached 10% after 48 h in the fridge and an additional 30% when worn around the waist for 24 h. Mean plasma drug concentrations achieved with 12 g of amoxicillin per day were 18.5 mg/L (95% CI 13.5-23.5), which is largely above the MIC of amoxicillin-susceptible bacteria. Nine patients treated for various complicated infections were cured and had no unexpected adverse effects. Adequate plasma drug concentrations and favourable clinical outcomes suggest that amoxicillin can be administered by continuous infusion using elastomeric pumps. This treatment modality does not fulfil formal requirements regarding pharmaceutical stability, but the resulting safety impact in patients is probably limited. Therapeutic drug monitoring and a close clinical follow-up are recommended if this route of administration is chosen. © The Author 2017. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Reduced antituberculosis drug concentrations in HIV-infected patients who are men or have low weight: implications for international dosing guidelines.

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McIlleron, Helen; Rustomjee, Roxana; Vahedi, Mahnaz; Mthiyane, Thuli; Denti, Paolo; Connolly, Catherine; Rida, Wasima; Pym, Alexander; Smith, Peter J; Onyebujoh, Philip C

2012-06-01

Reduced antituberculosis drug concentrations may contribute to unfavorable treatment outcomes among HIV-infected patients with more advanced immune suppression, and few studies have evaluated pharmacokinetics of the first-line antituberculosis drugs in such patients given fixed-dose combination tablets according to international guidelines using weight bands. In this study, pharmacokinetics were evaluated in 60 patients on 4 occasions during the first month of antituberculosis therapy. Multilevel linear mixed-effects regression analysis was used to examine the effects of age, sex, weight, drug dose/kilogram, CD4(+) lymphocyte count, treatment schedule (5 versus 7 days/week), and concurrent antiretrovirals (efavirenz plus lamivudine plus zidovudine) on the area under the concentration-time curve from 0 to 12 h (AUC(0-12)) of the respective antituberculosis drugs and to compare AUC(0-12)s at day 8, day 15, and day 29 with the day 1 AUC(0-12). Median (range) age, weight, and CD4(+) lymphocyte count were 32 (18 to 47) years, 55.2 (34.4 to 98.7) kg, and 252 (12 to 500)/μl. For every 10-kg increase in body weight, the predicted day 29 AUC(0-12) increased by 14.1% (95% confidence interval [CI], 7.5, 20.8), 14.1% (95% CI, -0.7, 31.1), 6.1% (95% CI, 2.7, 9.6) and 6.0% (95% CI, 0.8, 11.3) for rifampin, isoniazid, pyrazinamide, and ethambutol, respectively. Males had day 29 AUC(0-12)s 19.3% (95% CI, 3.6, 35.1) and 14.0% (95% CI, 5.6, 22.4) lower than females for rifampin and pyrazinamide, respectively. Level of immune suppression and concomitant antiretrovirals had little effect on the concentrations of the antituberculosis agents. As they had reduced drug concentrations, it is important to review treatment responses in patients in the lower weight bands and males to inform future treatment guidelines, and revision of doses in these patients should be considered.

Application of trajectory clustering and source attribution methods for investigating regional CO2 and CH4 concentrations at Germany's highest mountain site

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Giemsa, Esther; Jacobeit, Jucundus; Ries, Ludwig; Frank, Gabriele; Hachinger, Stephan; Meyer-Arnek, Julian

2017-04-01

Carbon dioxide (CO2) and methane (CH4) represent the most important contributors to increased radiative forcing enhancing it together by contemporary 2.65 W/m2 on the global average (IPCC 2013). The unbroken increase of atmospheric greenhouse gases (GHG) has been unequivocally attributed to human emissions mainly coming from fossil fuel burning and land-use changes, while the oceans and terrestrial ecosystems slightly attenuate this rise with seasonally varying strength. Short-term fluctuations in the GHG concentrations that superimpose the seasonal cycle and the climate change driven trend reflect the presence of regional sources and sinks. A perfect place for investigating the comprehensive influence of these regional emissions is provided by the Environmental Research Station Schneefernerhaus (47.42°N, 10.98°E, 2.650m a.s.l.) situated in the eastern Alps at the southern side of Zugspitze mountain. Located just 300m below the highest peak of the German Alps, the exposed site is one of the currently 30 global core sites of the World Meteorological Organisation (WMO) Global Atmosphere Watch (GAW) programme and thus provides ideal conditions to study source-receptor relationships for greenhouse gases. We propose a stepwise statistical methodology for examining the relationship between synoptic-scale atmospheric transport patterns and climate gas mole fractions to finally receive a characterization of the sampling site with regard to the key processes driving CO2 and CH4 concentration levels. The first step entails a reliable radon-based filtering approach to subdivide the detected air masses according to their regional or 'background' origin. Simultaneously, a large number of ten-day back-trajectories from Schneefernerhaus every two hours over the entire study period 2011 - 2015 is calculated with the Lagrangian transport and dispersion model FLEXPART (Stohl et al. 2005) and subjected to cluster analysis. The weather- and emission strength-related (short

Cost-effectiveness of routine measuring of serum drug concentrations and anti-drug antibodies in treatment of rheumatoid arthritis patients with TNF-α blockers

Directory of Open Access Journals (Sweden)

Laine J

2016-04-01

Full Text Available Juha Laine,1 T Sakari Jokiranta,2,3 Kari K Eklund,4,5 Merja Väkeväinen,1 Kari Puolakka6 1Pfizer Oy, Helsinki, 2United Medix Laboratories Ltd, Espoo, 3Research Programs Unit, Immunobiology, 4Department of Rheumatology, University of Helsinki, 5Helsinki University Central Hospital, Helsinki, 6Department of Medicine, South Karelia, Finland Abstract: Monitoring of anti-drug antibodies (ADAbs or serum concentrations of biologicals in treatment of rheumatoid arthritis could provide an explanation for a loss of efficacy and help in the choice of subsequent medication. Current clinical practices do not generally include such monitoring of tumor necrosis factor (TNF-α blockers on a routine basis. The main aims of this study were to estimate the probabilities of optimal and nonoptimal treatment decisions if infliximab or adalimumab drug trough level (DL and ADAbs are tested or not in rheumatoid arthritis, and to model cost-effectiveness of performing such monitoring on a routine basis. Data on DLs and ADAbs concentrations were obtained in Finland from clinically requested monitoring analyses of 486 and 1,137 samples from patients on adalimumab and infliximab, respectively. DL was within the target range in 42% of samples from adalimumab- and 50.4% of infliximab-treated patients. ADAbs were detected in approximately 20% and 13.5% of samples from adalimumab- and infliximab-treated patients, respectively. ADAbs were found in 52.3% and 41.3% of those with low adalimumab or infliximab DLs, respectively. The monitoring data were incorporated into probabilities for making the optimal treatment decision. Economic impact of clinical decision-making was modeled in a short-term (3–6 months scenario with 100 hypothetical patients. In the model, the combined measurement of DLs and ADAbs was cost-saving compared to the nontesting scenario when the monitoring results affected the treatment decision in at least 2–5 of 100 patients, a proportion which is easily

Effects of the summer holiday season on UV filter and illicit drug concentrations in the Korean wastewater system and aquatic environment.

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Kim, Ki Yong; Ekpeghere, Kalu Ibe; Jeong, Hee-Jin; Oh, Jeong-Eun

2017-08-01

Seasonal variations in the concentrations of eight ultraviolet (UV) filters and 22 illicit drugs including their metabolites in the Korean aquatic environment were investigated. Seawater samples from three beaches, water samples from two rivers, and influents and effluents from three wastewater treatment plants were analyzed. The UV filter concentrations in the seawater, river water, and effluent samples were 39.4-296, 35.4-117, and 6.84-51.1 ng L -1 , respectively. The total UV filter concentrations in the seawater samples were 1.9-4.4 times higher at the peak of the holiday season than outside the peak holiday season. An environmental risk assessment showed that ethylhexyl methoxy cinnamate (EHMC) could cause adverse effects on aquatic organisms in the seawater at the three beaches during the holiday period. Seven of the 22 target illicit drugs including their metabolites were detected in the wastewater influent samples, and the total illicit drug concentrations in the influent samples were 0.08-65.4 ng L -1 . The estimated daily consumption rates for cis-tramadol (Cis-TRM), methamphetamine (MTP), meperidine (MEP), and codeine (COD) were 25.7-118.4, 13.8-36.1, 1.36-12.6, and 1.75-8.64 mg d -1 (1000 people) -1 , respectively. In popular vacation area, the illicit drug consumption rates (Cis-TRM, MTP and MEP) were 1.6-2.6 times higher at the peak of the summer holiday season than at the beginning of the summer. Copyright © 2017 Elsevier Ltd. All rights reserved.

Impact of common cytostatic drugs on pollen fertility in higher plants.

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Mišík, Miroslav; Kundi, Michael; Pichler, Clemens; Filipic, Metka; Rainer, Bernhard; Mišíková, Katarina; Nersesyan, Armen; Knasmueller, Siegfried

2016-08-01

Cytostatic drugs are among the most toxic chemicals which are produced. Many of them cause damage of the genetic material which may affect the fertility of higher organisms. To study the impact of the widely used anticancer drugs [cisplatin (CisPt), etoposide (Et), and 5-fluorouracil (5-FU)] on the reproduction of higher plants, pollen abortion experiments were conducted with species which belong to major plant families, namely with Tradescantia paludosa (Commelinaceae), Arabidopsis thaliana (Brassicaceae), Chelidonium majus (Papaveraceae), and Alisma plantago-aquatica (Alismataceae). All compounds increased the frequencies of abortive grains. The lowest effective doses were in general in a narrow range (i.e., 1 and 10 mg/kg of dry soil). The effects of the individual drugs were similar in T. paludosa, A. plantago-aquatica, and Ch. majus, while A. thaliana was consistently less sensitive. The highest abortion rate was obtained in most experiments with CisPt, followed by 5-FU and Et. Comparisons of the doses which caused effects in the present experiments in the different species with the predicted environment concentrations and with the levels of the cytostatics which were detected in hospital wastewaters show that the realistic environmental concentrations of the drugs are 4-6 orders of magnitude lower. Therefore, it is unlikely that these drugs affect the fertility of higher plants in aquatic and terrestrial ecosystems.

Determination of safety margins for whole blood concentrations of alcohol and nineteen drugs in driving under the influence cases.

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Kristoffersen, Lena; Strand, Dag Helge; Liane, Veronica Horpestad; Vindenes, Vigdis; Tvete, Ingunn Fride; Aldrin, Magne

2016-02-01

Legislative limits for driving under the influence of 20 non-alcohol drugs were introduced in Norway in February 2012. Per se limits corresponding to blood alcohol concentrations (BAC) of 0.2g/kg were established for 20 psychoactive drugs, and limits for graded sanctions corresponding to BACs of 0.5 and 1.2g/kg were determined for 13 of these drugs. This new legislation made it possible for the courts to make sentences based on the analytical results, similar to the situation for alcohol. To ensure that the reported concentration is as least as high as the true concentration, with a 99% safety level, safety margins had to be calculated for each of the substances. Diazepam, tetrahydrocannabinol (THC) and alcohol were used as model substances to establish a new model for estimating the safety margins. The model was compared with a previous used model established several years ago, by a similar yet much simpler model, and they were found to be in agreement. The measurement uncertainties depend on the standard batch used, the work list and the measurements' replicate. A Bayesian modelling approach was used to determine the parameters in the model, using a dataset of 4700 diazepam positive specimens and 5400 THC positive specimens. Different safety margins were considered for low and high concentration levels of diazepam (≤2μM (0.6mg/L) and >2μM) and THC (≤0.01μM (0.003mg/L) and >0.01μM). The safety margins were for diazepam 19.5% (≤2μM) and 34% (>2μM), for THC 19.5% (≤0.01μM) and 24.9% (>0.01μM). Concentration dependent safety margins for BAC were based on a dataset of 29500 alcohol positive specimens, and were in the range 10.4% (0.1g/kg) to 4.0% (4.0g/kg) at a 99% safety level. A simplified approach was used to establish safety margins for the compounds amphetamine, MDMA, methamphetamine, alprazolam, phenazepam, flunitrazepam, clonazepam, nitrazepam, oxazepam, buprenorphine, GHB, methadone, ketamine, cocaine, morphine, zolpidem and zopiclone. The

Anticancer drugs in Portuguese surface waters - Estimation of concentrations and identification of potentially priority drugs.

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Santos, Mónica S F; Franquet-Griell, Helena; Lacorte, Silvia; Madeira, Luis M; Alves, Arminda

2017-10-01

Anticancer drugs, used in chemotherapy, have emerged as new water contaminants due to their increasing consumption trends and poor elimination efficiency in conventional water treatment processes. As a result, anticancer drugs have been reported in surface and even drinking waters, posing the environment and human health at risk. However, the occurrence and distribution of anticancer drugs depend on the area studied and the hydrological dynamics, which determine the risk towards the environment. The main objective of the present study was to evaluate the risk of anticancer drugs in Portugal. This work includes an extensive analysis of the consumption trends of 171 anticancer drugs, sold or dispensed in Portugal between 2007 and 2015. The consumption data was processed aiming at the estimation of predicted environmental loads of anticancer drugs and 11 compounds were identified as potentially priority drugs based on an exposure-based approach (PEC b > 10 ng L -1 and/or PEC c > 1 ng L -1 ). In a national perspective, mycophenolic acid and mycophenolate mofetil are suspected to pose high risk to aquatic biota. Moderate and low risk was also associated to cyclophosphamide and bicalutamide exposition, respectively. Although no evidences of risk exist yet for the other anticancer drugs, concerns may be associated with long term effects. Copyright © 2017 Elsevier Ltd. All rights reserved.

[Influence of quaternary ammonium salt on liberation of drug with antiseptic effect].

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Vitková, Zuzana; Herdová, Petra; Oremusová, Jarmila; Cižmárik, Jozef; Tóthová, Katarína

2013-12-01

The paper evaluates the influence of three surfactants (carbetopendecinium halogenides) on the liberation of the drug chlorhexidine dihydrochloride (CHX) in 0.1% (w/w) from the dosage form-gel and also the flow properties of gels. The following tensides were evaluated: carbetopendecinium bromide (SB), carbetopendecinium chloride (SC), and carbetopendecinium iodide (SI). The tenside concentration was set under the critical micelle concentration. The biopolymer - chitosan (CHIT) in 2.5% (w/w) concentration was used as a gel creating substance. Based on the flow properties of the studied gels, it was found that the employed tensides exhibited no influence on the character of the system. The gels exhibited the character of plastic systems with time-independent flow. The drug liberation was evaluated at the temperatures of 20, 30 and 40 °C. Between the types of the tensides, the statistically significant differences (P < 0.05) were found as to the amount of the liberated CHX, which was reflected by the increased amount of the liberated drug. Based on the obtained results, it can be concluded that the most suitable was the SI tenside. From the gel with this tenside the greatest amount of CHX was liberated, which had the highest value of the liberation rate constant.

Entry time effects and follow-on drug competition.

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Andrade, Luiz Flavio; Sermet, Catherine; Pichetti, Sylvain

2016-01-01

Pharmaceutical firms have been criticized for concentrating efforts of R&D on the so-called me-too or follow-on drugs. There have been many comments for and against the dissemination of these incremental innovations but few papers have broached the subject from an econometric point of view, possibly because identification of me-too or follow-on drugs is not so obvious. This paper focuses on the impact of entry order on follow-on drug competition in the French market between the years 2001 and 2007. More precisely, this study examines the effects on market share of first entrants in the follow-on drug market and how this possible competitive advantage changes over time. First results are coherent with theoretical microeconomic issues concerning the importance of being first. We find evidence that first movers in the follow-on drug market have the ability to capture and maintain greater market share for a long period of time. The hierarchical market position of follow-on drugs does not seem to be affected by generic drug emergence. From a dynamic perspective, our analysis shows that market share is positively correlated with the ability of follow-on drugs to set prices higher than the average follow-on drug prices in a specific therapeutic class, which means that market power remains considerably important for first movers. Moreover, we found that the optimum level of innovation to maximize market share is the highest one.

Postmortem Blood Concentrations of R- and S-Enantiomers of Methadone and EDDP in Drug Users: Influence of Co-Medication and P-glycoprotein Genotype

DEFF Research Database (Denmark)

Buchard, Anders; Linnet, Kristian; Johansen, Sys Stybe

2010-01-01

We investigated toxicological and pharmacogenetic factors that could influence methadone toxicity using postmortem samples. R- and S-methadone were measured in femoral blood from 90 postmortem cases, mainly drug users. The R-enantiomer concentrations significantly exceeded that of the S-enantiome......We investigated toxicological and pharmacogenetic factors that could influence methadone toxicity using postmortem samples. R- and S-methadone were measured in femoral blood from 90 postmortem cases, mainly drug users. The R-enantiomer concentrations significantly exceeded that of the S...

Short communication: cheminformatics analysis to identify predictors of antiviral drug penetration into the female genital tract.

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Thompson, Corbin G; Sedykh, Alexander; Nicol, Melanie R; Muratov, Eugene; Fourches, Denis; Tropsha, Alexander; Kashuba, Angela D M

2014-11-01

The exposure of oral antiretroviral (ARV) drugs in the female genital tract (FGT) is variable and almost unpredictable. Identifying an efficient method to find compounds with high tissue penetration would streamline the development of regimens for both HIV preexposure prophylaxis and viral reservoir targeting. Here we describe the cheminformatics investigation of diverse drugs with known FGT penetration using cluster analysis and quantitative structure-activity relationships (QSAR) modeling. A literature search over the 1950-2012 period identified 58 compounds (including 21 ARVs and representing 13 drug classes) associated with their actual concentration data for cervical or vaginal tissue, or cervicovaginal fluid. Cluster analysis revealed significant trends in the penetrative ability for certain chemotypes. QSAR models to predict genital tract concentrations normalized to blood plasma concentrations were developed with two machine learning techniques utilizing drugs' molecular descriptors and pharmacokinetic parameters as inputs. The QSAR model with the highest predictive accuracy had R(2)test=0.47. High volume of distribution, high MRP1 substrate probability, and low MRP4 substrate probability were associated with FGT concentrations ≥1.5-fold plasma concentrations. However, due to the limited FGT data available, prediction performances of all models were low. Despite this limitation, we were able to support our findings by correctly predicting the penetration class of rilpivirine and dolutegravir. With more data to enrich the models, we believe these methods could potentially enhance the current approach of clinical testing.

A new application of micellar liquid chromatography in the determination of free ampicillin concentration in the drug-human serum albumin standard solution in comparison with the adsorption method.

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Stępnik, Katarzyna E; Malinowska, Irena; Maciejewska, Małgorzata

2016-06-01

The determination of free drug concentration is a very important issue in the field of pharmacology because only the unbound drug fraction can achieve a pharmacological effect. Due to the ability to solubilize many different compounds in micellar aggregates, micellar liquid chromatography (MLC) can be used for direct determination of free drug concentration. Proteins are not retained on the stationary phase probably due to the formation of protein - surfactant complexes which are excluded from the pores of stationary phase. The micellar method is simple and fast. It does not require any pre-preparation of the tested samples for analysis. The main aim of this paper is to demonstrate a completely new applicability of the analytical use of MLC concerning the determination of free drug concentration in the standard solution of human serum albumin. The well-known adsorption method using RP-HPLC and the spectrophotometric technique was applied as the reference method. The results show that the free drug concentration value obtained in the MLC system (based on the RP-8 stationary phase and CTAB) is similar to that obtained by the adsorption method: both RP-HPLC (95.83μgmL(-1), 79.86% of free form) and spectrophotometry (95.71μgmL(-1), 79.76%). In the MLC the free drug concentration was 93.98μgmL(-1) (78.3%). This indicates that the obtained results are within the analytical range of % of free ampicillin fraction and the MLC with direct sample injection can be treated like a promising method for the determination of free drug concentration. Copyright © 2016 Elsevier B.V. All rights reserved.

Drug-Target Kinetics in Drug Discovery.

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Tonge, Peter J

2018-01-17

The development of therapies for the treatment of neurological cancer faces a number of major challenges including the synthesis of small molecule agents that can penetrate the blood-brain barrier (BBB). Given the likelihood that in many cases drug exposure will be lower in the CNS than in systemic circulation, it follows that strategies should be employed that can sustain target engagement at low drug concentration. Time dependent target occupancy is a function of both the drug and target concentration as well as the thermodynamic and kinetic parameters that describe the binding reaction coordinate, and sustained target occupancy can be achieved through structural modifications that increase target (re)binding and/or that decrease the rate of drug dissociation. The discovery and deployment of compounds with optimized kinetic effects requires information on the structure-kinetic relationships that modulate the kinetics of binding, and the molecular factors that control the translation of drug-target kinetics to time-dependent drug activity in the disease state. This Review first introduces the potential benefits of drug-target kinetics, such as the ability to delineate both thermodynamic and kinetic selectivity, and then describes factors, such as target vulnerability, that impact the utility of kinetic selectivity. The Review concludes with a description of a mechanistic PK/PD model that integrates drug-target kinetics into predictions of drug activity.

Five-year update on the occurrence of alcohol and other drugs in blood samples from drivers killed in road-traffic crashes in Sweden.

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Jones, Alan Wayne; Kugelberg, Fredrik C; Holmgren, Anita; Ahlner, Johan

2009-04-15

According to statistics provided by the Swedish National Road Administration (Vägverket), a total of 1403 drivers were killed in road-traffic crashes in Sweden between 2003 and 2007. Forensic autopsies were performed in approximately 97% of all deaths and specimens of blood and urine were sent for toxicological analysis. In 60% of cases (N=835) the toxicology results were negative and 83% of these victims were men. The blood-alcohol concentration (BAC) was above the legal limit for driving (>0.2g/L) in 22% of cases (N=315) at mean, median and highest concentrations of 1.7 g/L, 1.7 g/L and 4.9 g/L, respectively. The proportions of male to female drivers with BAC>0.2g/L were 93% vs 7% compared with 83% vs 17% for those with drugs other than alcohol in blood. Drivers with a punishable BAC were over-represented in single vehicle crashes compared with multiple vehicle crashes (67% vs 33%). The opposite held for drivers who had taken a prescription drug (39% vs 61%) and also for drug-negative cases (31% vs 69%). Drugs other than alcohol were identified in 253 cases (18%); illicit drugs only in 39 cases (2.8%), both licit and illicit in 28 cases (2.0%) and in 186 cases (13.3%) one or more therapeutic drugs were present. Amphetamine was the most common illicit drug identified at mean, median and highest concentrations of 1.5mg/L, 1.1mg/L and 5.0mg/L, respectively (N=39). Blood specimens contained a wide spectrum of pharmaceutical products (mean 2.4 drugs/person), comprising sedative-hypnotics (N=93), opiates/opioids (N=69) as well non-scheduled substances, such as paracetamol (N=78) and antidepressants (N=93). The concentrations of these substances in blood were mostly in the therapeutic range. Despite an appreciable increase (12-fold) in number of arrests made by the police for drug-impaired driving after a zero-tolerance law was introduced (July 1999), alcohol still remains the psychoactive substance most frequently identified in the blood of drivers killed in road

Linezolid Trough Concentrations Correlate with Mitochondrial Toxicity-Related Adverse Events in the Treatment of Chronic Extensively Drug-Resistant Tuberculosis.

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Song, Taeksun; Lee, Myungsun; Jeon, Han-Seung; Park, Yumi; Dodd, Lori E; Dartois, Véronique; Follman, Dean; Wang, Jing; Cai, Ying; Goldfeder, Lisa C; Olivier, Kenneth N; Xie, Yingda; Via, Laura E; Cho, Sang Nae; Barry, Clifton E; Chen, Ray Y

2015-11-01

Long-term linezolid use is limited by mitochondrial toxicity-associated adverse events (AEs). Within a prospective, randomized controlled trial of linezolid to treat chronic extensively drug-resistant tuberculosis, we serially monitored the translational competence of mitochondria isolated from peripheral blood of participants by determining the cytochrome c oxidase/citrate synthase activity ratio. We compared this ratio with AEs associated with mitochondrial dysfunction. Linezolid trough concentrations were determined for 38 participants at both 600 mg and 300 mg doses. Those on 600 mg had a significantly higher risk of AE than those on 300 mg (HR 3·10, 95% CI 1·23-7 · 86). Mean mitochondrial function levels were significantly higher in patients before starting linezolid compared to their concentrations on 300 mg (P = 0·004) or 600 mg (P linezolid trough concentrations were associated with lower mitochondrial function levels (Spearman's ρ = - 0.48; P = 0.005). Mitochondrial toxicity risk increased with increasing linezolid trough concentrations, with all patients with mean linezolid trough > 2 μg/ml developing an AE related to mitochondrial toxicity, whether on 300 mg or 600 mg. Therapeutic drug monitoring may be useful to prevent the development of mitochondrial toxicity associated with long-term linezolid use.

Green Pharmaceutical Analysis of Drugs Coformulated with Highly Different Concentrations Using Spiking and Manipulation of Their Ratio Spectra.

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Ayoub, Bassam M

2017-07-01

Introducing green analysis to pharmaceutical products is considered a significant approach to preserving the environment. This method can be an environmentally friendly alternative to the existing methods, accompanied by a validated automated procedure for the analysis of a drug with the lowest possible number of samples. Different simple spectrophotometric methods were developed for the simultaneous determination of empagliflozin (EG) and metformin (MT) by manipulating their ratio spectra in their application on a recently approved pharmaceutical combination, Synjardy tablets. A spiking technique was used to increase the concentration of EG in samples prepared from the tablets to allow for the simultaneous determination of EG with MT without prior separation. Validation parameters according to International Conference on Harmonization guidelines were acceptable over a concentration range of 2-12 μg/mL for both drugs using derivative ratio and ratio subtraction coupled with extended ratio subtraction. The optimized methods were compared using one-way analysis of variance and proved to be suitable as ecofriendly approaches for industrial QC laboratories.

Exploiting Large-Scale Drug-Protein Interaction Information for Computational Drug Repurposing

Science.gov (United States)

2014-06-20

studies that have reported antimalarial activities of azole compounds [39-43] lend support to our model predictions. The highest-scored non-malarial...Table 4, verapamil and cimetidine, do not have antimal- arial activities themselves but exhibit synergism when used in combination with antimalarial ... activators . Because of their high frequencies among the antimalarial drugs, according to Eq. 3, the drug-protein interactions contributing most to the

Role of drug transporters and drug accumulation in the temporal acquisition of drug resistance

International Nuclear Information System (INIS)

Hembruff, Stacey L; Laberge, Monique L; Villeneuve, David J; Guo, Baoqing; Veitch, Zachary; Cecchetto, Melanie; Parissenti, Amadeo M

2008-01-01

Anthracyclines and taxanes are commonly used in the treatment of breast cancer. However, tumor resistance to these drugs often develops, possibly due to overexpression of drug transporters. It remains unclear whether drug resistance in vitro occurs at clinically relevant doses of chemotherapy drugs and whether both the onset and magnitude of drug resistance can be temporally and causally correlated with the enhanced expression and activity of specific drug transporters. To address these issues, MCF-7 cells were selected for survival in increasing concentrations of doxorubicin (MCF-7 DOX-2 ), epirubicin (MCF-7 EPI ), paclitaxel (MCF-7 TAX-2 ), or docetaxel (MCF-7 TXT ). During selection cells were assessed for drug sensitivity, drug uptake, and the expression of various drug transporters. In all cases, resistance was only achieved when selection reached a specific threshold dose, which was well within the clinical range. A reduction in drug uptake was temporally correlated with the acquisition of drug resistance for all cell lines, but further increases in drug resistance at doses above threshold were unrelated to changes in cellular drug uptake. Elevated expression of one or more drug transporters was seen at or above the threshold dose, but the identity, number, and temporal pattern of drug transporter induction varied with the drug used as selection agent. The pan drug transporter inhibitor cyclosporin A was able to partially or completely restore drug accumulation in the drug-resistant cell lines, but had only partial to no effect on drug sensitivity. The inability of cyclosporin A to restore drug sensitivity suggests the presence of additional mechanisms of drug resistance. This study indicates that drug resistance is achieved in breast tumour cells only upon exposure to concentrations of drug at or above a specific selection dose. While changes in drug accumulation and the expression of drug transporters does occur at the threshold dose, the magnitude of

Plasma Drug Concentrations of Orally Administered Rosuvastatin in Hispaniolan Amazon Parrots (Amazona ventralis).

Science.gov (United States)

Beaufrère, Hugues; Papich, Mark G; Brandão, João; Nevarez, Javier; Tully, Thomas N

2015-03-01

Atherosclerotic diseases are common in pet psittacine birds, in particular Amazon parrots. While hypercholesterolemia and dyslipidemia have not definitely been associated with increased susceptibility to atherosclerosis in parrots, these are important and well-known risk factors in humans. Therefore statin drugs such as rosuvastatin constitute the mainstay of human treatment of dyslipidemia and the prevention of atherosclerosis. No pharmacologic studies have been performed in psittacine birds despite the high prevalence of atherosclerosis in captivity. Thirteen Hispaniolan Amazon parrots were used to test a single oral dose of 10 mg/kg of rosuvastatin with blood sampling performed according to a balanced incomplete block design over 36 hours. Because low plasma concentrations were produced in the first study, a subsequent pilot study using a dose of 25 mg/kg in 2 Amazon parrots was performed. Most plasma samples for the 10 mg/kg dose and all samples for the 25 mg/kg dose had rosuvastatin concentration below the limits of quantitation. For the 10 mg/kg study, the median peak plasma concentration and time to peak plasma concentration were 0.032 μg/mL and 2 hours, respectively. Our results indicate that rosuvastatin does not appear suitable in Amazon parrots as compounded and used at the dose in this study. Pharmacodynamic studies investigating lipid-lowering effects of statins rather than pharmacokinetic studies may be more practical and cost effective in future studies to screen for a statin with more ideal properties for potential use in psittacine dyslipidemia and atherosclerotic diseases.

A new self-emulsifying formulation of mefenamic acid with enhanced drug dissolution

Directory of Open Access Journals (Sweden)

Pornsak Sriamornsak

2015-04-01

Full Text Available To enhance the dissolution of poorly soluble mefenamic acid, self-emulsifying formulation (SEF, composing of oil, surfactant and co-surfactant, was formulated. Among the oils and surfactants studied, Imwitor® 742, Tween® 60, Cremophore® EL and Transcutol® HP were selected as they showed maximal solubility to mefenamic acid. The ternary phase diagram was constructed to find optimal concentration that provided the highest drug loading. The droplet size after dispersion and drug dissolution of selected formulations were investigated. The results showed that the formulation containing Imwitor® 742, Tween® 60 and Transcutol® HP (10:30:60 can encapsulate high amount of mefenamic acid. The dissolution study demonstrated that, in the medium containing surfactant, nearly 100% of mefenamic acid were dissolved from SEF within 5 min while 80% of drugs were dissolved from the commercial product in 45 min. In phosphate buffer (without surfactant, 80% of drug were dissolved from the developed SEF within 5 min while only about 13% of drug were dissolved in 45 min, from the commercial product. The results suggested that the SEF can enhance the dissolution of poorly soluble drug and has a potential to enhance drug absorption and improve bioavailability of drug.

Hyaluronan-decorated liposomes as drug delivery systems for cutaneous administration.

Science.gov (United States)

Franzé, Silvia; Marengo, Alessandro; Stella, Barbara; Minghetti, Paola; Arpicco, Silvia; Cilurzo, Francesco

2018-01-15

The work aimed to evaluate the feasibility to design hyaluronic acid (HA) decorated flexible liposomes to enhance the skin penetration of nifedipine. Egg phosphatidylcholine (e-PC) based transfersomes (Tween 80) and transethosomes (ethanol) were prepared. HA was reacted with 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine (HA-DPPE) and two molar ratios (0.5 and 3%) of conjugate with respect to e-PC were tested. The presence of HA significantly increased the packing order of the bilayer (as verified by differential scanning calorimetry), reducing both the encapsulation efficiency and the flexibility of the decorated liposomes in a dose-dependent manner. In fact, at the highest HA content the constant of deformability (K, N/mm) increased and the carriers remained on the skin surface after topical application. The stiffening effect of HA was counterbalanced by the addition of ethanol as fluidizing agent that allowed to maintain the highest HA concentration, meanwhile reducing the K value of the vesicles. HA-transethosomes allowed a suitable nifedipine permeation (J ∼ 30 ng/cm 2 /h) and significantly improved the drug penetration, favouring the formation of a drug depot in the epidermis. These data suggest the potentialities of HA-transethosomes as drug delivery systems intended for the treatment of cutaneous pathologies and underline the importance of studying the effect of surface functionalization on carrier deformability to rationalize the design of such systems. Copyright © 2017 Elsevier B.V. All rights reserved.

Reversible pH-Sensitive Chitosan-Based Hydrogels. Influence of Dispersion Composition on Rheological Properties and Sustained Drug Delivery

Directory of Open Access Journals (Sweden)

Nieves Iglesias

2018-04-01

Full Text Available The present work deals with the synthesis of micro-structured biomaterials based on chitosan (CTS for their applications as biocompatible carriers of drugs and bioactive compounds. Twelve dispersions were prepared by means of functional cross-linking with tricarballylic acid (TCA; they were characterized by Fourier transform infrared spectroscopy (FT-IR, modulated temperature differential scanning calorimetry (MTDSC and scanning electron microscopy (SEM, and their rheological properties were studied. To the best of the authors’ knowledge, no study has been carried out on the influence of CTS concentration, degree of cross-linking and drug loading on chitosan hydrogels for drug delivery systems (DDS and is investigated herein for the first time. The influence of dispersion composition (polymer concentration and degree of cross-linking revealed to exert a marked impact on its rheological properties, going from liquid-like to viscoelastic gels. The release profiles of a model drug, diclofenac sodium (DCNa, as well as their relationships with polymer concentration, drug loading and degree of cross-linking were evaluated. Similar to the findings on rheological properties, a wide range of release profiles was encountered. These formulations were found to display a well-controlled drug release strongly dependent on the formulation composition. Cumulative drug release under physiological conditions for 96 h ranged from 8% to 67%. For comparative purpose, Voltaren emulgel® from Novartis Pharmaceuticals was also investigated and the latter was the formulation with the highest cumulative drug release (85%. Some formulations showed similar spreadability values to the commercial hydrogel. The comparative study of three batches confirmed the reproducibility of the method, leading to systems particularly suitable for their use as drug carriers.

Registration for public drug benefits across areas of differing ethnic composition in British Columbia, Canada.

Science.gov (United States)

Leong, Vivian W; Morgan, Steve; Wong, Sabrina T; Hanley, Gillian E; Black, Charlyn

2010-06-17

In 2003, the government of British Columbia, Canada introduced a universal drug benefit plan to cover drug costs that are high relative to household income. Residents were required to register in order to be eligible for the income-based benefits. Given past research suggesting that registration processes may pose an access barrier to certain subpopulations, we aimed to determine whether registration rates varied across small geographic areas that differed in ethnic composition. Using linked population-based administrative databases and census data, we conducted multivariate logistic regression analyses to determine whether the probability of registration for the public drug plan varied across areas of differing ethnic composition, controlling for household-level predisposing, enabling and needs factors. The adjusted odds of registration did not differ across regions characterized by high concentrations (greater than 30%) of residents identifying as North American, British, French or other European. Households located in areas with concentrations of residents identifying as an Asian ethnicity had the highest odds of program registration: Chinese (OR = 1.21, CI: 1.19-1.23) and South Asian (OR = 1.19, CI: 1.16-1.22). Despite this positive finding, households residing in areas with relatively high concentrations of recent immigrants had slightly lower adjusted odds of registering for the program (OR = 0.97, CI: 0.95-0.98). This study identified ethnic variation in registration for a new public drug benefit program in British Columbia. However, unlike previous studies, the variation observed did not indicate that areas with high concentrations of certain ethnicities experienced disadvantages. Potential explanations are discussed.

Influence of tiamulin concentration in feed on its bioavailability in piglets.

Science.gov (United States)

Riond, J L; Schreiber, F; Wanner, M

1993-01-01

Tiamulin pharmacokinetic parameters were determined in 8 2-month-old male improved Swiss Landrace piglets after intake of 2,000 mg/kg feed, 500 mg/kg feed, 12.5 mg/ml aqueous solution administered via a stomach tube and 180 mg/kg feed offered ad libitum. In all cases, the total tiamulin dose received was 10 mg/kg body weight (bw) per day. For the 2,000 mg/kg and 500 mg/kg treatments, animals were restrictively fed a commercial mix in amounts corresponding to 3-fold their maintenance requirement of digestible energy. The piglets first individually received the amount of medicated feed and immediately thereafter the rest of the daily ration. The highest tiamulin serum concentrations (Cmax), the largest area under the curve (AUC0-->infinity), the largest absorption rate constant (Ka), and the shortest time at which the maximum serum concentration occurred (tmax) were obtained after administration via stomach tube followed in the respective order by the 2,000 mg/kg, 500 mg/kg and 180 mg/kg treatments. Ad libitum feeding of the medicated mix at 180 mg/kg failed to provide tiamulin serum concentration above minimum inhibitory concentrations (MIC) of some representative microorganisms. In conclusion, tiamulin concentration in medicated feed strongly influences its rate and extent of absorption and consequently serum concentrations. Larger tiamulin concentration in feed enhances its bioavailability. The common practice adopted by national regulatory agencies for the registration of a new drug is to conduct pharmacokinetic studies after administration agencies for the registration of a new drug is to conduct pharmacokinetic studies after administration via a stomach tube. This practice should be reevaluated because this mode of administration does not correspond to that in routine use.

Effect of sodium tripolyphosphate concentration and simulated gastrointestinal fluids on release profile of paracetamol from chitosan microsphere

Science.gov (United States)

Mulia, Kamarza; Andrie; Krisanti, Elsa A.

2018-03-01

The problem to overcome in oral drug administration is the significant pH changes present in the human digestive system. In this study, ionotropic gelation method employing 2-8% (w/v) tripolyphosphate solutions were used to crosslink chitosan microspheres for a controlled release of paracetamol as a model drug. The release profiles of paracetamol from chitosan microspheres were determined using simulated gastrointestinal fluids having pH values of 1.2, 6.8, and 7.4. The results showed that the paracetamol loading and the encapsulation efficiency values increased with increasing concentration of tripolyphosphate solutions used in the preparation step. Paracetamol released at pH 1.2 and 6.8 buffer solutions was significantly higher than that at pH 7.4; also, more paracetamol was released in the presence of α-amylase and β-glucosidase enzymes. The release profiles showed zero-order release behaviour up to 8 hours where the highest drug release was 39% of the paracetamol loaded in the chitosan microspheres, indicating a strong crosslinking between chitosan and TPP anions. The relatively low accumulated drug release could be compensated by employing suitable enzymes, lower TPP solution concentration, and addition of other biodegradable polymer to reduce the TPP crosslink.

Spectrophotometric Method for the Determination of Two Coformulated Drugs with Highly Different Concentrations. Application on Vildagliptin and Metformin Hydrochloride

Science.gov (United States)

Zaazaa, H. E.; Elzanfaly, E. S.; Soudi, A. T.; Salem, M. Y.

2016-03-01

A new smart simple validated spectrophotometric method was developed for the determination of two drugs one of which is in a very low concentration compared to the other. The method is based on spiking and dilution then simple mathematical manipulation of the absorbance spectra. This method was applied for the determination of a binary mixture of vildagliptin and metformin hydrochloride in the ratio 50:850 in laboratory prepared mixtures containing both drugs in this ratio and in pharmaceutical dosage form with good recoveries. The developed method was validated according to ICH guidelines and can be used for routine quality control testing.

"Time for dabs": Analyzing Twitter data on marijuana concentrates across the U.S.

Science.gov (United States)

Daniulaityte, Raminta; Nahhas, Ramzi W; Wijeratne, Sanjaya; Carlson, Robert G; Lamy, Francois R; Martins, Silvia S; Boyer, Edward W; Smith, G Alan; Sheth, Amit

2015-10-01

Media reports suggest increasing popularity of marijuana concentrates ("dabs"; "earwax"; "budder"; "shatter; "butane hash oil") that are typically vaporized and inhaled via a bong, vaporizer or electronic cigarette. However, data on the epidemiology of marijuana concentrate use remain limited. This study aims to explore Twitter data on marijuana concentrate use in the U.S. and identify differences across regions of the country with varying cannabis legalization policies. Tweets were collected between October 20 and December 20, 2014, using Twitter's streaming API. Twitter data filtering framework was available through the eDrugTrends platform. Raw and adjusted percentages of dabs-related tweets per state were calculated. A permutation test was used to examine differences in the adjusted percentages of dabs-related tweets among U.S. states with different cannabis legalization policies. eDrugTrends collected a total of 125,255 tweets. Almost 22% (n=27,018) of these tweets contained identifiable state-level geolocation information. Dabs-related tweet volume for each state was adjusted using a general sample of tweets to account for different levels of overall tweeting activity for each state. Adjusted percentages of dabs-related tweets were highest in states that allowed recreational and/or medicinal cannabis use and lowest in states that have not passed medical cannabis use laws. The differences were statistically significant. Twitter data suggest greater popularity of dabs in the states that legalized recreational and/or medical use of cannabis. The study provides new information on the epidemiology of marijuana concentrate use and contributes to the emerging field of social media analysis for drug abuse research. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Control of drug releasing from biodegradable polymer drug delivery system by gamma-ray irradiation

International Nuclear Information System (INIS)

Yoshioka, Sumie; Aso, Yukio; Kojima, Shigeo

1999-01-01

In order to introduce the drug to the target organ, we developed a gel to control the drug releasing velocity by response to change of temperature by means of γ-ray irradiation to gelatin-GMA modified dextran mixture aqueous solution. A certain level of molecular weight of drug is necessary. The response to the temperature (change of drug releasing velocity) was affected by the concentration of gelatin and the modification rate of GMA. The Higuchi equation was applied to the releasing of β-galactosidase from gelatin-dextran gel and the releasing velocity was calculated. The releasing velocity decreased with increasing GMA modification rate at 37degC and 15degC. The releasing velocity of β-galactosidase decreased with increasing the concentration of gelatin at 15degC, but the velocity increased with increasing the concentration at 37degC. These results indicated that the good drug releasing conditions are obtained by controlling the GMA modification rate and the concentration of gelatin. (S.Y.)

Discontinued drugs in 2012: cardiovascular drugs.

Science.gov (United States)

Zhao, Hong-Ping; Jiang, Hong-Min; Xiang, Bing-Ren

2013-11-01

The continued high rate of cardiovascular morbidity and mortality has attracted wide concern and great attention of pharmaceutical industry. In order to reduce the attrition of cardiovascular drug R&D, it might be helpful recapitulating previous failures and identifying the potential factors to success. This perspective mainly analyses the 30 cardiovascular drugs dropped from clinical development in 2012. Reasons causing the termination of the cardiovascular drugs in the past 5 years are also tabulated and analysed. The analysis shows that the attrition is highest in Phase II trials and financial and strategic factors and lack of clinical efficacy are the principal reasons for these disappointments. To solve the four problems (The 'better than the Beatles' problem, the 'cautious regulator' problem, the 'throw money at it' tendency and the 'basic researchbrute force' bias) is recommended as the main measure to increase the number and quality of approvable products.

Financial Burden of Cancer Drug Treatment in Lebanon.

Science.gov (United States)

Elias, Fadia; Khuri, Fadlo R; Adib, Salim M; Karam, Rita; Harb, Hilda; Awar, May; Zalloua, Pierre; Ammar, Walid

2016-01-01

The Ministry of Public Health (MOPH) in Lebanon provides cancer drugs free of charge for uninsured patients who account for more than half the total caseload. Other categories of cancer care are subsidized under more stringent eligibility criteria. MOPH's large database offers an excellent opportunity to analyze the cost of cancer treatment in Lebanon. Using utilization and spending data accumulated at MOPH during 20082013, the cost to the public budget of cancer drugs was assessed per case and per drug type. The average annual cost of cancer drugs was 6,475$ per patient. Total cancer drug costs were highest for breast cancer, followed by chronic myeloid leukemia (CML), colorectal cancer, lung cancer, and NonHodgkin's lymphoma (NHL), which together represented 74% of total MOPH cancer drug expenditure. The annual average cancer drug cost per case was highest for CML ($31,037), followed by NHL ($11,566). Trastuzumab represented 26% and Imatinib 15% of total MOPH cancer drug expenditure over six years. Sustained increase in cancer drug cost threatens the sustainability of MOPH coverage, so crucial for socially vulnerable citizens. To enhance the bargaining position with pharmaceutical firms for drug cost containment in a small market like Lebanon, drug price comparisons with neighboring countries which have already obtained lower prices may succeed in lowering drug costs.

The use of drugs and medicines behind the wheel. [Previously called Driving under the influence of drugs and medicines.

NARCIS (Netherlands)

2009-01-01

Research shows that about 4% of drivers in Europe participate in traffic after having taken drugs and/or medicines. With 3.4% this share was lower in the Netherlands; traces of drugs were found in approximately 2.8% of the car drivers and traces of drugs were found in 0.6%. Substance use is highest

Human drug metabolism: an introduction

National Research Council Canada - National Science Library

Coleman, Michael D

2010-01-01

... metabolism and its impact on patient welfare. After underlining the relationship between efficacy, toxicity and drug concentration, the book then considers how metabolizing systems operate and how they impact upon drug concentration...

Metals in the Scheldt estuary: From environmental concentrations to bioaccumulation.

Science.gov (United States)

Van Ael, Evy; Blust, Ronny; Bervoets, Lieven

2017-09-01

To investigate the relationship between metal concentrations in abiotic compartments and in aquatic species, sediment, suspended matter and several aquatic species (Polychaeta, Oligochaeta, four crustacean species, three mollusc species and eight fish species) were collected during three seasons at six locations along the Scheldt estuary (the Netherlands-Belgium) and analysed on their metal content (Ag, Cd, Co, Cr, Cu, Ni, Pb, Zn and the metalloid As). Sediment and biota tissue concentrations were significantly influenced by sampling location, but not by season. Measurements of Acid Volatile Sulphides (AVS) concentrations in relation to Simultaneously Extracted Metals (SEM) in the sediment suggested that not all metals in the sediment will be bound to sulphides and some metals might be bioavailable. For all metals but zinc, highest concentrations were measured in invertebrate species; Ag and Ni in periwinkle, Cr, Co and Pb in Oligochaete worms and As, Cd and Cu in crabs and shrimp. Highest concentrations of Zn were measured in the kidney of European smelt. In fish, for most of the metals, the concentrations were highest in liver or kidney and lowest in muscle. For Zn however, highest concentrations were measured in the kidney of European smelt. For less than half of the metals significant correlations between sediment metal concentrations and bioaccumulated concentrations were found (liver/hepatopancreas or whole organism). To calculate the possible human health risk by consumption, average and maximum metal concentrations in the muscle tissues were compared to the minimum risk levels (MRLs). Concentrations of As led to the highest risk potential for all consumable species. Cadmium and Cu posed only a risk when consuming the highest contaminated shrimp and shore crabs. Consuming blue mussel could result in a risk for the metals As, Cd and Cr. Copyright © 2017 Elsevier Ltd. All rights reserved.

Repurposing salicylanilide anthelmintic drugs to combat drug resistant Staphylococcus aureus.

Science.gov (United States)

Rajamuthiah, Rajmohan; Fuchs, Beth Burgwyn; Conery, Annie L; Kim, Wooseong; Jayamani, Elamparithi; Kwon, Bumsup; Ausubel, Frederick M; Mylonakis, Eleftherios

2015-01-01

Staphylococcus aureus is a Gram-positive bacterium that has become the leading cause of hospital acquired infections in the US. Repurposing Food and Drug Administration (FDA) approved drugs for antimicrobial therapy involves lower risks and costs compared to de novo development of novel antimicrobial agents. In this study, we examined the antimicrobial properties of two commercially available anthelmintic drugs. The FDA approved drug niclosamide and the veterinary drug oxyclozanide displayed strong in vivo and in vitro activity against methicillin resistant S. aureus (minimum inhibitory concentration (MIC): 0.125 and 0.5 μg/ml respectively; minimum effective concentration: ≤ 0.78 μg/ml for both drugs). The two drugs were also effective against another Gram-positive bacteria Enterococcus faecium (MIC 0.25 and 2 μg/ml respectively), but not against the Gram-negative species Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter aerogenes. The in vitro antimicrobial activity of niclosamide and oxyclozanide were determined against methicillin, vancomycin, linezolid or daptomycin resistant S. aureus clinical isolates, with MICs at 0.0625-0.5 and 0.125-2 μg/ml for niclosamide and oxyclozanide respectively. A time-kill study demonstrated that niclosamide is bacteriostatic, whereas oxyclozanide is bactericidal. Interestingly, oxyclozanide permeabilized the bacterial membrane but neither of the anthelmintic drugs exhibited demonstrable toxicity to sheep erythrocytes. Oxyclozanide was non-toxic to HepG2 human liver carcinoma cells within the range of its in vitro MICs but niclosamide displayed toxicity even at low concentrations. These data show that the salicylanilide anthelmintic drugs niclosamide and oxyclozanide are suitable candidates for mechanism of action studies and further clinical evaluation for treatment of staphylococcal infections.

Highest energy cosmic rays

International Nuclear Information System (INIS)

Nikolskij, S.

1984-01-01

Primary particles of cosmic radiation with highest energies cannot in view of their low intensity be recorded directly but for this purpose the phenomenon is used that these particles interact with nuclei in the atmosphere and give rise to what are known as extensive air showers. It was found that 40% of primary particles with an energy of 10 15 to 10 16 eV consist of protons, 12 to 15% of helium nuclei, 15% of iron nuclei, the rest of nuclei of other elements. Radiation intensity with an energy of 10 18 to 10 19 eV depends on the direction of incoming particles. Maximum intensity is in the direction of the centre of the nearest clustre of galaxies, minimal in the direction of the central area of our galaxy. (Ha)

Gentamicin concentration gradients in scala tympani perilymph following systemic applications.

Science.gov (United States)

Hahn, Hartmut; Salt, Alec N; Schumacher, Ulrike; Plontke, Stefan K

2013-01-01

It has been shown in prior studies that round window membrane (RWM) application of gentamicin produced a robust basal-apical concentration gradient in the perilymph of scala tympani (ST) with peak concentrations in the basal turn of ST. These gradients potentially contribute to the clinical efficacy and safety of intratympanic gentamicin applications for the treatment of Ménière's disease. The present study aimed to establish the distribution of gentamicin along ST perilymph after systemic applications. Gentamicin sulfate was applied intravenously in the amounts of 100, 300 and 600 mg/kg body weight (BW) over a period of 3 h or as a 300 mg/kg BW subcutaneous bolus injection. At 3 and 5 h after the start of the application perilymph of ST was aspirated from the cochlea apex of the right and left cochlea, respectively, and 10 sequential 1-µl perilymph samples from the apex of each cochlea were quantitatively analyzed using a fluorescence polarization immunoassay. In contrast to local RWM delivery, systemic application of gentamicin resulted in the highest perilymph levels in the apex of the cochlea with decreasing concentrations towards the basal regions of ST. The absolute gentamicin concentrations increased with the amount of drug applied and time before sampling. While it is likely that the basal-apical gradient measured after local drug applications to the round window niche is the result of the direct uptake of drugs into the perilymph of the ST, distribution by diffusion and a very low perilymph flow towards the cochlear apex, computer simulations suggested that the apical-basal gradient observed with these systemic applications can be explained by higher entry rates of gentamicin in the apex compared to the basal turns of the cochlea. It is also possible that gentamicin enters perilymph indirectly from the blood via the endolymph. In this case the faster kinetics in apical turns could be due to the smaller cross-sectional area of ST relative to endolymph in

Contamination profiles, mass loadings, and sewage epidemiology of neuropsychiatric and illicit drugs in wastewater and river waters from a community in the Midwestern United States.

Science.gov (United States)

Skees, Allie J; Foppe, Katelyn S; Loganathan, Bommanna; Subedi, Bikram

2018-08-01

In this study, residues of the neuropsychiatric and illicit drugs including stimulants, opioids, hallucinogens, antischizophrenics, sedatives, and antidepressants were determined in influent and effluent samples from a small wastewater treatment plant, a receiving creek, and river waters in the Four Rivers region of the Midwestern United States. Nineteen neuropsychiatric drugs, eight illicit drugs, and three metabolites of illicit drugs were detected and quantitated in the water samples using HPLC-MS/MS. Residual concentrations of the drugs varied from below the detection limit to sub-μg/L levels. The source of residual cocaine and benzoylecgonine in wastewater is primarily from human consumption of cocaine rather than direct disposal. Wastewater based epidemiology is utilized to estimate the community usage of drugs based on the concentration of drug residues in wastewater, wastewater inflow, and the population served by the centralized wastewater treatment plant. The per-capita consumption rate of methamphetamine (1740 mg/d/1000 people) and amphetamine (970 mg/d/1000 people) found in this study were the highest reported per-capita consumption rates in the USA. Antidepressant venlafaxine found to have the highest environmental emission from the WWTP (333 ± 160 mg/d/1000 people) followed by citalopram (132 ± 60.2 mg/d/1000 people), methamphetamine (111 ± 43.6 mg/d/1000 people), and hydrocodone (108 ± 90.1 mg/d/1000 people). Bee Creek, an immediate receiving water body, is found to be a source of several neuropsychiatric and illicit drugs including methamphetamine, methadone, alprazolam, oxazepam, temazepam, carbamazepine, venlafaxine, citalopram, sertraline, oxycodone, and hydrocodone (p < 0.036) in the Clarks River. Copyright © 2018 Elsevier B.V. All rights reserved.

ASSESSMENT OF PAHS AND SELECTED PESTICIDES IN SHALLOW GROUNDWATER IN THE HIGHEST PROTECTED AREAS IN THE OPOLE REGION, POLAND

Directory of Open Access Journals (Sweden)

Mariusz Głowacki

2014-04-01

Full Text Available The ground water quality was determined after the analyses of water samples from 18 wells. The wells were in the Groundwater Area with the Highest Protection (Triassic water, Opole region, Poland, rural build up. The water table level was low: 0.5 – 18.0 m below the ground surface level (except for one artesian well. The following parameters were determined: pH, EC, colour, ammonium, nitrite, nitrate, dissolved orthophosphate, total phosphorus, dissolved oxygen, BOD, COD-Mn, COD-Cr, humic substances, chloride, sulphate, total hardness, alkalinity, dry residue PAHs (16 compounds, pesticides (6 compounds, however, only selected data were presented in this paper. In all the analysed water samples chloro-organic pesticides were observed. The analysed water contained heptachlor in the highest concentrations of 15.97 mg/dm3. Good quality water must not include concentrations higher than 0.5 mg/dm3 of heptachlor. However, the concentration was circa 32 times higher than this value. The second pesticide determining poor water quality is dieldrin. This compound in the investigated groundwater was 1.94 mg/dm3 – 4 times higher than the limit for acceptable quality ground water. The concentration of pesticides also changed over the course of the research; the concentration in the analysed groundwater in the same well changed quite dramatically over a period of 1 year. Although PAHs and pesticides are potentially toxic for biological organisms they do exist in the environment as a product of the natural biological transformation of organic matter. The noted concentrations and compositions of PAH compounds were different to natural PAHs. It confirms the fact that agricultural activity influences groundwater quality.

“Time for dabs”: Analyzing Twitter data on marijuana concentrates across the U.S.

Science.gov (United States)

Daniulaityte, Raminta; Nahhas, Ramzi W.; Wijeratne, Sanjaya; Carlson, Robert G.; Lamy, Francois R.; Martins, Silvia S.; Boyer, Edward W.; Smith, G. Alan; Sheth, Amit

2015-01-01

Aims Media reports suggest increasing popularity of marijuana concentrates (“dabs”; “earwax”; “budder”; “shatter; “butane hash oil”) that are typically vaporized and inhaled via a bong, vaporizer or electronic cigarette. However, data on the epidemiology of marijuana concentrate use remain limited. This study aims to explore Twitter data on marijuana concentrate use in the U.S. and identify differences across regions of the country with varying cannabis legalization policies. Methods Tweets were collected between October 20 and December 20, 2014, using Twitter's streaming API. Twitter data filtering framework was available through the eDrugTrends platform. Raw and adjusted percentages of dabs-related tweets per state were calculated. A permutation test was used to examine differences in the adjusted percentages of dabs-related tweets among U.S. states with different cannabis legalization policies. Results eDrugTrends collected a total of 125,255 tweets. Almost 22% (n=27,018) of these tweets contained identifiable state-level geolocation information. Dabs-related tweet volume for each state was adjusted using a general sample of tweets to account for different levels of overall tweeting activity for each state. Adjusted percentages of dabs-related tweets were highest in states that allowed recreational and/or medicinal cannabis use and lowest in states that have not passed medical cannabis use laws. The differences were statistically significant. Conclusions Twitter data suggest greater popularity of dabs in the states that legalized recreational and/or medical use of cannabis. The study provides new information on the epidemiology of marijuana concentrate use and contributes to the emerging field of social media analysis for drug abuse research. PMID:26338481

Application of X-ray microanalysis to the study of drug uptake in cell culture

International Nuclear Information System (INIS)

Reasor, M.J.; Lee, P.; Kirk, R.G.

1990-01-01

X-ray microanalysis has been used previously to study the accumulation of iodine in alveolar macrophages of rats treated with the iodinated drug, amiodarone. Due to metabolism of the drug in vivo, primarily to desethylamiodarone, it was not possible to identify the source of the iodine signal. In the present study we have utilized primary cell cultures of alveolar macrophages to study the intracellular accumulation of each of these drug species in vitro. Neither drug is metabolized by these cells in culture, permitting characterization of the accumulation of each independent of the other. Cells were incubated with equimolar concentrations of either amiodarone or desethylamiodarone for 42 hr, and X-ray microanalysis of freeze-dried cryosections of cells was used to quantify accumulation by monitoring the iodine signal associated with each drug. For both drug exposures, the highest iodine content was present in amorphous bodies and dense granules, consistent with the pattern following in vivo exposure. Higher levels of desethylamiodarone, compared to amiodarone, were measured in all compartments of the cells. The results of the in vitro investigation further demonstrate the utility of X-ray microanalysis in the study of the cellular response to amiodarone and desethylamiodarone

Comparison of concentrations of drugs between blood samples with and without fluoride additive-important findings for Δ9-tetrahydrocannabinol and amphetamine.

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Wiedfeld, Christopher; Krueger, Julia; Skopp, Gisela; Musshoff, Frank

2018-02-17

Fluoride is a common stabilizing agent in forensic toxicology to avoid the frequent problem of degradation of drugs in blood samples especially described for cocaine. In cases only samples with addition of fluoride are available, it is a crucial question if also concentrations of common drugs other than cocaine (amphetamines, opiates and cannabinoids) are affected by fluoride. So far, there are only rare literature data available on discrepant results especially for Δ 9 -tetrahydrocannabinol (THC). In this study, comparative analysis of positive tested paired routine plasma/serum samples (n = 375), collected at the same time point (one device with and one without fluoride), was carried out with special focus on cannabinoids. Samples were measured with validated routine liquid chromatography-tandem mass spectrometry methods for THC, 11-hydroxy-THC (THC-OH), 11-nor-9-carboxy-THC (THC-COOH), cocaine, benzoylecgonine, ecgonine methyl ester, morphine, codeine, amphetamine, methamphetamine, 3,4-methylenedioxymethamphetamine, 3,4-methylenedioxyamphetamine, and 3,4-methylenedioxyethylamphetamine, and results were statistically evaluated. Beside the expected stabilization effect on cocaine and the consequently reduced concentration of ecgonine methyl ester in fluoride samples, benzoylecgonine was elevated compared to respective samples without fluoride. Most importantly, new findings were significantly reduced mean concentrations of THC (- 17%), THC-OH (- 17%), and THC-COOH (- 22%) in fluoride samples. Mean amphetamine concentration was significantly higher in samples with the additive (+ 6%). For the other amphetamine type of drugs as well as for morphine and codeine, no significant differences could be seen. Whenever specified thresholds have been set, such as in most European countries, the use of different blood sample systems may result in a motorist being differently charged or prosecuted. The findings will support forensic toxicologists at the

Registration for public drug benefits across areas of differing ethnic composition in British Columbia, Canada

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Wong Sabrina T

2010-06-01

Full Text Available Abstract Background In 2003, the government of British Columbia, Canada introduced a universal drug benefit plan to cover drug costs that are high relative to household income. Residents were required to register in order to be eligible for the income-based benefits. Given past research suggesting that registration processes may pose an access barrier to certain subpopulations, we aimed to determine whether registration rates varied across small geographic areas that differed in ethnic composition. Methods Using linked population-based administrative databases and census data, we conducted multivariate logistic regression analyses to determine whether the probability of registration for the public drug plan varied across areas of differing ethnic composition, controlling for household-level predisposing, enabling and needs factors. Results The adjusted odds of registration did not differ across regions characterized by high concentrations (greater than 30% of residents identifying as North American, British, French or other European. Households located in areas with concentrations of residents identifying as an Asian ethnicity had the highest odds of program registration: Chinese (OR = 1.21, CI: 1.19-1.23 and South Asian (OR = 1.19, CI: 1.16-1.22. Despite this positive finding, households residing in areas with relatively high concentrations of recent immigrants had slightly lower adjusted odds of registering for the program (OR = 0.97, CI: 0.95-0.98. Conclusions This study identified ethnic variation in registration for a new public drug benefit program in British Columbia. However, unlike previous studies, the variation observed did not indicate that areas with high concentrations of certain ethnicities experienced disadvantages. Potential explanations are discussed.

Epidemics of HIV, HCV and syphilis infection among synthetic drugs only users, heroin-only users and poly-drug users in Southwest China.

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Su, Shu; Mao, Limin; Zhao, Jinxian; Chen, Liang; Jing, Jun; Cheng, Feng; Zhang, Lei

2018-04-26

The number of poly-drug users who mix use heroin and synthetic drugs (SD) is increasing worldwide. The objective of this study is to measure the risk factors for being infected with hepatitis C (HCV), human immunodeficiency virus (HIV) and syphilis among SD-only users, heroin-only users and poly-drug users. A cross-sectional study was conducted in 2015 from a national HIV surveillance site in Southwest China, 447 poly-drug, 526 SD-only and 318 heroin-only users were recruited. Poly-drug users have higher drug-use frequency, higher rates of drug-sharing and unsafe sexual acts than other users (p users experienced sexual arousal due to drug effects, which is higher than the rate among other drug users. Poly-drug users had the highest prevalence of HIV (10.5%) and syphilis (3.6%), but heroin-only users had the highest prevalence of HCV (66.0%) (all p users, having sex following drug consumption and using drugs ≥1/day were the major risk factors for both HIV (Adjusted odds ratio (AOR) = 2.4, 95% CI [1.8-3.4]; 2.3, [1.6-3.1]) and syphilis infection (AOR = 4.1, [2.1-6.9]; 3.9, [1.8-5.4]). Elevated risk of both HIV and syphilis infection have been established among poly-drug users.

Comparison of direct sampling and brochoalveolar lavage for determining active drug concentrations in the pulmonary epithelial lining fluid of calves injected with enrofloxacin or tilmicosin.

Science.gov (United States)

Foster, D M; Sylvester, H J; Papich, M G

2017-12-01

Antibiotic distribution to interstitial fluid (ISF) and pulmonary epithelial fluid (PELF) was measured and compared to plasma drug concentrations in eight healthy calves. Enrofloxacin (Baytril ® 100) was administered at a dose of 12.5 mg/kg subcutaneously (SC), and tilmicosin (Micotil ® 300) was administered at a dose of 20 mg/kg SC. PELF, sampled by two different methods-bronchoalveolar lavage (BAL) and direct sampling (DS)-plasma, and ISF were collected from each calf and measured for tilmicosin, enrofloxacin and its metabolite ciprofloxacin by HPLC. Pharmacokinetic analysis was performed on the concentrations in each fluid, for each drug. The enrofloxacin/ciprofloxacin concentration as measured by AUC in DS samples was 137 ± 72% higher than in plasma, but in BAL samples, this value was 535 ± 403% (p enrofloxacin/ciprofloxacin concentrations collected by DS were significantly different than those collected by BAL, but the tilmicosin concentrations were not significantly different between the two methods. Concentrations of enrofloxacin/ciprofloxacin exceeded the MIC values for bovine respiratory disease pathogens but tilmicosin did not reach MIC levels for these pathogens in any fluids. © 2017 John Wiley & Sons Ltd.

Comparison of Plasma, Saliva, and Hair Levetiracetam Concentrations.

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Karaś-Ruszczyk, Katarzyna; Kuczyńska, Julita; Sienkiewicz-Jarosz, Halina; Kurkowska-Jastrzębska, Iwona; Bienkowski, Przemyslaw; Restel, Magdalena; Samochowiec, Jerzy; Mierzejewski, Pawel

2017-06-01

Previous findings revealed high correlations between serum/plasma and saliva levetiracetam concentrations, indicating saliva as an alternative matrix for monitoring levetiracetam therapy. Levetiracetam concentration in the hair, which could reflect long-term drug exposure and patients' compliance, has not been systematically tested, as yet. The aim of this study was to determine the correlation between plasma, saliva, and hair levetiracetam concentrations in 47 patients with epilepsy. Plasma, saliva, and hair levetiracetam concentrations were measured by liquid chromatography-tandem mass spectrometry with positive ionization. Levetiracetam saliva and plasma concentrations were highly correlated (r = 0.93). Plasma concentrations were not influenced by sex, age, and other concomitant antiepileptic drugs. Levetiracetam hair concentrations correlated with plasma concentrations (r = 0.36) but not daily dose (mg/kg). Drug hair concentrations were not influenced by hair color or treatment (dyed). The results tend to indicate that saliva may be a reliable alternative to plasma for monitoring levetiracetam concentrations. Levetiracetam can also be detected in human hair.

Differential mechanism of Escherichia coli Inactivation by (+)-limonene as a function of cell physiological state and drug's concentration.

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Chueca, Beatriz; Pagán, Rafael; García-Gonzalo, Diego

2014-01-01

(+)-limonene is a lipophilic antimicrobial compound, extracted from citrus fruits' essential oils, that is used as a flavouring agent and organic solvent by the food industry. A recent study has proposed a common and controversial mechanism of cell death for bactericidal antibiotics, in which hydroxyl radicals ultimately inactivated cells. Our objective was to determine whether the mechanism of Escherichia coli MG1655 inactivation by (+)-limonene follows that of bactericidal antibiotics. A treatment with 2,000 μL/L (+)-limonene inactivated 4 log10 cycles of exponentially growing E. coli cells in 3 hours. On one hand, an increase of cell survival in the ΔacnB mutant (deficient in a TCA cycle enzyme), or in the presence of 2,2'-dipyridyl (inhibitor of Fenton reaction by iron chelation), thiourea, or cysteamine (hydroxyl radical scavengers) was observed. Moreover, the ΔrecA mutant (deficient in an enzyme involved in SOS response to DNA damage) was more sensitive to (+)-limonene. Thus, this indirect evidence indicates that the mechanism of exponentially growing E. coli cells inactivation by 2,000 μL/L (+)-limonene is due to the TCA cycle and Fenton-mediated hydroxyl radical formation that caused oxidative DNA damage, as observed for bactericidal drugs. However, several differences have been observed between the proposed mechanism for bactericidal drugs and for (+)-limonene. In this regard, our results demonstrated that E. coli inactivation was influenced by its physiological state and the drug's concentration: experiments with stationary-phase cells or 4,000 μL/L (+)-limonene uncovered a different mechanism of cell death, likely unrelated to hydroxyl radicals. Our research has also shown that drug's concentration is an important factor influencing the mechanism of bacterial inactivation by antibiotics, such as kanamycin. These results might help in improving and spreading the use of (+)-limonene as an antimicrobial compound, and in clarifying the controversy about

Dissolved Platinum Concentrations in Coastal Seawater: Boso to Sanriku Areas, Japan.

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Mashio, Asami Suzuki; Obata, Hajime; Gamo, Toshitaka

2017-08-01

Platinum, one of the rarest elements in the earth's crust, is now widely used in a range of products, such as catalytic converters in automobiles and anticancer drugs. Increasing use and dispersal of platinum has the potential to affect aquatic environments. Platinum concentrations in open ocean seawater have been found to be very low (approximately 0.2 pmol/L); however, Pt distributions and biogeochemical cycles in coastal areas are unknown. In this study, we investigated Pt concentrations in coastal waters between the Boso and Sanriku areas, Japan, after the 2011 tsunami. We determined sub-picomolar levels of dissolved Pt using isotope-dilution Inductively coupled plasma mass spectrometry after column preconcentration with an anion exchange resin. Dissolved Pt concentrations were found to be in the range 0.20-1.5 pmol/L, with the highest concentration in bottom water of the Boso coastal area, and at stations close to Tokyo Bay. Assuming thermodynamical equilibrium, Pt was determined to be present in the form PtCl 5 (OH) 2- , even in low-oxygen coastal waters. Vertical profiles indicated Pt levels increased toward seafloors near coastal stations and were similar to those of the open ocean at trench stations. High concentrations of dissolved Pt are thought to be derived from coastal sediments.

Increased Risk of Drug-Induced Hyponatremia during High Temperatures

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Anna K Jönsson

2017-07-01

Full Text Available Purpose: To investigate the relationship between outdoor temperature in Sweden and the reporting of drug-induced hyponatremia to the Medical Products Agency (MPA. Methods: All individual adverse drug reactions (ADR reported to MPA from 1 January 2010 to 31 October 2013 of suspected drug-induced hyponatremia and random controls were identified. Reports where the ADR had been assessed as having at least a possible relation to the suspected drug were included. Information on administered drugs, onset date, causality assessment, sodium levels, and the geographical origin of the reports was extracted. A case-crossover design was used to ascertain the association between heat exposure and drug-induced hyponatremia at the individual level, while linear regression was used to study its relationship to sodium concentration in blood. Temperature exposure data were obtained from the nearest observation station to the reported cases. Results: During the study period, 280 reports of hyponatremia were identified. More cases of drug-induced hyponatremia were reported in the warmer season, with a peak in June, while other ADRs showed an opposite annual pattern. The distributed lag non-linear model indicated an increasing odds ratio (OR with increasing temperature in the warm season with a highest odds ratio, with delays of 1–5 days after heat exposure. A cumulative OR for a lag time of 1 to 3 days was estimated at 2.21 at an average daily temperature of 20 °C. The change in sodium per 1 °C increase in temperature was estimated to be −0.37 mmol/L (95% CI: −0.02, −0.72. Conclusions: Warm weather appears to increase the risk of drug-induced hyponatremia

Effect of intravenous drug administration mode on drug distribution in a tumor slab: a finite Fourier transform analysis.

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Subramaniam, B; Claudius, J S

1990-03-08

Cancer therapy using chemotherapeutic drugs frequently involves injection of the drug into the body through some intravenous mode of administration, viz, continuous (drip) infusion or single/multiple bolus injection(s). An understanding of the effect of the various modes of administration upon tumor penetration of drug is essential to rational design of drug therapy. This paper investigates drug penetration into a model tumor of slab geometry (between two capillaries) in which the overall transport rate of drug is limited by intra-tumor transport characterized by an effective diffusion coefficient. Employing the method of Finite Fourier Transforms (FFT), analytical solutions have been obtained for transient drug distribution in both the plasma and the tumor following three modes of administration, viz, continuous infusion, single bolus injection and equally-spaced equal-dose multiple bolus injections, of a given amount of drug. The qualitative trends exhibited by the plasma drug distribution profiles are consistent with reported experimental studies. Two concepts, viz, the dimensionless decay constant and the plasma/tumor drug concentration trajectories, are found to be particularly useful in the rational design of drug therapy. The dimensionless decay constant provides a measure of the rate of drug decay in the plasma relative to the rate of drug diffusion into the tumor and is thus characteristic of the tumor/drug system. The magnitude of this parameter dictates the choice of drug administration mode for minimizing drug decay in the plasma while simultaneously maximizing drug transport into the tumor. The concentration trajectories provide a measure of the plasma drug concentration relative to the tumor drug concentration at various times following injection. When the tumor drug concentration exceeds the plasma drug concentration, the drug will begin to diffuse out of the tumor. Knowledge of the time at which this diffusion reversal occurs is especially useful

Acyclic cucurbit[n]uril-type molecular containers: influence of aromatic walls on their function as solubilizing excipients for insoluble drugs.

Science.gov (United States)

Zhang, Ben; Isaacs, Lyle

2014-11-26

We studied the influence of the aromatic sidewalls on the ability of acyclic CB[n]-type molecular containers (1a-1e) to act as solubilizing agents for 19 insoluble drugs including the developmental anticancer agent PBS-1086. All five containers exhibit good water solubility and weak self-association (Ks ≤ 624 M(-1)). We constructed phase solubility diagrams to extract Krel and Ka values for the container·drug complexes. The acyclic CB[n]-type containers generally display significantly higher Ka values than HP-β-CD toward drugs. Containers 1a-1e bind the steroidal ring system and aromatic moieties of insoluble drugs. Compound 1b displays highest affinity toward most of the drugs studied. Containers 1a and 1b are broadly applicable and can be used to formulate a wider variety of insoluble drugs than was previously possible with cyclodextrin technology. For drugs that are solubilized by both HP-β-CD and 1a-1e, lower concentrations of 1a-1e are required to achieve identical [drug].

Extent of Drug Coverage across Generic Drug Discount Programs offered by Community Pharmacies: A look at five Chronic Conditions

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Harshali K. Patel, MS

2012-01-01

Full Text Available Background: Chronic conditions are expensive to treat because of the ongoing prescription cost burden. Generic drug discount programs (GDDPs that offer generics at discounted price may prove beneficial to reduce pharmacy costs for the same.Objective: The objective of this study was to assess the extent to which GDDPs provide drug coverage for five common chronic conditions.Methods: A content analyses of preexisting information was conducted. Extent of coverage based on top 200 generic drugs prescribed during 2008 for the treatment of chronic conditions such as hypertension, mental disorders, arthritis, pulmonary/respiratory conditions, and diabetes were identified. Commonly prescribed medications for these diseases were identified using published peer reviewed clinical guidelines. List of drugs covered under a GDDP for stores, Wal-Mart, Walgreens, CVS, Kroger, HEB, Target, and Randalls were obtained and compared to assess drug coverage by retail dollar sales and sales volume. Descriptive statistics and frequency/percentage of coverage were reported using SAS 9.2.Results: GDDPs covered the highest number of drugs for hypertension (21-27 across different GDDPs and the least (3-5 across different GDDPs for pulmonary/respiratory conditions. Arthritis (5-11, mental disorders (6-11 and diabetes (5-7 had similar coverage. When compared to the top 200 drugs by retail dollars spent during 2008, hypertension (68%-87% and diabetes (63%-88% had the highest coverage followed by respiratory conditions (30%-50%, arthritis (22%-48%, and mental disorders (21%-38%. Similar result was obtained when GDDP coverage was compared with the top 200 generic drugs by sales volume, where diabetes (63-88% and hypertension (57%-74% had the highest coverage and mental disorders remained the lowest (23%-37%.Conclusion/Implications: Drug coverage in GDDPs varied by pharmacies across the five common chronic conditions evaluated which may limit accessibility of these programs for

Relation between CYP2D6 Genotype, Phenotype and Therapeutic Drug Concentrations among Nortriptyline and Venlafaxine Users in Old Age Psychiatry

NARCIS (Netherlands)

Berm, E; Kok, R.; Hak, E; Wilffert, B

2016-01-01

Objectives: To determine relations between drug concentrations and the cytochrome P450-CYP2D6 genotype or phenotype among elderly patients treated with nortriptyline or venlafaxine. Methods: A post-hoc analysis of a clinical trial was performed. Patients were grouped into phenotypes according to the

Optimization of Drug Delivery by Drug-Eluting Stents.

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Franz Bozsak

Full Text Available Drug-eluting stents (DES, which release anti-proliferative drugs into the arterial wall in a controlled manner, have drastically reduced the rate of in-stent restenosis and revolutionized the treatment of atherosclerosis. However, late stent thrombosis remains a safety concern in DES, mainly due to delayed healing of the endothelial wound inflicted during DES implantation. We present a framework to optimize DES design such that restenosis is inhibited without affecting the endothelial healing process. To this end, we have developed a computational model of fluid flow and drug transport in stented arteries and have used this model to establish a metric for quantifying DES performance. The model takes into account the multi-layered structure of the arterial wall and incorporates a reversible binding model to describe drug interaction with the cells of the arterial wall. The model is coupled to a novel optimization algorithm that allows identification of optimal DES designs. We show that optimizing the period of drug release from DES and the initial drug concentration within the coating has a drastic effect on DES performance. Paclitaxel-eluting stents perform optimally by releasing their drug either very rapidly (within a few hours or very slowly (over periods of several months up to one year at concentrations considerably lower than current DES. In contrast, sirolimus-eluting stents perform optimally only when drug release is slow. The results offer explanations for recent trends in the development of DES and demonstrate the potential for large improvements in DES design relative to the current state of commercial devices.

Pharmacokinetic-Pharmacodynamic (PKPD) Analysis with Drug Discrimination.

Science.gov (United States)

Negus, S Stevens; Banks, Matthew L

2016-08-30

Discriminative stimulus and other drug effects are determined by the concentration of drug at its target receptor and by the pharmacodynamic consequences of drug-receptor interaction. For in vivo procedures such as drug discrimination, drug concentration at receptors in a given anatomical location (e.g., the brain) is determined both by the dose of drug administered and by pharmacokinetic processes of absorption, distribution, metabolism, and excretion that deliver drug to and from that anatomical location. Drug discrimination data are often analyzed by strategies of dose-effect analysis to determine parameters such as potency and efficacy. Pharmacokinetic-Pharmacodynamic (PKPD) analysis is an alternative to conventional dose-effect analysis, and it relates drug effects to a measure of drug concentration in a body compartment (e.g., venous blood) rather than to drug dose. PKPD analysis can yield insights on pharmacokinetic and pharmacodynamic determinants of drug action. PKPD analysis can also facilitate translational research by identifying species differences in pharmacokinetics and providing a basis for integrating these differences into interpretation of drug effects. Examples are discussed here to illustrate the application of PKPD analysis to the evaluation of drug effects in rhesus monkeys trained to discriminate cocaine from saline.

Toward the establishment of standardized in vitro tests for lipid-based formulations. 2. The effect of bile salt concentration and drug loading on the performance of type I, II, IIIA, IIIB, and IV formulations during in vitro digestion.

Science.gov (United States)

Williams, Hywel D; Anby, Mette U; Sassene, Philip; Kleberg, Karen; Bakala-N'Goma, Jean-Claude; Calderone, Marilyn; Jannin, Vincent; Igonin, Annabel; Partheil, Anette; Marchaud, Delphine; Jule, Eduardo; Vertommen, Jan; Maio, Mario; Blundell, Ross; Benameur, Hassan; Carrière, Frédéric; Müllertz, Anette; Pouton, Colin W; Porter, Christopher J H

2012-11-05

The LFCS Consortium was established to develop standardized in vitro tests for lipid-based formulations (LBFs) and to examine the utility of these tests to probe the fundamental mechanisms that underlie LBF performance. In this publication, the impact of bile salt (sodium taurodeoxycholate, NaTDC) concentration and drug loading on the ability of a range of representative LBFs to generate and sustain drug solubilization and supersaturation during in vitro digestion testing has been explored and a common driver of the potential for drug precipitation identified. Danazol was used as a model poorly water-soluble drug throughout. In general, increasing NaTDC concentrations increased the digestion of the most lipophilic LBFs and promoted lipid (and drug) trafficking from poorly dispersed oil phases to the aqueous colloidal phase (AP(DIGEST)). High NaTDC concentrations showed some capacity to reduce drug precipitation, although, at NaTDC concentrations ≥3 mM, NaTDC effects on either digestion or drug solubilization were modest. In contrast, increasing drug load had a marked impact on drug solubilization. For LBFs containing long-chain lipids, drug precipitation was limited even at drug loads approaching saturation in the formulation and concentrations of solubilized drug in AP(DIGEST) increased with increased drug load. For LBFs containing medium-chain lipids, however, significant precipitation was evident, especially at higher drug loads. Across all formulations a remarkably consistent trend emerged such that the likelihood of precipitation was almost entirely dependent on the maximum supersaturation ratio (SR(M)) attained on initiation of digestion. SR(M) defines the supersaturation "pressure" in the system and is calculated from the maximum attainable concentration in the AP(DIGEST) (assuming zero precipitation), divided by the solubility of the drug in the colloidal phases formed post digestion. For LBFs where phase separation of oil phases did not occur, a

Vaginal drug distribution modeling.

Science.gov (United States)

Katz, David F; Yuan, Andrew; Gao, Yajing

2015-09-15

This review presents and applies fundamental mass transport theory describing the diffusion and convection driven mass transport of drugs to the vaginal environment. It considers sources of variability in the predictions of the models. It illustrates use of model predictions of microbicide drug concentration distribution (pharmacokinetics) to gain insights about drug effectiveness in preventing HIV infection (pharmacodynamics). The modeling compares vaginal drug distributions after different gel dosage regimens, and it evaluates consequences of changes in gel viscosity due to aging. It compares vaginal mucosal concentration distributions of drugs delivered by gels vs. intravaginal rings. Finally, the modeling approach is used to compare vaginal drug distributions across species with differing vaginal dimensions. Deterministic models of drug mass transport into and throughout the vaginal environment can provide critical insights about the mechanisms and determinants of such transport. This knowledge, and the methodology that obtains it, can be applied and translated to multiple applications, involving the scientific underpinnings of vaginal drug distribution and the performance evaluation and design of products, and their dosage regimens, that achieve it. Copyright © 2015 Elsevier B.V. All rights reserved.

Update on HIV-1 acquired and transmitted drug resistance in Africa.

Science.gov (United States)

Ssemwanga, Deogratius; Lihana, Raphael W; Ugoji, Chinenye; Abimiku, Alash'le; Nkengasong, John; Dakum, Patrick; Ndembi, Nicaise

2015-01-01

The last ten years have witnessed a significant scale-up and access to antiretroviral therapy in Africa, which has improved patient quality of life and survival. One major challenge associated with increased access to antiretroviral therapy is the development of antiretroviral resistance due to inconsistent drug supply and/or poor patient adherence. We review the current state of both acquired and transmitted drug resistance in Africa over the past ten years (2001-2011) to identify drug resistance associated with the different drug regimens used on the continent and to help guide affordable strategies for drug resistance surveillance. A total of 161 references (153 articles, six reports and two conference abstracts) were reviewed. Antiretroviral resistance data was available for 40 of 53 African countries. A total of 5,541 adult patients from 99 studies in Africa were included in this analysis. The pooled prevalence of drug resistance mutations in Africa was 10.6%, and Central Africa had the highest prevalence of 54.9%. The highest prevalence of nucleoside reverse transcriptase inhibitor mutations was in the west (55.3%) and central (54.8%) areas; nonnucleoside reverse transcriptase inhibitor mutations were highest in East Africa (57.0%) and protease inhibitors mutations highest in Southern Africa (16.3%). The major nucleoside reverse transcriptase inhibitor mutation in all four African regions was M184V. Major nonnucleoside reverse transcriptase inhibitor as well as protease inhibitor mutations varied by region. The prevalence of drug resistance has remained low in several African countries although the emergence of drug resistance mutations varied across countries. Continued surveillance of antiretroviral therapy resistance remains crucial in gauging the effectiveness of country antiretroviral therapy programs and strategizing on effective and affordable strategies for successful treatment.

Sonophoresis Using Ultrasound Contrast Agents: Dependence on Concentration.

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Donghee Park

Full Text Available Sonophoresis can increase skin permeability to various drugs in transdermal drug delivery. Cavitation is recognized as the predominant mechanism of sonophoresis. Recently, a new logical approach to enhance the efficiency of transdermal drug delivery was tried. It is to utilize the engineered microbubble and its resonant frequency for increase of cavitation activity. Actively-induced cavitation with low-intensity ultrasound (less than ~1 MPa causes disordering of the lipid bilayers and the formation of aqueous channels by stable cavitation which indicates a continuous oscillation of bubbles. Furthermore, the mutual interactions of microbubble determined by concentration of added bubble are also thought to be an important factor for activity of stable cavitation, even in different characteristics of drug. In the present study, we addressed the dependence of ultrasound contrast agent concentration using two types of drug on the efficiency of transdermal drug delivery. Two types of experiment were designed to quantitatively evaluate the efficiency of transdermal drug delivery according to ultrasound contrast agent concentration. First, an experiment of optical clearing using a tissue optical clearing agent was designed to assess the efficiency of sonophoresis with ultrasound contrast agents. Second, a Franz diffusion cell with ferulic acid was used to quantitatively determine the amount of drug delivered to the skin sample by sonophoresis with ultrasound contrast agents. The maximum enhancement ratio of sonophoresis with a concentration of 1:1,000 was approximately 3.1 times greater than that in the ultrasound group without ultrasound contrast agent and approximately 7.5 times greater than that in the control group. These results support our hypothesis that sonophoresis becomes more effective in transdermal drug delivery due to the presence of engineered bubbles, and that the efficiency of transdermal drug delivery using sonophoresis with

Sonophoresis Using Ultrasound Contrast Agents: Dependence on Concentration.

Science.gov (United States)

Park, Donghee; Song, Gillsoo; Jo, Yongjun; Won, Jongho; Son, Taeyoon; Cha, Ohrum; Kim, Jinho; Jung, Byungjo; Park, Hyunjin; Kim, Chul-Woo; Seo, Jongbum

2016-01-01

Sonophoresis can increase skin permeability to various drugs in transdermal drug delivery. Cavitation is recognized as the predominant mechanism of sonophoresis. Recently, a new logical approach to enhance the efficiency of transdermal drug delivery was tried. It is to utilize the engineered microbubble and its resonant frequency for increase of cavitation activity. Actively-induced cavitation with low-intensity ultrasound (less than ~1 MPa) causes disordering of the lipid bilayers and the formation of aqueous channels by stable cavitation which indicates a continuous oscillation of bubbles. Furthermore, the mutual interactions of microbubble determined by concentration of added bubble are also thought to be an important factor for activity of stable cavitation, even in different characteristics of drug. In the present study, we addressed the dependence of ultrasound contrast agent concentration using two types of drug on the efficiency of transdermal drug delivery. Two types of experiment were designed to quantitatively evaluate the efficiency of transdermal drug delivery according to ultrasound contrast agent concentration. First, an experiment of optical clearing using a tissue optical clearing agent was designed to assess the efficiency of sonophoresis with ultrasound contrast agents. Second, a Franz diffusion cell with ferulic acid was used to quantitatively determine the amount of drug delivered to the skin sample by sonophoresis with ultrasound contrast agents. The maximum enhancement ratio of sonophoresis with a concentration of 1:1,000 was approximately 3.1 times greater than that in the ultrasound group without ultrasound contrast agent and approximately 7.5 times greater than that in the control group. These results support our hypothesis that sonophoresis becomes more effective in transdermal drug delivery due to the presence of engineered bubbles, and that the efficiency of transdermal drug delivery using sonophoresis with microbubbles depends on the

Plasma drug concentrations and clinical effects of a peripheral alpha-2-adrenoceptor antagonist, MK-467, in horses sedated with detomidine.

Science.gov (United States)

Vainionpää, Mari H; Raekallio, Marja R; Pakkanen, Soile A E; Ranta-Panula, Ville; Rinne, Valtteri M; Scheinin, Mika; Vainio, Outi M

2013-05-01

To investigate plasma drug concentrations and the effect of MK-467 (L-659'066) on sedation, heart rate and gut motility in horses sedated with intravenous (IV) detomidine. Experimental randomized blinded crossover study. Six healthy horses. Detomidine (10 μg kg(-1) IV) was administered alone (DET) and in combination with MK-467 (250 μg kg(-1) IV; DET + MK). The level of sedation and intestinal sounds were scored. Heart rate (HR) and central venous pressure (CVP) were measured. Blood was collected to determine plasma drug concentrations. Repeated measures anova was used for HR, CVP and intestinal sounds, and the Student's t-test for pairwise comparisons between treatments for the area under the time-sedation curve (AUCsed ) and pharmacokinetic parameters. Significance was set at p Detomidine-induced intestinal hypomotility was prevented by MK-467. AUCsed was significantly higher with DET than DET + MK, but maximal sedations scores did not differ significantly between treatments. MK-467 lowered the AUC of the plasma concentration of detomidine, and increased its volume of distribution and clearance. MK-467 prevented detomidine induced bradycardia and intestinal hypomotility. MK-467 did not affect the clinical quality of detomidine-induced sedation, but the duration of the effect was reduced, which may have been caused by the effects of MK-467 on the plasma concentration of detomidine. MK-467 may be useful clinically in the prevention of certain peripheral side effects of detomidine in horses. © 2013 The Authors. Veterinary Anaesthesia and Analgesia © 2013 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia.

A REVIEW ON OSMOTIC DRUG DELIVERY SYSTEM

OpenAIRE

Harnish Patel; Upendra Patel; Hiren Kadikar; Bhavin Bhimani; Dhiren Daslaniya; Ghanshyam Patel

2012-01-01

Conventional oral drug delivery systems supply an instantaneous release of drug, which cannot control the release of the drug and effective concentration at the target site. This kind of dosing pattern may result in constantly changing, unpredictable plasma concentrations. Drugs can be delivered in a controlled pattern over a long period of time by the process of osmosis. Osmotic devices are the most promising strategy based systems for controlled drug delivery. They are the most reliable con...

Raltegravir cerebrospinal fluid concentrations in HIV-1 infection.

Directory of Open Access Journals (Sweden)

Aylin Yilmaz

2009-09-01

Full Text Available Raltegravir is an HIV-1 integrase inhibitor currently used in treatment-experienced HIV-1-infected patients resistant to other drug classes. In order to assess its central nervous system penetration, we measured raltegravir concentrations in cerebrospinal fluid (CSF and plasma in subjects receiving antiretroviral treatment regimens containing this drug.Raltegravir concentrations were determined by liquid chromatography tandem mass spectrometry in 25 paired CSF and plasma samples from 16 HIV-1-infected individuals. The lower limit of quantitation was 2.0 ng/ml for CSF and 10 ng/ml for plasma.Twenty-four of the 25 CSF samples had detectable raltegravir concentrations with a median raltegravir concentration of 18.4 ng/ml (range, <2.0-126.0. The median plasma raltegravir concentration was 448 ng/ml (range, 37-5180. CSF raltegravir concentrations correlated with CSF:plasma albumin ratios and CSF albumin concentrations.Approximately 50% of the CSF specimens exceeded the IC(95 levels reported to inhibit HIV-1 strains without resistance to integrase inhibitors. In addition to contributing to control of systemic HIV-1 infection, raltegravir achieves local inhibitory concentrations in CSF in most, but not all, patients. Blood-brain and blood-CSF barriers likely restrict drug entry, while enhanced permeability of these barriers enhances drug entry.

Raltegravir cerebrospinal fluid concentrations in HIV-1 infection.

Science.gov (United States)

Yilmaz, Aylin; Gisslén, Magnus; Spudich, Serena; Lee, Evelyn; Jayewardene, Anura; Aweeka, Francesca; Price, Richard W

2009-09-01

Raltegravir is an HIV-1 integrase inhibitor currently used in treatment-experienced HIV-1-infected patients resistant to other drug classes. In order to assess its central nervous system penetration, we measured raltegravir concentrations in cerebrospinal fluid (CSF) and plasma in subjects receiving antiretroviral treatment regimens containing this drug. Raltegravir concentrations were determined by liquid chromatography tandem mass spectrometry in 25 paired CSF and plasma samples from 16 HIV-1-infected individuals. The lower limit of quantitation was 2.0 ng/ml for CSF and 10 ng/ml for plasma. Twenty-four of the 25 CSF samples had detectable raltegravir concentrations with a median raltegravir concentration of 18.4 ng/ml (range, <2.0-126.0). The median plasma raltegravir concentration was 448 ng/ml (range, 37-5180). CSF raltegravir concentrations correlated with CSF:plasma albumin ratios and CSF albumin concentrations. Approximately 50% of the CSF specimens exceeded the IC(95) levels reported to inhibit HIV-1 strains without resistance to integrase inhibitors. In addition to contributing to control of systemic HIV-1 infection, raltegravir achieves local inhibitory concentrations in CSF in most, but not all, patients. Blood-brain and blood-CSF barriers likely restrict drug entry, while enhanced permeability of these barriers enhances drug entry.

Biodegradable drug-eluting nanofiber-enveloped implants for sustained release of high bactericidal concentrations of vancomycin and ceftazidime: in vitro and in vivo studies

Directory of Open Access Journals (Sweden)

Hsu YH

2014-09-01

Full Text Available Yung-Heng Hsu,1,2 Dave Wei-Chih Chen,1 Chun-Der Tai,3 Ying-Chao Chou,1,2 Shih-Jung Liu,2 Steve Wen-Neng Ueng,1 Err-Cheng Chan4 1Department of Orthopedic Surgery, Chang Gung Memorial Hospital, Guishan Township, 2Department of Mechanical Engineering, Chang Gung University, Guishan Township, 3Graduate Institute of Medical Mechatronics, Chang Gung University, Guishan Township, 4School of Medical Technology, Chang Gung University, Guishan Township, Taiwan Abstract: We developed biodegradable drug-eluting nanofiber-enveloped implants that provided sustained release of vancomycin and ceftazidime. To prepare the biodegradable nanofibrous membranes, poly(D,L-lactide-co-glycolide and the antibiotics were first dissolved in 1,1,1,3,3,3-hexafluoro-2-propanol. They were electrospun into biodegradable drug-eluting membranes, which were then enveloped on the surface of stainless plates. An elution method and a high-performance liquid chromatography assay were employed to characterize the in vivo and in vitro release rates of the antibiotics from the nanofiber-enveloped plates. The results showed that the biodegradable nanofiber-enveloped plates released high concentrations of vancomycin and ceftazidime (well above the minimum inhibitory concentration for more than 3 and 8 weeks in vitro and in vivo, respectively. A bacterial inhibition test was carried out to determine the relative activity of the released antibiotics. The bioactivity ranged from 25% to 100%. In addition, the serum creatinine level remained within the normal range, suggesting that the high vancomycin concentration did not affect renal function. By adopting the electrospinning technique, we will be able to manufacture biodegradable drug-eluting implants for the long-term drug delivery of different antibiotics. Keywords: biodegradable nanofiber-enveloped plates, electrospinning, antibiotics, release characteristics

Effects of Spray-Drying and Choice of Solid Carriers on Concentrations of Labrasol® and Transcutol® in Solid Self-Microemulsifying Drug Delivery Systems (SMEDDS

Directory of Open Access Journals (Sweden)

Christopher Wai-Kei Lam

2013-01-01

Full Text Available Solid self-microemulsifying drug delivery systems (SMEDDS have been used increasingly for improving the bioavailability of hydrophobic drugs. Labrasol® and Transcutol® are used widely as surfactant and solubilizer in the formulation of solid SMEDDS. We investigated the effects of spray-drying and the use of different solid carriers on concentrations of Labrasol® and Transcutol® in solid SMEDDS with scutellarin as the formulated drug. Liquid and gas chromatography tandem mass spectrometry (LC-MS and GC-MS methods were developed for measuring low concentrations of Labrasol® and Transcutol®. In the preparation of solid SMEDDS, lactose, hydroxypropylmethyl cellulose (HPMC and microcrystalline cellulose (MCC were used as solid carriers. Judging from the retention ratios of Labrasol® and Transcutol®, the droplet size of solid SMEDDS increased after spray-drying of liquid SMEDDS, and concentrations of these excipients decreased after the solidifying procedure. In such reduction, Lactose and HPMC were found to preserve Labrasol® and Transcutol® better than MCC during spray-drying, and the resultant droplet sizes were smaller than that of MCC. Labrasol® and Transcutol® showed good thermal stability at 60 °C degree for 10 days. It can be concluded that spray-drying could increase the droplet size of solid SMEDDS and decreased the concentration of Labrasol® and Transcutol® therein, while water-soluble solid carriers could preserve Labrasol® and Transcutol® better than insoluble carriers in the solid SMEDDS.

Herb-drug interactions.

Science.gov (United States)

Fugh-Berman, A

2000-01-08

Concurrent use of herbs may mimic, magnify, or oppose the effect of drugs. Plausible cases of herb-drug interactions include: bleeding when warfarin is combined with ginkgo (Ginkgo biloba), garlic (Allium sativum), dong quai (Angelica sinensis), or danshen (Salvia miltiorrhiza); mild serotonin syndrome in patients who mix St John's wort (Hypericum perforatum) with serotonin-reuptake inhibitors; decreased bioavailability of digoxin, theophylline, cyclosporin, and phenprocoumon when these drugs are combined with St John's wort; induction of mania in depressed patients who mix antidepressants and Panax ginseng; exacerbation of extrapyramidal effects with neuroleptic drugs and betel nut (Areca catechu); increased risk of hypertension when tricyclic antidepressants are combined with yohimbine (Pausinystalia yohimbe); potentiation of oral and topical corticosteroids by liquorice (Glycyrrhiza glabra); decreased blood concentrations of prednisolone when taken with the Chinese herbal product xaio chai hu tang (sho-salko-to); and decreased concentrations of phenytoin when combined with the Ayurvedic syrup shankhapushpi. Anthranoid-containing plants (including senna [Cassia senna] and cascara [Rhamnus purshiana]) and soluble fibres (including guar gum and psyllium) can decrease the absorption of drugs. Many reports of herb-drug interactions are sketchy and lack laboratory analysis of suspect preparations. Health-care practitioners should caution patients against mixing herbs and pharmaceutical drugs.

Refractometry for quality control of anesthetic drug mixtures.

Science.gov (United States)

Stabenow, Jennifer M; Maske, Mindy L; Vogler, George A

2006-07-01

Injectable anesthetic drugs used in rodents are often mixed and further diluted to increase the convenience and accuracy of dosing. We evaluated clinical refractometry as a simple and rapid method of quality control and mixing error detection of rodent anesthetic or analgesic mixtures. Dilutions of ketamine, xylazine, acepromazine, and buprenorphine were prepared with reagent-grade water to produce at least 4 concentration levels. The refraction of each concentration then was measured with a clinical refractometer and plotted against the percentage of stock concentration. The resulting graphs were linear and could be used to determine the concentration of single-drug dilutions or to predict the refraction of drug mixtures. We conclude that refractometry can be used to assess the concentration of dilutions of single drugs and can verify the mixing accuracy of drug combinations when the components of the mixture are known and fall within the detection range of the instrument.

Relationship between self-reported adherence, antiretroviral drug concentration measurement and self-reported symptoms in patients treated for HIV-1 infection.

Science.gov (United States)

Fabbiani, Massimiliano; Di Giambenedetto, Simona; Cingolani, Antonella; Fanti, Iuri; Colafigli, Manuela; Tamburrini, Enrica; Cauda, Roberto; Navarra, Pierluigi; De Luca, Andrea; Murri, Rita

2016-01-01

The aim of the study was to explore relationships between self-reported adherence, antiretroviral drug concentration measurement (TDM) and self-reported symptoms. We systematically administered to human immunodeficiency (HIV)-infected outpatients a questionnaire evaluating measures of self-reported adherence (missing doses during last week, deviations from the prescribed timing of therapy, self-initiated discontinuations for > 24 or 48 h, exhausting drugs and present sense of how patients are taking therapy) and a panel of referred symptoms (a symptom score was built summing self-reported scores for each listed symptom). We selected patients who completed the questionnaire and also had a TDM (mainly reflecting adherence in the past few days or weeks), thus comparing these two tools as measures of adherence. A total of 130 patients (64.6% males, median age 44 years, 76.2% with HIV RNA HIV RNA symptom score was associated with a lower self-reported adherence and with a higher proportion of undetectable drug levels. Self-reported adherence and TDM showed a correlation and seemed to be comparable tools for adherence estimation. Self-reported symptoms were associated with lower adherence and undetectable drug levels.

[Evaporation of selected cytotoxic drugs and permeation of protective gloves--research into the occupational risks of health care personnel handling hazardous cytotoxic drugs (CYTO project)].

Science.gov (United States)

Dolezalová, L; Odráska, P; Gorná, L; Prudilová, M; Vejpustková, R; Bláha, L

2009-01-01

The CYTO project studies an important aspect of healthcare provision -long-term occupational exposure, both threshold and below-threshold, to chemical agents with carcinogenic and mutagenic properties, with the major focus on antineoplastic drugs.This contribution presents experimental results from the first stages of the project's experimental work, i.e. an evaluation of the physico-chemical characteristics of cytostatic agents (evaporation) and an investigation into protective glove permeation. In co-operation with IUTA (Institut für Energie- und Umwelttechnik e.V., Duisburg, Germany), the vapour pressure of paclitaxel, doxorubicin and dacarbazine was measured following OECD guideline No. 104: Vapour pressure curve--vapour pressure balance. Furthermore, the evaporation of cytostatic drugs was examined in actual laboratory conditions by monitoring the airborne concentration using the passive sampling technique. Besides the evaporation of selected drugs, the permeation of cisplatin, cyclophosphamide, doxorubicin, 5-fluorouracil and paclitaxel through different types of gloves (vinyl, latex, nitrile) was assessed. Although our experiments showed relatively slow evaporation of the evaluated cytostatic drugs (the highest pressure in paclitaxel was 0.024 Pa), equilibrium concentrations may go up to milligrams per cubic metre. Nevertheless, analytical measurements of airborne contamination did not confirm these concentration levels. The glove permeation experiments with cytostatics showed good resistance of nitrile gloves (which were impermeable to all five drugs). Other materials should be avoided while handling cytostatic agents (e.g. maximum permeation of cyclophosphamide through latex was 19 microg/sq cm/hr). Although the volatility of cytostatic agents is low, it cannot be neglected considering the chronic character of exposure. However, in order to estimate actual occupational exposure, future research should focus on the development of sensitive analytical

Chemical dependency and drug testing in the workplace.

OpenAIRE

Osterloh, J D; Becker, C E

1990-01-01

Urine testing for drug use in the workplace is now widespread, with the prevalence of positive drug tests in the work force being 0% to 15%. The prevalence of marijuana use is highest, and this can be reliably tested. Though it is prudent to rid the workplace of drug use, there is little scientific study on the relationship of drug use and workplace outcomes, such as productivity and safety. Probable-cause testing and preemployment testing are the most common applications. Random testing has ...

Target concentration intervention: beyond Y2K.

Science.gov (United States)

Holford, N H

2001-01-01

Target concentration intervention (TCI) is proposed as an alternative conceptual strategy to therapeutic drug monitoring (TDM). It is argued that the idea of a therapeutic range has limited the interpretation of measured drug concentrations and diminished the anticipated clinical benefit to patients by use of an oversimplified pharmacodynamic model. TCI on the other hand embraces pharmacokinetic and pharmacodynamic concepts and uses the idea of a target effect and associated target concentration to make rational individual dose decisions.

21 CFR 131.115 - Concentrated milk.

Science.gov (United States)

2010-04-01

... 21 Food and Drugs 2 2010-04-01 2010-04-01 false Concentrated milk. 131.115 Section 131.115 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) FOOD FOR HUMAN CONSUMPTION MILK AND CREAM Requirements for Specific Standardized Milk and Cream § 131.115...

Projecting ADME Behavior and Drug-Drug Interactions in Early Discovery and Development: Application of the Extended Clearance Classification System.

Science.gov (United States)

El-Kattan, Ayman F; Varma, Manthena V; Steyn, Stefan J; Scott, Dennis O; Maurer, Tristan S; Bergman, Arthur

2016-12-01

To assess the utility of Extended Clearance Classification System (ECCS) in understanding absorption, distribution, metabolism, and elimination (ADME) attributes and enabling victim drug-drug interaction (DDI) predictions. A database of 368 drugs with relevant ADME parameters, main metabolizing enzymes, uptake transporters, efflux transporters, and highest change in exposure (%AUC) in presence of inhibitors was developed using published literature. Drugs were characterized according to ECCS using ionization, molecular weight and estimated permeability. Analyses suggested that ECCS class 1A drugs are well absorbed and systemic clearance is determined by metabolism mediated by CYP2C, esterases, and UGTs. For class 1B drugs, oral absorption is high and the predominant clearance mechanism is hepatic uptake mediated by OATP transporters. High permeability neutral/basic drugs (class 2) showed high oral absorption, with metabolism mediated generally by CYP3A, CYP2D6 and UGTs as the predominant clearance mechanism. Class 3A/4 drugs showed moderate absorption with dominant renal clearance involving OAT/OCT2 transporters. Class 3B drugs showed low to moderate absorption with hepatic uptake (OATPs) and/or renal clearance as primary clearance mechanisms. The highest DDI risk is typically seen with class 2/1B/3B compounds manifested by inhibition of either CYP metabolism or active hepatic uptake. Class 2 showed a wider range in AUC change likely due to a variety of enzymes involved. DDI risk for class 3A/4 is small and associated with inhibition of renal transporters. ECCS provides a framework to project ADME profiles and further enables prediction of victim DDI liabilities in drug discovery and development.

Antibacterial effect of Allium sativum cloves and Zingiber officinale rhizomes against multiple-drug resistant clinical pathogens.

Science.gov (United States)

Karuppiah, Ponmurugan; Rajaram, Shyamkumar

2012-08-01

To evaluate the antibacterial properties of Allium sativum (garlic) cloves and Zingiber officinale (ginger) rhizomes against multi-drug resistant clinical pathogens causing nosocomial infection. The cloves of garlic and rhizomes of ginger were extracted with 95% (v/v) ethanol. The ethanolic extracts were subjected to antibacterial sensitivity test against clinical pathogens. Anti-bacterial potentials of the extracts of two crude garlic cloves and ginger rhizomes were tested against five gram negative and two gram positive multi-drug resistant bacteria isolates. All the bacterial isolates were susceptible to crude extracts of both plants extracts. Except Enterobacter sp. and Klebsiella sp., all other isolates were susceptible when subjected to ethanolic extracts of garlic and ginger. The highest inhibition zone was observed with garlic (19.45 mm) against Pseudomonas aeruginosa (P. aeruginosa). The minimal inhibitory concentration was as low as 67.00 µg/mL against P. aeruginosa. Natural spices of garlic and ginger possess effective anti-bacterial activity against multi-drug clinical pathogens and can be used for prevention of drug resistant microbial diseases and further evaluation is necessary.

Metals in the Scheldt estuary: From environmental concentrations to bioaccumulation

International Nuclear Information System (INIS)

Van Ael, Evy; Blust, Ronny; Bervoets, Lieven

2017-01-01

To investigate the relationship between metal concentrations in abiotic compartments and in aquatic species, sediment, suspended matter and several aquatic species (Polychaeta, Oligochaeta, four crustacean species, three mollusc species and eight fish species) were collected during three seasons at six locations along the Scheldt estuary (the Netherlands-Belgium) and analysed on their metal content (Ag, Cd, Co, Cr, Cu, Ni, Pb, Zn and the metalloid As). Sediment and biota tissue concentrations were significantly influenced by sampling location, but not by season. Measurements of Acid Volatile Sulphides (AVS) concentrations in relation to Simultaneously Extracted Metals (SEM) in the sediment suggested that not all metals in the sediment will be bound to sulphides and some metals might be bioavailable. For all metals but zinc, highest concentrations were measured in invertebrate species; Ag and Ni in periwinkle, Cr, Co and Pb in Oligochaete worms and As, Cd and Cu in crabs and shrimp. Highest concentrations of Zn were measured in the kidney of European smelt. In fish, for most of the metals, the concentrations were highest in liver or kidney and lowest in muscle. For Zn however, highest concentrations were measured in the kidney of European smelt. For less than half of the metals significant correlations between sediment metal concentrations and bioaccumulated concentrations were found (liver/hepatopancreas or whole organism). To calculate the possible human health risk by consumption, average and maximum metal concentrations in the muscle tissues were compared to the minimum risk levels (MRLs). Concentrations of As led to the highest risk potential for all consumable species. Cadmium and Cu posed only a risk when consuming the highest contaminated shrimp and shore crabs. Consuming blue mussel could result in a risk for the metals As, Cd and Cr. - Highlights: • This is the first study investigating metal distribution along the aquatic ecosystem of the Scheldt

Interaction of cephalosporin drugs with dodecyltrimethylammonium Bromide

International Nuclear Information System (INIS)

Hoque, Md. Anamul; Hossain, Mohammed Delwar; Khan, Mohammed Abdullah

2013-01-01

Highlights: • We carry out the interaction of cephalosporin drugs with DTAB conductometrically. • We examine the effect of drugs on the critical micelle concentration of DTAB. • Three critical micelle concentrations are obtained for drug- DTAB system. • Electrostatic and hydrophobic interactions between drugs and DTAB are proposed. • Drug supported micelle formation of DTAB is much favoured in aq. solution of K 2 SO 4 . -- Abstract: The interaction of three cephalosporin drugs namely cefadroxyl monohydrate (CFM), cephalexin monohydrate (CLM) and cephradine monohydrate (CDM) with dodecyltrimethylammonium Bromide (DTAB) has been carried out by conductance measurements in aqueous medium and in aqueous solution of K 2 SO 4 salt over temperature range of (303.15 to 318.15) K. For pure DTAB and drug-DTAB systems, three critical micelle concentrations were obtained. The third critical micelle concentration (c ∗ 3 ) indicates that the spherical micelle turns into rod shape that is sphere to rod transition. The c ∗ values of DTAB are changed due to the addition of cephalosporin drugs. In addition, the change of the values of c ∗ 1 , c ∗ 2 and c ∗ 3 with increase of the concentration of drugs indicate the presence of interaction between drug and DTAB. The c ∗ values indicate that micellization for the cephalosporins-surfactant systems in water follow the order: CFM-surfactant ∗ values for the cephalosporins - DTAB systems in aqueous K 2 SO 4 are lower in magnitude than those in pure water and the values decrease with increase of the concentrations of K 2 SO 4 at a particular temperature. A significant decrease of c ∗ values in the presence of K 2 SO 4 for cephalosporins-DTAB systems indicates that drug supported ionic micelle formation is much favoured in aqueous K 2 SO 4 solution compared to that in pure water. For cephalosporin-DTAB systems, ΔG 0 m values are negative which indicate that the drugs mediated ionic micelle formation processes are

Drugs in breast milk.

Science.gov (United States)

Hervada, A R; Feit, E; Sagraves, R

1978-09-01

The amount of drug excreted into breast milk is dependent upon the lipid solubility of the medication, the mechanism of transport, the degree of ionization, and change in plasma pH. The higher the lipid solubility, the greater the concentration in human milk. The majority of drugs are transported into mammary blood capillaries by passive diffusion. The rest are transported by reverse pinocytosis. Once the drug has entered the epithelial cells of breast tissue, the drug molecules are excreted into the human milk by active transport, passive diffusion, or apocrine secretion. The amount of free (active) drug available for transport depends on the degree of protein binding the plasma pH. Another factor affecting excretion of drugs is the time when breast feeding occurs. In the 1st few days of life, when colostrum is present, water-soluble drugs pass through the breast more easily than afterwards when milk is produced. Then lipid-soluble drugs cross in higher concentrations. The effect on nursing infants is dependent on the amount excreted into the milk, the total amount absorbed by the infant, and the toxicity of the drug. The use of the following drugs in breast feeding mothers is reviewed: anticoagulants, antihypertensives and diuretics, antimicrobials, drugs affecting the central nervous system (alcohol, chloral hydrate, meprobamate, lithium, and aspirin), marijuana, other drugs (antihistamines, atropine, ergot alkaloids, laxatives, nicotine, iodides, propylthiouracil, theophylline), hormones (insulin, thyroxine, and oral contraceptives), and radiopharmaceuticals.

Which Kids Are at Highest Risk for Suicide?

Science.gov (United States)

... Share Which Kids are at Highest Risk for Suicide? Page Content Article Body No child is immune, ... who have lost a friend or relative to suicide. Studies show that a considerable number of youth ...

Enhanced drug delivery capabilities from stents coated with absorbable polymer and crystalline drug

OpenAIRE

Carlyle, Wenda C.; McClain, James B.; Tzafriri, Abraham R.; Bailey, Lynn; Zani, Brett G.; Markham, Peter M.; Stanley, James R.L.; Edelman, Elazer R.

2012-01-01

Current drug eluting stent (DES) technology is not optimized with regard to the pharmacokinetics of drug delivery. A novel, absorbable-coating sirolimus-eluting stent (AC-SES) was evaluated for its capacity to deliver drug more evenly within the intimal area rather than concentrating drug around the stent struts and for its ability to match coating erosion with drug release. The coating consisted of absorbable poly-lactide-co-glycolic acid (PLGA) and crystalline sirolimus deposited by a dry-p...

Cortex Matures Faster in Youths With Highest IQ

Science.gov (United States)

... NIH Cortex Matures Faster in Youths With Highest IQ Past Issues / Summer 2006 Table of Contents For ... on. Photo: Getty image (StockDisc) Youths with superior IQ are distinguished by how fast the thinking part ...

Pharmacokinetics of antiretroviral drugs in anatomical sanctuary sites: the male and female genital tract.

Science.gov (United States)

Else, Laura J; Taylor, Stephen; Back, David J; Khoo, Saye H

2011-01-01

HIV resides within anatomical 'sanctuary sites', where local drug exposure and viral dynamics may differ significantly from the systemic compartment. Suboptimal antiretroviral concentrations in the genital tract may result in compartmentalized viral replication, selection of resistant mutations and possible re-entry of wild-type/resistant virus into the systemic circulation. Therefore, achieving adequate antiretroviral exposure in the genital tract has implications for the prevention of sexual and vertical transmission of HIV. Penetration of antiretrovirals in the genital tract is expressed by accumulation ratios derived from the measurement of drug concentrations in time-matched seminal plasma/cervicovaginal fluid and plasma samples. Penetration varies by gender and may be drug (as opposed to class) specific with high interindividual variability. Concentrations in seminal plasma are highest for nucleoside analogues and lowest for protease inhibitors and efavirenz. Seminal accumulation of newer agents, raltegravir and maraviroc, is moderate (rank order of accumulation is nucleoside/nucleotide reverse transcriptase inhibitors [lamivudine/zidovudine/tenofovir/didanosine > stavudine/abacavir] > raltegravir > indinavir/maraviroc/nevirapine > efavirenz/protease inhibitors [amprenavir/atazanavir/darunavir > lopinavir/ritonavir > saquinavir] > enfuvirtide). In the female genital tract, the nucleoside analogues exhibit high accumulation ratios, whereas protease inhibitors have limited penetration; however, substantial variability exists between individuals and study centres. Second generation non-nucleoside reverse transcriptase inhibitor etravirine, and maraviroc and raltegravir, demonstrate effective accumulation in cervicovaginal secretions (rank order of accumulation is nucleoside/nucleotide reverse transcriptase inhibitor [zidovudine/lamivudine/didanosine > emtricitabine/tenofovir] > indinavir > maraviroc/raltegravir/darunavir/etravirine > nevirapine

Drug: D08821 [KEGG MEDICUS

Lifescience Database Archive (English)

Full Text Available D08821 Drug Concentrated human red blood cells; Red cells concentrates -leukocytes... reduced (RCC-LR) (TN); Irradiated red cells concentrates -leukocytes reduced (Ir-RCC-LR) (TN) ... PubChem: 96025504 ...

Drug adsorption to plastic containers and retention of drugs in cultured cells under in vitro conditions.

Science.gov (United States)

Palmgrén, Joni J; Mönkkönen, Jukka; Korjamo, Timo; Hassinen, Anssi; Auriola, Seppo

2006-11-01

Loss of drug content during cell culture transport experiment can lead to misinterpretations in permeability analysis. This study analyses drug adsorption to various plastic containers and drug retention in cultured cells under in vitro conditions. The loss of various drugs to polystyrene tubes and well plates was compared to polypropylene and glass tubes both in deionised water and buffer solution. In cellular uptake experiments, administered drugs were obtained from cultured cells by liquid extraction. Samples were collected at various time points and drug concentrations were measured by a new HPLC-MS/MS method. Acidic drugs (hydrochlorothiazide, naproxen, probenicid, and indomethacin) showed little if any sorption to all tested materials in either water or buffer. In the case of basic drugs, substantial loss to polystyrene tubes and well plates was observed. After 4.5 h, the relative amount remaining in aqueous test solution stored in polystyrene tubes was 64.7 +/- 6.8%, 38.4 +/- 9.1%, 31.9 +/- 6.7%, and 23.5 +/- 6.1% for metoprolol, medetomidine, propranolol, and midazolam, respectively. Interestingly, there was no significant loss of drugs dissolved in buffer to any of the tested materials indicating that buffer reduced surficial interaction. The effect of drug concentration to sorption was also tested. Results indicated that the higher the concentration in the test solution the lower the proportional drug loss, suggesting that the polystyrene contained a limited amount of binding sites. Cellular uptake studies showed considerable retention of drugs in cultured cells. The amounts of absorbed drugs in cellular structures were 0.45%, 4.88%, 13.15%, 43.80%, 23.57% and 11.22% for atenolol, metoprolol, medetomidine, propranolol, midazolam, and diazepam, respectively. Overall, these findings will benefit development and validation of further in vitro drug permeation experiments.

Variable Linezolid Exposure in Intensive Care Unit Patients-Possible Role of Drug-Drug Interactions.

Science.gov (United States)

Töpper, Christoph; Steinbach, Cathérine L; Dorn, Christoph; Kratzer, Alexander; Wicha, Sebastian G; Schleibinger, Michael; Liebchen, Uwe; Kees, Frieder; Salzberger, Bernd; Kees, Martin G

2016-10-01

Standard doses of linezolid may not be suitable for all patient groups. Intensive care unit (ICU) patients in particular may be at risk of inadequate concentrations. This study investigated variability of drug exposure and its potential sources in this population. Plasma concentrations of linezolid were determined by high-performance liquid chromatography in a convenience sample of 20 ICU patients treated with intravenous linezolid 600 mg twice daily. Ultrafiltration applying physiological conditions (pH 7.4/37°C) was used to determine the unbound fraction. Individual pharmacokinetic (PK) parameters were estimated by population PK modeling. As measures of exposure to linezolid, area under the concentration-time curve (AUC) and trough concentrations (Cmin) were calculated and compared with published therapeutic ranges (AUC 200-400 mg*h/L, Cmin 2-10 mg/L). Coadministered inhibitors or inducers of cytochrome P450 and/or P-glycoprotein were noted. Data from 18 patients were included into the PK evaluation. Drug exposure was highly variable (median, range: AUC 185, 48-618 mg*h/L, calculated Cmin 2.92, 0.0062-18.9 mg/L), and only a minority of patients had values within the target ranges (6 and 7, respectively). AUC and Cmin were linearly correlated (R = 0.98), and classification of patients (underexposed/within therapeutic range/overexposed) according to AUC or Cmin was concordant in 15 cases. Coadministration of inhibitors was associated with a trend to higher drug exposure, whereas 3 patients treated with levothyroxine showed exceedingly low drug exposure (AUC ∼60 mg*h/L, Cmin linezolid is highly variable and difficult to predict in ICU patients, and therapeutic drug monitoring seems advisable. PK drug-drug interactions might partly be responsible and should be further investigated; protein binding appears to be stable and irrelevant.

CSF drug levels for children with acute lymphoblastic leukemia treated by 5 g/m2 methotrexate. A study from the EORTC Children's Leukemia Cooperative Group.

Science.gov (United States)

Milano, G; Thyss, A; Serre Debeauvais, F; Laureys, G; Benoit, Y; Deville, A; Dutour, C; Robert, A; Otten, J; Behar, C

1990-04-01

A multicenter EORTC study was conducted in children with acute lymphocytic leukemia to determine whether 5 g/m2 of methotrexate (MTX) (24 h i.v. infusion, four cycles) is an appropriate dosage for obtaining CSF drug concentrations approaching the critical cytotoxic level of 10(-6) M. A total of 193 cycles were analyzed for 58 patients. At the end of the 24 h infusion, the mean MTX serum level was 65.27 +/- 33.11 microM; the mean CSF MTX level was 1.47 +/- 1.1 microM; no significant difference in CSF MTX levels was observed between patients with (n = 20) and those without i.v. Ara-C (n = 38). The mean CSF MTX/serum MTX ratio was 0.029 +/- 0.027. CSF drug concentrations greater than or equal to 10(-6) M were achieved in 81% of the courses. The highest level was 8.4 X 10(-6) M. Only 5% of patients failed to achieve this drug concentration in at least one cycle. No significant correlation was observed between blood and CSF MTX levels. Mean CSF MTX levels were comparable from one cycle to another.

Highest priority in Pakistan.

Science.gov (United States)

Adil, E

1968-01-01

Responding to the challenge posed by its population problem, Pakistan's national leadership gave the highest priority to family planning in its socioeconomic development plan. In Pakistan, as elsewhere in the world, the first family planning effort originated in the private sector. The Family Planning Association of Pakistan made a tentative beginning in popularizing family planning in the country. Some clinics were opened and some publicity and education were undertaken to emphasize the need for family limitation. It was recognized soon that the government needed to assume the primarily responsibility if family planning efforts were to be successful. For the 1st plan period, 1955-60, about $10 million was allocated by the central government in the social welfare sector for voluntary family planning. The level of support continued on the same basis during the 2nd plan, 1960-65, but has been raised 4-fold in the 1965-70 scheme of family planning. Pakistan's Family Planning Association continues to play vital collaborative roles in designing and pretesting of prototype publicity material, involvement of voluntary social workers, and functional research in the clinical and public relations fields. The real breakthrough in the program came with the 3rd 5-year plan, 1965-70. High priority assigned to family planning is reflected by the total initial budget of Rs.284 million (about $60,000,000) for the 5-year period. Current policy is postulated on 6 basic assumptions: family planning efforts need to be public relations-oriented; operations should be conducted through autonomous bodies with decentralized authority at all tiers down to the grassroots level, for expeditious decision making; monetary incentives play an important role; interpersonal motivation in terms of life experience of the clientele through various contacts, coupled with mass media for publicity, can produce a sociological breakthrough; supplies and services in all related disciplines should be

Synergism between plant extract and antimicrobial drugs used on Staphylococcus aureus diseases

Directory of Open Access Journals (Sweden)

Joyce Elaine Cristina Betoni

2006-06-01

Full Text Available Searches for substances with antimicrobial activity are frequent, and medicinal plants have been considered interesting by some researchers since they are frequently used in popular medicine as remedies for many infectious diseases. The aim of this study was to verify the synergism between 13 antimicrobial drugs and 8 plant extracts - "guaco" (Mikania glomerata, guava (Psidium guajava, clove (Syzygium aromaticum, garlic (Allium sativum, lemongrass (Cymbopogon citratus, ginger (Zingiber officinale, "carqueja" (Baccharis trimera, and mint (Mentha piperita - against Staphylococcus aureus strains, and for this purpose, the disk method was the antimicrobial susceptibility test performed. Petri dishes were prepared with or without dilution of plant extracts at sub-inhibitory concentrations in Mueller-Hinton Agar (MHA, and the inhibitory zones were recorded in millimeters. In vitro anti-Staphylococcus aureus activities of the extracts were confirmed, and synergism was verified for all the extracts; clove, guava, and lemongrass presented the highest synergism rate with antimicrobial drugs, while ginger and garlic showed limited synergistic capacity.

Blood lead concentration and related factors in Korea from the 2008 National Survey for Environmental Pollutants in the Human Body.

Science.gov (United States)

Jeong, Seong Wook; Lee, Chae Kwan; Suh, Chun Hui; Kim, Kun Hyung; Son, Byung Chul; Kim, Jeong Ho; Lee, Jong Tae; Lee, Soo Woong; Park, Yeong Beom; Lee, Jong Wha; Yu, Seung-Do; Moon, Chan Seok; Kim, Dae Hwan; Lee, Sang Yoon

2014-11-01

This study evaluated blood lead concentrations in the Korean general population and the correlation between various exposure sources using data from the 2008 Korea National Survey for Environmental Pollutants in the Human Body (National Institute of Environmental Research, Korea). The general and occupational characteristics were gathered from 5136 participants who were 20 years of age and older using a structured questionnaire. Blood lead concentrations were analyzed using an atomic absorption spectrophotometer. Statistical analysis was performed using multiple linear regressions of the log lead concentrations to the independent variables such as age, gender, smoke, herbal medication and drug consumption, drinking water, and living area. Geometric mean (GM) blood lead concentrations in Korean adults were 19.7 μg/l. The blood lead concentrations increased with age; the highest concentrations were found in the 50-69-year age group (pdrug consumption were higher than those who did not (plead concentration (plead concentration (plead concentration, but not significantly. For drinking water, the underground water (spring or well water) drinking group had higher concentrations than other types of water drinking groups, but not significantly (p=0.063). The blood lead concentrations by occupation were significant (plead concentrations tended to decrease with increasing delivery times, but not significantly. The blood lead concentration (GM) of the general adult population in Korea has decreased over time from 45.8 μg/l (1999) to 19.7 μg/l (2008). Although it is still higher than in other countries such as the United States and Canada, it is rapidly decreasing. Gender, age, smoking and alcohol drinking status, herbal medication and drug consumption, education level, living area and occupation were significantly related to the blood lead concentrations in Korea. Copyright © 2014. Published by Elsevier GmbH.

Modeling the drug transport in the anterior segment of the eye.

Science.gov (United States)

Avtar, Ram; Tandon, Deepti

2008-10-02

The aim of the present work is the development of a simple mathematical model for the time course concentration profile of topically administered drugs in the anterior chamber aqueous humor and investigation of the effects of various model parameters on the aqueous humor concentration of lipophilic and hydrophilic drugs. A simple pharmacokinetic model for the transient drug transport in the anterior segment has been developed by using the conservation of mass in the precorneal tear film, Fick's law of diffusion and Michaelis-Menten kinetics of drug metabolism in cornea, and the conservation of mass in the anterior chamber. An analytical solution describing the drug concentration in the anterior chamber has been obtained. The model predicts that an increase in the drug metabolic (consumption) rate in the corneal epithelium reduces the drug concentration in the anterior chamber for both lipophilic and hydrophilic molecules. A decrease in the clearance rate and distribution volume of the drug in the anterior chamber raises the aqueous humor concentration significantly. It is also observed that decay rate of drug concentration in the anterior chamber is higher for lipophilic molecules than that for hydrophilic molecules. The bioavailability of drugs applied topically to the eye may be improved by a rise in the precorneal tear volume, diffusion coefficient in corneal epithelium and distribution coefficient across the endothelium anterior chamber interface, and by reducing the drug metabolism, drug clearance rate and distribution volume in anterior chamber.

The concentrations of uranium in marine organisms

Energy Technology Data Exchange (ETDEWEB)

Matsuba, Mitsue; Ishii, Toshiaki; Nakahara, Motokazu; Nakamura, Ryoichi; Watabe, Teruhisa; Hirano, Shigeki [National Inst. of Radiological Sciences, Hitachinaka, Ibaraki (Japan). Laboratory for Radioecology

2000-07-01

Determination of uranium in sixty-one species of marine organisms was carried out by inductively coupled plasma mass spectrometry to obtain concentration factors and to estimate the internal radiation dose. The concentrations of uranium in soft tissues of marine animals were ranged from 0.077 to 5040 ng/g wet wt. Especially, the branchial heart of cephalopod molluscs showed the specific accumulation of uranium. The concentration factor of the branchial heart of Octopus vulgaris, which indicated the highest value, was calculated to be about 1.6 x 10{sup 3}, comparing with that (3.1 ng/ml) in coastal seawaters of Japan. The concentrations of uranium in hard tissues of marine invertebrates such as clam and sea urchin were similar to those in soft tissues. In contrast, hard tissues like bone, scale, fin, etc. of fishes showed much higher concentrations of uranium than soft tissues like muscle. The concentrations of uranium of twenty-two species of algae were ranged from 2 to 310 ng/g wet wt. Particularly, the brown alga Undaria pinnatifida showed the highest value of the uranium content in the algae and its concentration factor was calculated to be 10{sup 2}. (author)

The concentrations of uranium in marine organisms

International Nuclear Information System (INIS)

Matsuba, Mitsue; Ishii, Toshiaki; Nakahara, Motokazu; Nakamura, Ryoichi; Watabe, Teruhisa; Hirano, Shigeki

2000-01-01

Determination of uranium in sixty-one species of marine organisms was carried out by inductively coupled plasma mass spectrometry to obtain concentration factors and to estimate the internal radiation dose. The concentrations of uranium in soft tissues of marine animals were ranged from 0.077 to 5040 ng/g wet wt. Especially, the branchial heart of cephalopod molluscs showed the specific accumulation of uranium. The concentration factor of the branchial heart of Octopus vulgaris, which indicated the highest value, was calculated to be about 1.6 x 10 3 , comparing with that (3.1 ng/ml) in coastal seawaters of Japan. The concentrations of uranium in hard tissues of marine invertebrates such as clam and sea urchin were similar to those in soft tissues. In contrast, hard tissues like bone, scale, fin, etc. of fishes showed much higher concentrations of uranium than soft tissues like muscle. The concentrations of uranium of twenty-two species of algae were ranged from 2 to 310 ng/g wet wt. Particularly, the brown alga Undaria pinnatifida showed the highest value of the uranium content in the algae and its concentration factor was calculated to be 10 2 . (author)

Venetoclax (ABT-199) Might Act as a Perpetrator in Pharmacokinetic Drug-Drug Interactions.

Science.gov (United States)

Weiss, Johanna; Gajek, Thomas; Köhler, Bruno Christian; Haefeli, Walter Emil

2016-02-24

Venetoclax (ABT-199) represents a specific B-cell lymphoma 2 (Bcl-2) inhibitor that is currently under development for the treatment of lymphoid malignancies. So far, there is no published information on its interaction potential with important drug metabolizing enzymes and drug transporters, or its efficacy in multidrug resistant (MDR) cells. We therefore scrutinized its drug-drug interaction potential in vitro. Inhibition of cytochrome P450 enzymes (CYPs) was quantified by commercial kits. Inhibition of drug transporters (P-glycoprotein (P-gp, ABCB1), breast cancer resistance protein (BCRP), and organic anion transporting polypeptides (OATPs)) was evaluated by the use of fluorescent probe substrates. Induction of drug transporters and drug metabolizing enzymes was quantified by real-time RT-PCR. The efficacy of venetoclax in MDR cells lines was evaluated with proliferation assays. Venetoclax moderately inhibited P-gp, BCRP, OATP1B1, OATP1B3, CYP3A4, and CYP2C19, whereas CYP2B6 activity was increased. Venetoclax induced the mRNA expression of CYP1A1, CYP1A2, UGT1A3, and UGT1A9. In contrast, expression of ABCB1 was suppressed, which might revert tumor resistance towards antineoplastic P-gp substrates. P-gp over-expression led to reduced antiproliferative effects of venetoclax. Effective concentrations for inhibition and induction lay in the range of maximum plasma concentrations of venetoclax, indicating that it might act as a perpetrator drug in pharmacokinetic drug-drug interactions.

Application of gold nanoparticles for improved drug efficiency

Science.gov (United States)

Shittu, K. O.; Bankole, M. T.; Abdulkareem, A. S.; Abubakre, O. K.; Ubaka, A. U.

2017-09-01

Due to increasing resistance of microorganisms towards current antibiotics, there is a need for new or enhanced antibiotics. Nanotechnology is a technology that enhances the use of gold nanoparticles (AuNP) in area of medical applications, especially as a drug carrier for targeted drug delivery. In this research, AuNPs was synthesized using biological method via bioreduction of Piper guineense aqueous leaf extract on tetra gold chloride, characterized using UV-Vis spectrophometer, DLS, TEM/EDS and FTIR. The synthesized AuNPs was covalently functionalized with polyethylene glycol and encapsulated with Lincomycin and in vitro dissolution methods was used to evaluate the potential performance of the formulated nanodrug. The nanodrug has highest release efficiency at the 9th minutes (23.4 mg ml-1 for 40 °C) and (29.5 mg ml-1 for 60 °C) compared with the non-nanodrug. The antibacterial potential of the nanodrug was seen on the gram-positive bacteria of Staphylococcus aureus and Streptococcus pyogenes with highest inhibitions of 18 mm (at 40 °C) and 16 mm (at 60 °C) for S. aureus, and 16 mm for S. pyogenes (both at 40 °C and 60 °C). The bacteria growth inhibition continued and lasted for 15 min, while that of non-nanodrug lasted for 9 min with lesser growth inhibition compared to the formulated nanodrug. This work shows that the presence of the AuNPs increased the release efficiency of lincomycin even at a lower concentration and also bacteria growth inhibition thereby suggesting the effectiveness of the nanodrug formulation.

Evaluation of Flexible Tacrolimus Drug Concentration Monitoring Approach in Patients Receiving Extended-Release Once-Daily Tacrolimus Tablets.

Science.gov (United States)

Philosophe, Benjamin; Leca, Nicolae; West-Thielke, Patricia M; Horwedel, Timothy; Culkin-Gemmell, Christine; Kistler, Kristin; Stevens, Daniel R

2018-02-20

The majority of United States kidney transplant patients are treated with tacrolimus, a drug effective in preventing graft rejection, but with a narrow therapeutic range, necessitating close monitoring to avoid increased risks of transplant rejection or toxicity if the tacrolimus concentration is too low or too high, respectively. The trough drug concentration tests are time sensitive; patients treated on a twice-daily basis have blood draws exactly 12 hours after their previous dose. The schedule's rigidity causes problems for both patients and health care providers. Novel once-daily tacrolimus formulations such as LCPT (an extended-release tablet by Veloxis Pharmaceuticals, Inc., Cary, North Carolina) have allowed for blood draws on a once-daily basis; however, even that schedule can be restrictive. Results from tests taken either before or after that 24-hour target time may be discarded, or worse, may lead to inappropriate dose changes. Data from ASTCOFF, a phase 3B pharmacokinetic clinical trial (NCT02339246), demonstrated that the unique pharmacokinetic curve of LCPT may allow for a therapeutic monitoring window that extends for 3 hours before or after the 24-hour monitoring target. Furthermore, important tools to help clinicians interpret these levels, such as formulas to estimate the 24-hour trough level if an alternative monitoring time is used, were constructed from these data. These study results give treating clinicians access to data that allow them to safely use and monitor LCPT in their patients and expand the body of evidence surrounding differentiation and practical application of the novel LCPT tacrolimus formulation. © 2018, The Authors. The Journal of Clinical Pharmacology published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology.

Interdependence of initial cell density, drug concentration and exposure time revealed by real-time impedance spectroscopic cytotoxicity assay

DEFF Research Database (Denmark)

Caviglia, Claudia; Zor, Kinga; Canepa, Silvia

2015-01-01

We investigated the combined effect of the initial cell density (12 500, 35 000, 75 000, and 100 000 cells cm−2) and concentration of the anti-cancer drug doxorubicin on HeLa cells by performing timedependent cytotoxicity assays using real-time electrochemical impedance spectroscopy. A correlation...... between the rate of cell death and the initial cell seeding density was found at 2.5 μM doxorubicin concentration, whereas this was not observed at 5 or 100 μM. By sensing the changes in the cell–substrate interaction using impedance spectroscopy under static conditions, the onset of cytotoxicity...... was observed 5 h earlier than when using a standard colorimetric end-point assay (MTS) which measures changes in the mitochondrial metabolism. Furthermore, with the MTS assay no cytotoxicity was observed after 15 h of incubation with 2.5 μM doxorubicin, whereas the impedance showed at this time point cell...

A paradigm shift in pharmacokinetic-pharmacodynamic (PKPD) modeling: rule of thumb for estimating free drug level in tissue compared with plasma to guide drug design.

Science.gov (United States)

Poulin, Patrick

2015-07-01

A basic assumption in pharmacokinetics-pharmacodynamics research is that the free drug concentration is similar in plasma and tissue, and, hence, in vitro plasma data can be used to estimate the in vivo condition in tissue. However, in a companion manuscript, it has been demonstrated that this assumption is violated for the ionized drugs. Nonetheless, these observations focus on in vitro static environments and do not challenge data with an in vivo dynamic system. Therefore, an extension from an in vitro to an in vivo system becomes the necessary next step. The objective of this study was to perform theoretical simulations of the free drug concentration in tissue and plasma by using a physiologically based pharmacokinetics (PBPK) model reproducing the in vivo conditions in human. Therefore, the effects of drug ionization, lipophilicity, and clearance have been taken into account in a dynamic system. This modeling exercise was performed as a proof of concept to demonstrate that free drug concentration in tissue and plasma may also differ in a dynamic system for passively permeable drugs that are ionized at the physiological pH. The PBPK model simulations indicated that free drug concentrations in tissue cells and plasma significantly differ for the ionized drugs because of the pH gradient effect between cells and interstitial space. Hence, a rule of thumb for potentially performing more accurate PBPK/PD modeling is suggested, which states that the free drug concentration in tissue and plasma will differ for the ionizable drugs in contrast to the neutral drugs. In addition to the pH gradient effect for the ionizable drugs, lipophilicity and clearance effects will increase or decrease the free drug concentration in tissue and plasma for each class of drugs; thus, higher will be the drug lipophilicity and clearance, lower would be the free drug concentration in plasma, and, hence, in tissue, in a dynamic in vivo system. Therefore, only considering the value of free

Drug-likeness analysis of traditional Chinese medicines: 2. Characterization of scaffold architectures for drug-like compounds, non-drug-like compounds, and natural compounds from traditional Chinese medicines.

Science.gov (United States)

Tian, Sheng; Li, Youyong; Wang, Junmei; Xu, Xiaojie; Xu, Lei; Wang, Xiaohong; Chen, Lei; Hou, Tingjun

2013-01-21

In order to better understand the structural features of natural compounds from traditional Chinese medicines, the scaffold architectures of drug-like compounds in MACCS-II Drug Data Report (MDDR), non-drug-like compounds in Available Chemical Directory (ACD), and natural compounds in Traditional Chinese Medicine Compound Database (TCMCD) were explored and compared. First, the different scaffolds were extracted from ACD, MDDR and TCMCD by using three scaffold representations, including Murcko frameworks, Scaffold Tree, and ring systems with different complexity and side chains. Then, by examining the accumulative frequency of the scaffolds in each dataset, we observed that the Level 1 scaffolds of the Scaffold Tree offer advantages over the other scaffold architectures to represent the scaffold diversity of the compound libraries. By comparing the similarity of the scaffold architectures presented in MDDR, ACD and TCMCD, structural overlaps were observed not only between MDDR and TCMCD but also between MDDR and ACD. Finally, Tree Maps were used to cluster the Level 1 scaffolds of the Scaffold Tree and visualize the scaffold space of the three datasets. The analysis of the scaffold architectures of MDDR, ACD and TCMCD shows that, on average, drug-like molecules in MDDR have the highest diversity while natural compounds in TCMCD have the highest complexity. According to the Tree Maps, it can be observed that the Level 1 scaffolds present in MDDR have higher diversity than those presented in TCMCD and ACD. However, some representative scaffolds in MDDR with high frequency show structural similarities to those in TCMCD and ACD, suggesting that some scaffolds in TCMCD and ACD may be potentially drug-like fragments for fragment-based and de novo drug design.

Local drug delivery - the early Berlin experience: single drug administration versus sustained release.

Science.gov (United States)

Speck, Ulrich; Scheller, Bruno; Rutsch, Wolfgang; Laule, Michael; Stangl, Verena

2011-05-01

Our initial investigations into restenosis inhibition by local drug delivery were prompted by reports on an improved outcome of coronary interventions, including a lower rate of target lesion revascularisation, when the intervention was performed with an ionic instead of non-ionic contrast medium. Although this was not confirmed in an animal study, the short exposure of the vessel wall to paclitaxel dissolved in contrast agent or coated on balloons proved to be efficacious. A study comparing three methods of local drug delivery to the coronary artery in pigs indicated the following order of efficacy in inhibiting neointimal proliferation: paclitaxel-coated balloons > sirolimus-eluting stents, sustained drug release > paclitaxel in contrast medium. Cell culture experiments confirmed that cell proliferation can be inhibited by very short exposure to the drug. Shorter exposure times require higher drug concentrations. Effective paclitaxel concentrations in porcine arteries are achieved when the drug is dissolved in contrast medium or coated on balloons. Paclitaxel is an exceptional drug in that it stays in the treated tissue for a long time. This may explain the long-lasting efficacy of paclitaxel-coated balloons, but does not disprove the hypothesis that the agent blocks a process initiating long-lasting excessive neointimal proliferation, which occurs early after vessel injury.

Adverse drug reactions induced by cardiovascular drugs in outpatients.

Science.gov (United States)

Gholami, Kheirollah; Ziaie, Shadi; Shalviri, Gloria

2008-01-01

Considering increased use of cardiovascular drugs and limitations in pre-marketing trials for drug safety evaluation, post marketing evaluation of adverse drug reactions (ADRs) induced by this class of medicinal products seems necessary. To determine the rate and seriousness of adverse reactions induced by cardiovascular drugs in outpatients. To compare sex and different age groups in developing ADRs with cardiovascular agents. To assess the relationship between frequencies of ADRs and the number of drugs used. This cross-sectional study was done in cardiovascular clinic at a teaching hospital. All patients during an eight months period were evaluated for cardiovascular drugs induced ADRs. Patient and reaction factors were analyzed in detected ADRs. Patients with or without ADRs were compared in sex and age by using chi-square test. Assessing the relationship between frequencies of ADRs and the number of drugs used was done by using Pearson analysis. The total number of 518 patients was visited at the clinic. ADRs were detected in 105 (20.3%) patients. The most frequent ADRs were occurred in the age group of 51-60. The highest rate of ADRs was recorded to be induced by Diltiazem (23.5%) and the lowest rate with Atenolol (3%). Headache was the most frequent detected ADR (23%). Assessing the severity and preventability of ADRs revealed that 1.1% of ADRs were detected as severe and 1.9% as preventable reactions. Women significantly developed more ADRs in this study (chi square = 3.978, PPearson=0.259, P<0.05). Monitoring ADRs in patients using cardiovascular drugs is a matter of importance since this class of medicines is usually used by elderly patients with critical conditions and underlying diseases.

Potential drug-drug interactions with direct oral anticoagulants in elderly hospitalized patients.

Science.gov (United States)

Forbes, Heather L; Polasek, Thomas M

2017-10-01

To determine the prevalence and nature of potential drug-drug interactions (DDIs) with direct oral anticoagulants (DOACs) in elderly hospitalized patients. This was a retrospective observational study. Inclusion criteria were: aged over 65 years; taking apixaban, rivaroxaban or dabigatran; and admitted to the Repatriation General Hospital between April 2014 and July 2015. A list of clinically relevant 'perpetrator' drugs was compiled from product information, the Australian Medicines Handbook, the Australian National Prescribing Service resources, and local health network guidelines. The prevalence and nature of potential DDIs with DOACs was determined by comparing inpatient drug charts with the list of perpetrator drugs. There were 122 patients in the study with a mean age of 82 years. Most patients had nonvalvular atrial fibrillation and were taking DOACs to prevent thrombotic stroke (83%). Overall, 45 patients (37%) had a total of 54 potential DDIs. Thirty-five patients had potential pharmacodynamic DDIs with antidepressants, nonsteroidal anti-inflammatory drugs and antiplatelets (35/122, 29%). Nineteen patients had potential pharmacokinetic DDIs (19/122, 16%). Of these, 68% (13/19) were taking drugs that increase DOAC plasma concentrations (amiodarone, erythromycin, diltiazem or verapamil) and 32% (6/19) were taking drugs that decrease DOAC plasma concentrations (carbamazepine, primidone or phenytoin). There were no cases of patients taking contraindicated interacting drugs. Potential DDIs with DOACs in elderly hospital inpatients are relatively common, particularly interactions that may increase the risk of bleeding. The risk-benefit ratio of DOACs in elderly patients on polypharmacy should always be carefully considered.

Anti-addiction drug ibogaine inhibits voltage-gated ionic currents: A study to assess the drug's cardiac ion channel profile

International Nuclear Information System (INIS)

Koenig, Xaver; Kovar, Michael; Rubi, Lena; Mike, Agnes K.; Lukacs, Peter; Gawali, Vaibhavkumar S.; Todt, Hannes; Hilber, Karlheinz; Sandtner, Walter

2013-01-01

The plant alkaloid ibogaine has promising anti-addictive properties. Albeit not licenced as a therapeutic drug, and despite hints that ibogaine may perturb the heart rhythm, this alkaloid is used to treat drug addicts. We have recently reported that ibogaine inhibits human ERG (hERG) potassium channels at concentrations similar to the drugs affinity for several of its known brain targets. Thereby the drug may disturb the heart's electrophysiology. Here, to assess the drug's cardiac ion channel profile in more detail, we studied the effects of ibogaine and its congener 18-Methoxycoronaridine (18-MC) on various cardiac voltage-gated ion channels. We confirmed that heterologously expressed hERG currents are reduced by ibogaine in low micromolar concentrations. Moreover, at higher concentrations, the drug also reduced human Na v 1.5 sodium and Ca v 1.2 calcium currents. Ion currents were as well reduced by 18-MC, yet with diminished potency. Unexpectedly, although blocking hERG channels, ibogaine did not prolong the action potential (AP) in guinea pig cardiomyocytes at low micromolar concentrations. Higher concentrations (≥ 10 μM) even shortened the AP. These findings can be explained by the drug's calcium channel inhibition, which counteracts the AP-prolonging effect generated by hERG blockade. Implementation of ibogaine's inhibitory effects on human ion channels in a computer model of a ventricular cardiomyocyte, on the other hand, suggested that ibogaine does prolong the AP in the human heart. We conclude that therapeutic concentrations of ibogaine have the propensity to prolong the QT interval of the electrocardiogram in humans. In some cases this may lead to cardiac arrhythmias. - Highlights: • We study effects of anti-addiction drug ibogaine on ionic currents in cardiomyocytes. • We assess the cardiac ion channel profile of ibogaine. • Ibogaine inhibits hERG potassium, sodium and calcium channels. • Ibogaine’s effects on ion channels are a potential

The highest energies in the Universe

International Nuclear Information System (INIS)

Rebel, H.

2006-01-01

There are not many issues of fundamental importance which have induced so many problems for astrophysicists like the question of the origin of cosmic rays. This radiation from the outer space has an energy density comparable with that of the visible starlight or of the microwave background radiation. It is an important feature of our environment with many interesting aspects. A most conspicuous feature is that the energy spectrum of cosmic rays seems to have no natural end, though resonant photopion production with the cosmic microwave background predicts a suppression of extragalactic protons above the so-called Greisen-Zatsepin-Kuz’min cutoff at about EGZK = 5 × 10"1"9 eV. In fact the highest particle energies ever observed on the Earth, stem from observations of Ultrahigh Energy Cosmic Rays (E > 3 × 10"1"9 eV). But the present observations by the AGASA and HiRes Collaborations, partly a matter of debate, are origin of a number of puzzling questions, where these particles are coming from, by which gigantic acceleration mechanism they could gain such tremendous energies and how they have been able to propagate to our Earth. These questions imply serious problems of the understanding of our Universe. There are several approaches to clarify the mysteries of the highest energies and to base the observations on larger statistical accuracy. The Pierre Auger Observatory, being in installation in the Pampa Amarilla in the Province Mendoza in Argentina, is a hybrid detector, combining a large array of water Cerenkov detectors (registering charged particles generated in giant extended air showers) with measurements of the fluorescence light produced during the air shower development. This contribution will illustrate the astrophysical motivation and the current status of the experimental efforts, and sketch the ideas about the origin of these particles.

21 CFR 169.176 - Concentrated vanilla extract.

Science.gov (United States)

2010-04-01

... content of ethyl alcohol is not less than 35 percent by volume. (b) The specified name of the food is... 21 Food and Drugs 2 2010-04-01 2010-04-01 false Concentrated vanilla extract. 169.176 Section 169.176 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED...

Canada’s highest court unchains injection drug users; implications for harm reduction as standard of healthcare

Directory of Open Access Journals (Sweden)

Small Dan

2012-07-01

Full Text Available Abstract North America’s only supervised injection facility, Insite, opened its doors in September of 2003 with a federal exemption as a three-year scientific study. The results of the study, evaluated by an independent research team, showed it to be successful in engaging the target group in healthcare, preventing overdose death and HIV infections while increasing uptake and retention in detox and treatment. The research, published in peer-reviewed medical and scientific journals, also showed that the program did not increase public disorder, crime or drug use. Despite the substantial evidence showing the effectiveness of the program, the future of Insite came under threat with the election of a conservative federal government in 2006. As a result, the PHS Community Services Society (PHS, the non-profit organization that operates Insite, launched a legal case to protect the program. On 30 September 2011, Supreme Court of Canada ruled in favour of Insite and underscored the rights of people with addictions to the security of their person under section 7 of the Charter of Rights and Freedoms (Charter of Rights. The decision clears the ground for other jurisdictions in Canada, and perhaps North America, to implement supervised injection and harm reduction where it is epidemiologically indicated. The legal case validates the personhood of people with addictions while metaphorically unchaining them from the criminal justice system.

Drug poisoning deaths in Sweden show a predominance of ethanol in mono-intoxications, adverse drug-alcohol interactions and poly-drug use.

Science.gov (United States)

Jones, A W; Kugelberg, F C; Holmgren, A; Ahlner, J

2011-03-20

Over a 10-year period (1998-2007) all deaths in Sweden classified by forensic pathologists as fatal drug poisonings (N = 6894) were retrieved from a toxicology database (TOXBASE) belonging to the National Board of Forensic Medicine. The deaths were further classified as suicides N = 2288 (33%), undetermined N = 2260 (33%) and accidental N = 2346 (34%). The average age (± SD) of all victims was 49.1 ± 15.9 years and men 47.4 ± 15.6 years were 5-year younger than women 52.2 ± 15.8 years (p intoxications) was found in 22% of all poisoning deaths (p intoxication deaths were mostly ethanol-related (N = 976) and the mean and median blood-alcohol concentration (BAC) was 3.06 g/L and 3.10 g/L, respectively. The BAC decreased as the number of additional drugs in blood increased from 2.15 g/L with one drug to 1.25 g/L with 6 or more drugs. The mean (median) concentrations of non-alcohol drugs in mono-intoxication deaths were morphine (N = 93) 0.5mg/L (0.2mg/L), amphetamine (N = 39) 2.0mg/L (1.2mg/L), dextropropoxyphene (N = 33) 3.9 mg/L (2.9 mg/L), dihydro-propiomazine (N = 32) 1.6 mg/L (1.0mg/L) and 7-amino-flunitrazepam (N = 28), 0.4 mg/L (0.3mg/L). Elevated blood morphine in these poisoning deaths mostly reflected abuse of heroin as verified by finding 6-monoacetyl morphine (6-MAM) in the blood samples. When investigating drug poisoning deaths a comprehensive toxicological analysis is essential although the results do not reveal the extent of prior exposure to drugs or the development of pharmacological tolerance. The concentrations of drugs determined in post-mortem blood are one element in the case. The autopsy report, the police investigation, the findings at the scene and eye-witness statements should all be carefully considered when the cause and manner of death are determined. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

Study on drug resistance of mycobacterium tuberculosis in patients with pulmonary tuberculosis by drug resistance gene detecting

International Nuclear Information System (INIS)

Wang Wei; Li Hongmin; Wu Xueqiong; Wang Ansheng; Ye Yixiu; Wang Zhongyuan; Liu Jinwei; Chen Hongbing; Lin Minggui; Wang Jinhe; Li Sumei; Jiang Ping; Feng Bai; Chen Dongjing

2004-01-01

To investigate drug resistance of mycobacterium tuberculosis in different age group, compare detecting effect of two methods and evaluate their the clinical application value, all of the strains of mycobacterium tuberculosis were tested for resistance to RFP, INH SM PZA and EMB by the absolute concentration method on Lowenstein-Jensen medium and the mutation of the rpoB, katG, rpsL, pncA and embB resistance genes in M. tuberculosis was tested by PCR-SSCP. In youth, middle and old age group, the rate of acquired drug resistance was 89.2%, 85.3% and 67.6% respectively, the gene mutation rate was 76.2%, 81.3% and 63.2% respectively. The rate of acquired drug resistance and multiple drug resistance in youth group was much higher than those in other groups. The gene mutation was correlated with drug resistance level of mycobacterium tuberculosis. The gene mutation rate was higher in strains isolated from high concentration resistance than those in strains isolated from low concentration resistance. The more irregular treatment was longer, the rate of drug resistance was higher. Acquired drug resistance varies in different age group. It suggested that surveillance of drug resistence in different age group should be taken seriously, especially in youth group. PCR - SSCP is a sensitive and specific method for rapid detecting rpoB, katG, rpsL, pncA and embB genes mutations of MTB. (authors)

Drug screen in patient cells suggests quinacrine to be repositioned for treatment of acute myeloid leukemia

International Nuclear Information System (INIS)

Eriksson, A; Österroos, A; Hassan, S; Gullbo, J; Rickardson, L; Jarvius, M; Nygren, P; Fryknäs, M; Höglund, M; Larsson, R

2015-01-01

To find drugs suitable for repositioning for use against leukemia, samples from patients with chronic lymphocytic, acute myeloid and lymphocytic leukemias as well as peripheral blood mononuclear cells (PBMC) were tested in response to 1266 compounds from the LOPAC 1280 library (Sigma). Twenty-five compounds were defined as hits with activity in all leukemia subgroups (<50% cell survival compared with control) at 10 μM drug concentration. Only one of these compounds, quinacrine, showed low activity in normal PBMCs and was therefore selected for further preclinical evaluation. Mining the NCI-60 and the NextBio databases demonstrated leukemia sensitivity and the ability of quinacrine to reverse myeloid leukemia gene expression. Mechanistic exploration was performed using the NextBio bioinformatic software using gene expression analysis of drug exposed acute myeloid leukemia cultures (HL-60) in the database. Analysis of gene enrichment and drug correlations revealed strong connections to ribosomal biogenesis nucleoli and translation initiation. The highest drug–drug correlation was to ellipticine, a known RNA polymerase I inhibitor. These results were validated by additional gene expression analysis performed in-house. Quinacrine induced early inhibition of protein synthesis supporting these predictions. The results suggest that quinacrine have repositioning potential for treatment of acute myeloid leukemia by targeting of ribosomal biogenesis

Dissolution rate enhancement of the poorly water-soluble drug Tibolone using PVP, SiO2, and their nanocomposites as appropriate drug carriers.

Science.gov (United States)

Papadimitriou, Sofia; Bikiaris, Dimitrios

2009-09-01

Creation of immediate release formulations for the poorly water-soluble drug Tibolone through the use of solid dispersions (SDs). SD systems of Tibolone (Tibo) with poly(vinylpyrrolidone) (PVP), fumed SiO(2) nanoparticles, and their corresponding ternary systems (PVP/SiO(2)/Tibo) were prepared and studied in order to produce formulations with enhanced drug dissolution rates. The prepared SDs were characterized by the use of differential scanning calorimetry and wide-angle X-ray diffractometry techniques. Also dissolution experiments were performed. From the results it was concluded that PVP as well as SiO(2) can be used as appropriate carriers for the amorphization of Tibo, even when the drug is used at high concentrations (20-30%, w/w). This is due to the evolved interactions taking place between the drug and the used carriers, as was verified by Fourier transform infrared spectroscopy. At higher concentrations the drug was recrystallized. Similar are the observations on the ternary PVP/SiO(2)/Tibo SDs. The dissolution profiles of the drug in PVP/Tibo and SiO(2)/Tibo SDs are directly dependent on the physical state of the drug. Immediately release rates are observed in SD with low drug concentrations, in which Tibo was in amorphous state. However, these release profiles are drastically changed in the ternary PVP/SiO(2)/Tibo SDs. An immediate release profile is observed for low drug concentrations and an almost sustained release as the concentration of Tibo increases. This is due to the weak interactions that take place between PVP and SiO(2), which result in alterations of the characteristics of the carrier (PVP/SiO(2) nanocomposites). Immediate release formulation was created for Tibolone as well as new nanocomposite matrices of PVP/SiO((2)), which drastically change the release profile of the drug to a sustained delivery.

Triple-component nanocomposite films prepared using a casting method: Its potential in drug delivery

Directory of Open Access Journals (Sweden)

Sadia Gilani

2018-04-01

Full Text Available The purpose of this study was to fabricate a triple-component nanocomposite system consisting of chitosan, polyethylene glycol (PEG, and drug for assessing the application of chitosan–PEG nanocomposites in drug delivery and also to assess the effect of different molecular weights of PEG on nanocomposite characteristics. The casting/solvent evaporation method was used to prepare chitosan–PEG nanocomposite films incorporating piroxicam-β-cyclodextrin. In order to characterize the morphology and structure of nanocomposites, X-ray diffraction technique, scanning electron microscopy, thermogravimetric analysis, and Fourier transmission infrared spectroscopy were used. Drug content uniformity test, swelling studies, water content, erosion studies, dissolution studies, and anti-inflammatory activity were also performed. The permeation studies across rat skin were also performed on nanocomposite films using Franz diffusion cell. The release behavior of films was found to be sensitive to pH and ionic strength of release medium. The maximum swelling ratio and water content was found in HCl buffer pH 1.2 as compared to acetate buffer of pH 4.5 and phosphate buffer pH 7.4. The release rate constants obtained from kinetic modeling and flux values of ex vivo permeation studies showed that release of piroxicam-β-cyclodextrin increased with an increase in concentration of PEG. The formulation F10 containing 75% concentration of PEG showed the highest swelling ratio (3.42±0.02 in HCl buffer pH 1.2, water content (47.89±1.53% in HCl buffer pH 1.2, maximum cumulative drug permeation through rat skin (2405.15±10.97 μg/cm2 in phosphate buffer pH 7.4, and in vitro drug release (35.51±0.26% in sequential pH change mediums, and showed a significantly (p<0.0001 higher anti-inflammatory effect (0.4 cm. It can be concluded from the results that film composition had a particular impact on drug release properties. The different molecular weights of PEG have a

The Female Genital Tract Microbiome Is Associated With Vaginal Antiretroviral Drug Concentrations in Human Immunodeficiency Virus-Infected Women on Antiretroviral Therapy.

Science.gov (United States)

Donahue Carlson, Renee; Sheth, Anandi N; Read, Timothy D; Frisch, Michael B; Mehta, C Christina; Martin, Amy; Haaland, Richard E; Patel, Anar S; Pau, Chou-Pong; Kraft, Colleen S; Ofotokun, Igho

2017-11-15

The female genital tract (FGT) microbiome may affect vaginal pH and other factors that influence drug movement into the vagina. We examined the relationship between the microbiome and antiretroviral concentrations in the FGT. Over one menstrual cycle, 20 human immunodeficiency virus (HIV)-infected women virologically suppressed on tenofovir (TFV) disoproxil fumarate/emtricitabine and ritonavir-boosted atazanavir (ATV) underwent serial paired cervicovaginal and plasma sampling for antiretroviral concentrations using high-performance liquid chromatography-tandem mass spectrometry. Analysis of 16S ribosomal RNA gene sequencing of cervicovaginal lavage clustered each participant visit into a unique microbiome community type (mCT). Participants were predominantly African American (95%), with a median age of 38 years. Cervicovaginal lavage sequencing (n = 109) resulted in a low-diversity mCT dominated by Lactobacillus (n = 40), and intermediate-diversity (n = 28) and high-diversity (n = 41) mCTs with abundance of anaerobic taxa. In multivariable models, geometric mean FGT:plasma ratios varied significantly by mCT for all 3 drugs. For both ATV and TFV, FGT:plasma was significantly lower in participant visits with high- and low-diversity mCT groups (all P < .02). For emtricitabine, FGT:plasma was significantly lower in participant visits with low- vs intermediate-diversity mCT groups (P = .002). Certain FGT mCTs are associated with decreased FGT antiretroviral concentrations. These findings are relevant for optimizing antiretrovirals used for biomedical HIV prevention in women. © The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

Drugs of abuse, cytostatic drugs and iodinated contrast media in tap water from the Madrid region (central Spain):A case study to analyse their occurrence and human health risk characterization.

Science.gov (United States)

Mendoza, A; Zonja, B; Mastroianni, N; Negreira, N; López de Alda, M; Pérez, S; Barceló, D; Gil, A; Valcárcel, Y

2016-01-01

This work analyses the presence of forty-eight emerging pollutants, including twenty-five drugs of abuse and metabolites, seventeen cytostatic drugs and six iodinated contrast media, in tap water from the Madrid Region. Analysis of the target compounds in the tap water was performed by means of (on-line or off-line) solid-phase extraction followed by analysis by liquid chromatography-tandem mass spectrometry. A preliminary human health risk characterization was undertaken for each individual compound and for different groups of compounds with a common mechanism of action found in tap water. The results of the study showed the presence of eight out of the twenty-five drugs of abuse and metabolites analysed, namely, the cocainics cocaine and benzoylecgonine, the amphetamine-type stimulants ephedrine, 3,4-methylenedioxymethamphetamine and methamphetamine, the opioid methadone and its metabolite 2-ethylene-1,5-dimethyl-3,3-diphenylpyrrolidine and, finally caffeine at concentrations ranging from 0.11 to 502 ng L(-1). Four out of the six analysed iodinated contrast media, namely, diatrizoate, iohexol, iomeprol and iopromide, were detected in at least one sample, with concentration values varying between 0.4 and 5 ng L(-1). Cytostatic compounds were not detected in any sample. Caffeine was the substance showing the highest concentrations, up to 502 ng L(-1), mainly in the drinking water sampling point located in Madrid city. Among the other drugs of abuse, the most abundant compounds were cocaine and benzoylecgonine, detected at concentrations ranging from 0.11 to 86 ng L(-1) and from 0.11 to 53 ng L(-1), respectively. Regarding iodinated contrast media, iohexol was the most ubiquitous and abundant compound, with a frequency of detection of 100% and concentrations from 0.5 to 5.0 ng L(-1) in basically the same range in all sampling points. Taking into account the results and types of treatment applied, ozonisation plus granular activated carbon filtration appears to be

Therapeutic drug monitoring: how to improve drug dosage and patient safety in tuberculosis treatment

Directory of Open Access Journals (Sweden)

Giovanni Sotgiu

2015-03-01

Full Text Available In this article we describe the key role of tuberculosis (TB treatment, the challenges (mainly the emergence of drug resistance, and the opportunities represented by the correct approach to drug dosage, based on the existing control and elimination strategies. In this context, the role and contribution of therapeutic drug monitoring (TDM is discussed in detail. Treatment success in multidrug-resistant (MDR TB cases is low (62%, with 7% failing or relapsing and 9% dying and in extensively drug-resistant (XDR TB cases is even lower (40%, with 22% failing or relapsing and 15% dying. The treatment of drug-resistant TB is also more expensive (exceeding €50 000 for MDR-TB and €160 000 for XDR-TB and more toxic if compared to that prescribed for drug-susceptible TB. Appropriate dosing of first- and second-line anti-TB drugs can improve the patient's prognosis and lower treatment costs. TDM is based on the measurement of drug concentrations in blood samples collected at appropriate times and subsequent dose adjustment according to the target concentration. The ‘dried blood spot’ technique offers additional advantages, providing the rationale for discussions regarding a possible future network of selected, quality-controlled reference laboratories for the processing of dried blood spots of difficult-to-treat patients from reference TB clinics around the world.

Identification of intestinal loss of a drug through physiologically based pharmacokinetic simulation of plasma concentration-time profiles.

Science.gov (United States)

Peters, Sheila Annie

2008-01-01

Despite recent advances in understanding of the role of the gut as a metabolizing organ, recognition of gut wall metabolism and/or other factors contributing to intestinal loss of a compound has been a challenging task due to the lack of well characterized methods to distinguish it from first-pass hepatic extraction. The implications of identifying intestinal loss of a compound in drug discovery and development can be enormous. Physiologically based pharmacokinetic (PBPK) simulations of pharmacokinetic profiles provide a simple, reliable and cost-effective way to understand the mechanisms underlying pharmacokinetic processes. The purpose of this article is to demonstrate the application of PBPK simulations in bringing to light intestinal loss of orally administered drugs, using two example compounds: verapamil and an in-house compound that is no longer in development (referred to as compound A in this article). A generic PBPK model, built in-house using MATLAB software and incorporating absorption, metabolism, distribution, biliary and renal elimination models, was employed for simulation of concentration-time profiles. Modulation of intrinsic hepatic clearance and tissue distribution parameters in the generic PBPK model was done to achieve a good fit to the observed intravenous pharmacokinetic profiles of the compounds studied. These optimized clearance and distribution parameters are expected to be invariant across different routes of administration, as long as the kinetics are linear, and were therefore employed to simulate the oral profiles of the compounds. For compounds with reasonably good solubility and permeability, an area under the concentration-time curve for the simulated oral profile that far exceeded the observed would indicate some kind of loss in the intestine. PBPK simulations applied to compound A showed substantial loss of the compound in the gastrointestinal tract in humans but not in rats. This accounted for the lower bioavailability of the

Do optimally ripe blackberries contain the highest levels of metabolites?

Science.gov (United States)

Mikulic-Petkovsek, Maja; Koron, Darinka; Zorenc, Zala; Veberic, Robert

2017-01-15

Five blackberry cultivars were selected for the study ('Chester Thornless', 'Cacanska Bestrna', 'Loch Ness', 'Smoothstem' and 'Thornfree') and harvested at three different maturity stages (under-, optimal- and over-ripe). Optimally ripe and over-ripe blackberries contained significantly higher levels of total sugars compared to under-ripe fruit. 'Loch Ness' cultivar was characterized by 2.2-2.6-fold higher levels of total sugars than other cultivars and consequently, the highest sugar/acids ratio. 'Chester Thornless' stands out as the cultivar with the highest level of vitamin C in under-ripe (125.87mgkg(-1)) and optimally mature fruit (127.66mgkg(-1)). Maturity stage significantly affected the accumulation of phenolic compounds. The content of total anthocyanins increased for 43% at optimal maturity stage and cinnamic acid derivatives for 57% compared to under-ripe fruit. Over-ripe blackberries were distinguished by the highest content of total phenolics (1251-2115mg GAE kg(-1) FW) and greatest FRAP values (25.9-43.2mM TE kg(-1) FW). Copyright © 2016 Elsevier Ltd. All rights reserved.

Managing Drug-Drug Interaction Between Ombitasvir, Paritaprevir/Ritonavir, Dasabuvir, and Mycophenolate Mofetil.

Science.gov (United States)

Lemaitre, Florian; Ben Ali, Zeineb; Tron, Camille; Jezequel, Caroline; Boglione-Kerrien, Christelle; Verdier, Marie-Clémence; Guyader, Dominique; Bellissant, Eric

2017-08-01

No drug-drug interaction study has been conducted to date for the combination of ombitasvir, paritaprevir/ritonavir, dasabuvir (3D), and mycophenolic acid (MPA). We here report the case of a hepatitis C virus-infected patient treated with 3D and MPA for vasculitis. In light of the threat of drug-drug interaction, the concentration of MPA was measured before, during, and 15 days after the end of the 3D treatment. Similar values were found at all 3 time points, thus indicating that there is probably no need to adapt MPA dosage to 3D.

Target mediated drug disposition with drug-drug interaction, Part II: competitive and uncompetitive cases.

Science.gov (United States)

Koch, Gilbert; Jusko, William J; Schropp, Johannes

2017-02-01

We present competitive and uncompetitive drug-drug interaction (DDI) with target mediated drug disposition (TMDD) equations and investigate their pharmacokinetic DDI properties. For application of TMDD models, quasi-equilibrium (QE) or quasi-steady state (QSS) approximations are necessary to reduce the number of parameters. To realize those approximations of DDI TMDD models, we derive an ordinary differential equation (ODE) representation formulated in free concentration and free receptor variables. This ODE formulation can be straightforward implemented in typical PKPD software without solving any non-linear equation system arising from the QE or QSS approximation of the rapid binding assumptions. This manuscript is the second in a series to introduce and investigate DDI TMDD models and to apply the QE or QSS approximation.

Drug-drug interactions as a determinant of elevated lithium serum levels in daily clinical practice

NARCIS (Netherlands)

Wilting, [No Value; Movig, KL; Moolenaar, M; Hekster, YA; Brouwers, [No Value; Heerdink, ER; Nolen, WA; Egberts, AC

Objective: Lithium is a drug with a narrow therapeutic window. Concomitantly used medication is a potentially influencing factor of lithium serum concentrations. We conducted a multicentre retrospective case-control study with the aim of investigating lithium-related drug interactions as

The influence of drug distribution and drug-target binding on target occupancy : The rate-limiting step approximation

NARCIS (Netherlands)

Witte, de W.E.A.; Vauquelin, G.; Graaf, van der P.H.; Lange, de E.C.M.

2017-01-01

The influence of drug-target binding kinetics on target occupancy can be influenced by drug distribution and diffusion around the target, often referred to as "rebinding" or "diffusion-limited binding". This gives rise to a decreased decline of the drug-target complex concentration as a result of a

Altered drug metabolism during pregnancy: hormonal regulation of drug-metabolizing enzymes.

Science.gov (United States)

Jeong, Hyunyoung

2010-06-01

Medication use during pregnancy is prevalent, but pharmacokinetic information of most drugs used during pregnancy is lacking in spite of known effects of pregnancy on drug disposition. Accurate pharmacokinetic information is essential for optimal drug therapy in mother and fetus. Thus, understanding how pregnancy influences drug disposition is important for better prediction of pharmacokinetic changes of drugs in pregnant women. Pregnancy is known to affect hepatic drug metabolism, but the underlying mechanisms remain unknown. Physiological changes accompanying pregnancy are probably responsible for the reported alteration in drug metabolism during pregnancy. These include elevated concentrations of various hormones such as estrogen, progesterone, placental growth hormones and prolactin. This review covers how these hormones influence expression of drug-metabolizing enzymes (DMEs), thus potentially responsible for altered drug metabolism during pregnancy. The reader will gain a greater understanding of the altered drug metabolism in pregnant women and the regulatory effects of pregnancy hormones on expression of DMEs. In-depth studies in hormonal regulatory mechanisms as well as confirmatory studies in pregnant women are warranted for systematic understanding and prediction of the changes in hepatic drug metabolism during pregnancy.

Influence of multidrug resistance and drug transport proteins on chemotherapy drug metabolism.

Science.gov (United States)

Joyce, Helena; McCann, Andrew; Clynes, Martin; Larkin, Annemarie

2015-05-01

Chemotherapy involving the use of anticancer drugs remains an important strategy in the overall management of patients with metastatic cancer. Acquisition of multidrug resistance remains a major impediment to successful chemotherapy. Drug transporters in cell membranes and intracellular drug metabolizing enzymes contribute to the resistance phenotype and determine the pharmacokinetics of anticancer drugs in the body. ATP-binding cassette (ABC) transporters mediate the transport of endogenous metabolites and xenobiotics including cytotoxic drugs out of cells. Solute carrier (SLC) transporters mediate the influx of cytotoxic drugs into cells. This review focuses on the substrate interaction of these transporters, on their biology and what role they play together with drug metabolizing enzymes in eliminating therapeutic drugs from cells. The majority of anticancer drugs are substrates for the ABC transporter and SLC transporter families. Together, these proteins have the ability to control the influx and the efflux of structurally unrelated chemotherapeutic drugs, thereby modulating the intracellular drug concentration. These interactions have important clinical implications for chemotherapy because ultimately they determine therapeutic efficacy, disease progression/relapse and the success or failure of patient treatment.

Development and validation of a general approach to predict and quantify the synergism of anti-cancer drugs using experimental design and artificial neural networks.

Science.gov (United States)

Pivetta, Tiziana; Isaia, Francesco; Trudu, Federica; Pani, Alessandra; Manca, Matteo; Perra, Daniela; Amato, Filippo; Havel, Josef

2013-10-15

The combination of two or more drugs using multidrug mixtures is a trend in the treatment of cancer. The goal is to search for a synergistic effect and thereby reduce the required dose and inhibit the development of resistance. An advanced model-free approach for data exploration and analysis, based on artificial neural networks (ANN) and experimental design is proposed to predict and quantify the synergism of drugs. The proposed method non-linearly correlates the concentrations of drugs with the cytotoxicity of the mixture, providing the possibility of choosing the optimal drug combination that gives the maximum synergism. The use of ANN allows for the prediction of the cytotoxicity of each combination of drugs in the chosen concentration interval. The method was validated by preparing and experimentally testing the combinations with the predicted highest synergistic effect. In all cases, the data predicted by the network were experimentally confirmed. The method was applied to several binary mixtures of cisplatin and [Cu(1,10-orthophenanthroline)2(H2O)](ClO4)2, Cu(1,10-orthophenanthroline)(H2O)2(ClO4)2 or [Cu(1,10-orthophenanthroline)2(imidazolidine-2-thione)](ClO4)2. The cytotoxicity of the two drugs, alone and in combination, was determined against human acute T-lymphoblastic leukemia cells (CCRF-CEM). For all systems, a synergistic effect was found for selected combinations. © 2013 Elsevier B.V. All rights reserved.

Cardiovascular safety of non-steroidal anti-inflammatory drugs: network meta-analysis.

Science.gov (United States)

Trelle, Sven; Reichenbach, Stephan; Wandel, Simon; Hildebrand, Pius; Tschannen, Beatrice; Villiger, Peter M; Egger, Matthias; Jüni, Peter

2011-01-11

To analyse the available evidence on cardiovascular safety of non-steroidal anti-inflammatory drugs. Network meta-analysis. Bibliographic databases, conference proceedings, study registers, the Food and Drug Administration website, reference lists of relevant articles, and reports citing relevant articles through the Science Citation Index (last update July 2009). Manufacturers of celecoxib and lumiracoxib provided additional data. All large scale randomised controlled trials comparing any non-steroidal anti-inflammatory drug with other non-steroidal anti-inflammatory drugs or placebo. Two investigators independently assessed eligibility. The primary outcome was myocardial infarction. Secondary outcomes included stroke, death from cardiovascular disease, and death from any cause. Two investigators independently extracted data. 31 trials in 116 429 patients with more than 115 000 patient years of follow-up were included. Patients were allocated to naproxen, ibuprofen, diclofenac, celecoxib, etoricoxib, rofecoxib, lumiracoxib, or placebo. Compared with placebo, rofecoxib was associated with the highest risk of myocardial infarction (rate ratio 2.12, 95% credibility interval 1.26 to 3.56), followed by lumiracoxib (2.00, 0.71 to 6.21). Ibuprofen was associated with the highest risk of stroke (3.36, 1.00 to 11.6), followed by diclofenac (2.86, 1.09 to 8.36). Etoricoxib (4.07, 1.23 to 15.7) and diclofenac (3.98, 1.48 to 12.7) were associated with the highest risk of cardiovascular death. Although uncertainty remains, little evidence exists to suggest that any of the investigated drugs are safe in cardiovascular terms. Naproxen seemed least harmful. Cardiovascular risk needs to be taken into account when prescribing any non-steroidal anti-inflammatory drug.

Illicit drug use and HIV risk in the Dominican Republic: tourism areas create drug use opportunities.

Science.gov (United States)

Guilamo-Ramos, Vincent; Lee, Jane J; Ruiz, Yumary; Hagan, Holly; Delva, Marlyn; Quiñones, Zahira; Kamler, Alexandra; Robles, Gabriel

2015-01-01

While the Caribbean has the second highest global human immunodeficiency virus (HIV) prevalence, insufficient attention has been paid to contributing factors of the region's elevated risk. Largely neglected is the potential role of drugs in shaping the Caribbean HIV/acquired immune deficiency syndrome epidemic. Caribbean studies have almost exclusively focused on drug transportation and seldom acknowledged local user economies and drug-related health and social welfare consequences. While tourism is consistently implicated within the Caribbean HIV epidemic, less is known about the intersection of drugs and tourism. Tourism areas represent distinct ecologies of risk often characterised by sex work, alcohol consumption and population mixing between lower and higher risk groups. Limited understanding of availability and usage of drugs in countries such as the Dominican Republic (DR), the Caribbean country with the greatest tourist rates, presents barriers to HIV prevention. This study addresses this gap by conducting in-depth interviews with 30 drug users in Sosúa, a major sex tourism destination of the DR. A two-step qualitative data analysis process was utilised and interview transcripts were systematically coded using a well-defined thematic codebook. Results suggest three themes: (1) local demand shifts drug routes to tourism areas, (2) drugs shape local economies and (3) drug use facilitates HIV risk behaviours in tourism areas.

Anti-addiction drug ibogaine inhibits voltage-gated ionic currents: A study to assess the drug's cardiac ion channel profile

Energy Technology Data Exchange (ETDEWEB)

Koenig, Xaver; Kovar, Michael; Rubi, Lena; Mike, Agnes K.; Lukacs, Peter; Gawali, Vaibhavkumar S.; Todt, Hannes [Center for Physiology and Pharmacology, Department of Neurophysiology and -pharmacology, Medical University of Vienna, 1090 Vienna (Austria); Hilber, Karlheinz, E-mail: karlheinz.hilber@meduniwien.ac.at [Center for Physiology and Pharmacology, Department of Neurophysiology and -pharmacology, Medical University of Vienna, 1090 Vienna (Austria); Sandtner, Walter [Center for Physiology and Pharmacology, Institute of Pharmacology, Medical University of Vienna, 1090 Vienna (Austria)

2013-12-01

The plant alkaloid ibogaine has promising anti-addictive properties. Albeit not licenced as a therapeutic drug, and despite hints that ibogaine may perturb the heart rhythm, this alkaloid is used to treat drug addicts. We have recently reported that ibogaine inhibits human ERG (hERG) potassium channels at concentrations similar to the drugs affinity for several of its known brain targets. Thereby the drug may disturb the heart's electrophysiology. Here, to assess the drug's cardiac ion channel profile in more detail, we studied the effects of ibogaine and its congener 18-Methoxycoronaridine (18-MC) on various cardiac voltage-gated ion channels. We confirmed that heterologously expressed hERG currents are reduced by ibogaine in low micromolar concentrations. Moreover, at higher concentrations, the drug also reduced human Na{sub v}1.5 sodium and Ca{sub v}1.2 calcium currents. Ion currents were as well reduced by 18-MC, yet with diminished potency. Unexpectedly, although blocking hERG channels, ibogaine did not prolong the action potential (AP) in guinea pig cardiomyocytes at low micromolar concentrations. Higher concentrations (≥ 10 μM) even shortened the AP. These findings can be explained by the drug's calcium channel inhibition, which counteracts the AP-prolonging effect generated by hERG blockade. Implementation of ibogaine's inhibitory effects on human ion channels in a computer model of a ventricular cardiomyocyte, on the other hand, suggested that ibogaine does prolong the AP in the human heart. We conclude that therapeutic concentrations of ibogaine have the propensity to prolong the QT interval of the electrocardiogram in humans. In some cases this may lead to cardiac arrhythmias. - Highlights: • We study effects of anti-addiction drug ibogaine on ionic currents in cardiomyocytes. • We assess the cardiac ion channel profile of ibogaine. • Ibogaine inhibits hERG potassium, sodium and calcium channels. • Ibogaine’s effects on

Intracellular Drug Bioavailability: Effect of Neutral Lipids and Phospholipids.

Science.gov (United States)

Treyer, Andrea; Mateus, André; Wiśniewski, Jacek R; Boriss, Hinnerk; Matsson, Pär; Artursson, Per

2018-06-04

Intracellular unbound drug concentrations are the pharmacologically relevant concentrations for targets inside cells. Intracellular drug concentrations are determined by multiple processes, including the extent of drug binding to intracellular structures. The aim of this study was to evaluate the effect of neutral lipid (NL) and phospholipid (PL) levels on intracellular drug disposition. The NL and/or PL content of 3T3-L1 cells were enhanced, resulting in phenotypes (in terms of morphology and proteome) reminiscent of adipocytes (high NL and PL) or mild phospholipidosis (only high PL). Intracellular bioavailability ( F ic ) was then determined for 23 drugs in these cellular models and in untreated wild-type cells. A higher PL content led to higher intracellular drug binding and a lower F ic . The induction of NL did not further increase drug binding but led to altered F ic due to increased lysosomal pH. Further, there was a good correlation between binding to beads coated with pure PL and intracellular drug binding. In conclusion, our results suggest that PL content is a major determinant of drug binding in cells and that PL beads may constitute a simple alternative to estimating this parameter. Further, the presence of massive amounts of intracellular NLs did not influence drug binding significantly.

Adverse drug reactions induced by cardiovascular drugs in outpatients

Directory of Open Access Journals (Sweden)

Gholami K

2008-03-01

Full Text Available Considering increased use of cardiovascular drugs and limitations in pre-marketing trials for drug safety evaluation, post marketing evaluation of adverse drug reactions (ADRs induced by this class of medicinal products seems necessary.Objectives: To determine the rate and seriousness of adverse reactions induced by cardiovascular drugs in outpatients. To compare sex and different age groups in developing ADRs with cardiovascular agents. To assess the relationship between frequencies of ADRs and the number of drugs used. Methods: This cross-sectional study was done in cardiovascular clinic at a teaching hospital. All patients during an eight months period were evaluated for cardiovascular drugs induced ADRs. Patient and reaction factors were analyzed in detected ADRs. Patients with or without ADRs were compared in sex and age by using chi-square test. Assessing the relationship between frequencies of ADRs and the number of drugs used was done by using Pearson analysis. Results: The total number of 518 patients was visited at the clinic. ADRs were detected in 105 (20.3% patients. The most frequent ADRs were occurred in the age group of 51-60. The highest rate of ADRs was recorded to be induced by Diltiazem (23.5% and the lowest rate with Atenolol (3%. Headache was the most frequent detected ADR (23%. Assessing the severity and preventability of ADRs revealed that 1.1% of ADRs were detected as severe and 1.9% as preventable reactions. Women significantly developed more ADRs in this study (chi square = 3.978, P<0.05. ADRs more frequently occurred with increasing age in this study (chi square = 15.871, P<0.05. With increasing the number of drugs used, the frequency of ADRs increased (Pearson=0.259, P<0.05. Conclusion: Monitoring ADRs in patients using cardiovascular drugs is a matter of importance since this class of medicines is usually used by elderly patients with critical conditions and underlying diseases.

Postmortem Femoral Blood Concentrations of Risperidone

DEFF Research Database (Denmark)

Linnet, Kristian; Johansen, Sys Stybe

2014-01-01

Postmortem femoral blood concentrations of the antipsychotic drug risperidone and the active metabolite 9-hydroxyrisperidone were determined by an achiral LC-MS/MS method in 38 cases. The cause of death was classified as unrelated to risperidone in 30 cases, in which the sum of the concentration ...

Does the placebo effect modulate drug bioavailability? Randomized cross-over studies of three drugs.

Science.gov (United States)

Hammami, Muhammad M; Yusuf, Ahmed; Shire, Faduma S; Hussein, Rajaa; Al-Swayeh, Reem

2017-05-23

Medication effect is the sum of its drug, placebo, and drug*placebo interaction effects. It is conceivable that the interaction effect involves modulating drug bioavailability; it was previously observed that being aware of caffeine ingestion may prolong caffeine plasma half-life. This study was set to evaluate such concept using different drugs. Balanced single-dose, two-period, two-group, cross-over design was used to compare the pharmacokinetics of oral cephalexin, ibuprofen, and paracetamol, each described by its name (overt) or as placebo (covert). Volunteers and study coordinators were deceived as to study aim. Drug concentrations were determined blindly by in-house, high performance liquid chromatography assays. Terminal-elimination half-life (t ½ ) (primary outcome), maximum concentration (C max ), C max first time (T max ), terminal-elimination-rate constant (λ), area-under-the-concentration-time-curve, to last measured concentration (AUC T ), extrapolated to infinity (AUC I ), or to T max of overt drug (AUC Overttmax ), and C max /AUC I were calculated blindly using standard non-compartmental method. Covert-vs-overt effect on drug pharmacokinetics was evaluated by analysis-of-variance (ANOVA, primary analysis), 90% confidence interval (CI) using the 80.00-125.00% bioequivalence range, and percentage of individual pharmacokinetic covert/overt ratios that are outside the +25% range. Fifty, 30, and 50 healthy volunteers (18%, 10%, and 6% females, mean (SD) age 30.8 (6.2), 31.4 (6.6), and 31.2 (5.4) years) participated in 3 studies on cephalexin, ibuprofen, and paracetamol, respectively. Withdrawal rate was 4%, 0%, and 4%, respectively. Eighteen blood samples were obtained over 6, 10, and 14 h in each study period of the three drugs, respectively. ANOVA showed no significant difference in any pharmacokinetic parameter for any of the drugs. The 90% CIs for AUC T , AUC I , C max , AUC Overttmax , and C max /AUC I were within the bioequivalence range, except

A Drug Combination Screen Identifies Drugs Active against Amoxicillin-induced Round Bodies of Borrelia burgdorferi Persisters from an FDA Drug Library

Directory of Open Access Journals (Sweden)

Jie eFeng

2016-05-01

Full Text Available Although currently recommended antibiotics for Lyme disease such as doxycycline or amoxicillin cure the majority of the patients, about 10-20% of patients treated for Lyme disease may experience lingering symptoms including fatigue, pain, or joint and muscle aches. Under stress conditions such as starvation or antibiotic exposure, Borrelia burgdorferi can develop round body forms, which are a type of persister bacteria that are not killed by current Lyme antibiotics. To identify more effective drugs that are active against the round bodies of B. burgdorferi, we established a round body persister model induced by amoxicillin and screened the Food and Drug Administration (FDA drug library consisting of 1581 drug compounds and also 22 drug combinations using the SYBR Green I/propidium iodide (PI viability assay. We identified 23 drug candidates that have higher activity against the round bodies of B. burgdorferi than either amoxicillin or doxycycline. Eleven of these scored better than metronidazole and tinidazole which have been previously described to be active against round bodies. While some drug candidates such as daptomycin and clofazimine overlapped with a previous screen against stationary phase B. burgdorferi persisters, additional drug candidates active against round bodies we identified include artemisinin, ciprofloxacin, nifuroxime, fosfomycin, chlortetracycline, sulfacetamide, sulfamethoxypyridazine and sulfathiozole. Two triple drug combinations had the highest activity against round bodies and stationary phase B. burgdorferi persisters: artemisinin/cefoperazone/doxycycline and sulfachlorpyridazine/daptomycin/doxycycline. These findings confirm and extend previous findings that certain drug combinations have superior activity against B. burgdorferi persisters in vitro, even if pre-treated with amoxicillin. These findings may have implications for improved treatment of Lyme disease.

Up to the highest peak!

CERN Multimedia

CERN Bulletin

2010-01-01

In the early hours of this morning, the beam energy was ramped up to 3.5 TeV, a new world record and the highest energy for this year’s run. Now operators will prepare the machine to make high-energy collisions later this month. CERN Operations Group leader Mike Lamont (foreground) and LHC engineer in charge Alick Macpherson in the CERN Control Centre early this morning. At 5:23 this morning, Friday 19 March, the energy of both beams in the LHC was ramped up to 3.5 TeV, a new world record. During the night, operators had tested the performance of the whole machine with two so-called ‘dry runs’, that is, without beams. Given the good overall response, beams were injected at around 3:00 a.m. and stabilized soon after. The ramp started at around 4:10 and lasted about one hour. Over the last couple of weeks, operation of the LHC at 450 GeV has become routinely reproducible. The operators were able to test and optimize the beam orbit, the beam collimation, the injection and ext...

Risk Factors for Suicide Attempt in Drug Abusers

OpenAIRE

farideh faraji; Neda Kakayi; Mohammad Kazem Atef Vahid; Ahmad Sohraby; Samira Purghorbani

2015-01-01

Objective: The present study was conducted to identify risk and prediction factors of suicide attempts among drug abusers. Method: This causal-comparative study was conducted on 91 drug abusers that included 42 male and female suicide attempters and 49 male and female counterparts. Millon multi-axial personality inventory-II (MCMI-II), Dass-42 (depression, anxiety, stress), and coping styles inventory were used for data collection purposes. Results: The highest rate of suicide attempt was fou...

Effect of Na2SO3 concentration to drug loading and drug release of ascorbic acid in chitosan edible film as drug delivery system membrane

Directory of Open Access Journals (Sweden)

Kistriyani Lilis

2018-01-01

Full Text Available Chitosan is a type of carbohydrate compounds produced from waste marine products, in particular the class of shrimp, crabs and clams. Chitosan is often process into edible films and utilized for food packaging also has potential as a membrane for drug delivery system. Drug loading and drug release can be controlled by improve the characteristics of the membrane by adding crosslinker. The purpose of this research is to study the effect of addition of crosslinker to the rate of loading and release of ascorbic acid in the chitosan edible film. Na2SO3 was used as crosslinker. Two grams of chitosan was dissolved into 100 ml of distilled water. Acetic acid and plasticizer were added in the solution then heated at 50°C. Na2SO3 solution with mass various of Na2SO3 dissolved, 01026 0.3; and 0.5 grams were added about 30 mL to make edible film. The analysis include of drug loading, drug release and tensile strength. The result showed that the loading of edible film with crosslinker 0.15 g; 0.3 g; and 0.5 g respectively were 60.98 ppm; 52.53 ppm; and 40.88 ppm, meanwhile for the release with crosslinker 0.15 g; 0.3 g; and 0.5 g respectively were 3.78 ppm; 5.72 ppm; and 5.97 ppm.

Grapefruit and drug interactions.

Science.gov (United States)

2012-12-01

Since the late 1980s, grapefruit juice has been known to affect the metabolism of certain drugs. Several serious adverse effects involving drug interactions with grapefruit juice have been published in detail. The components of grapefruit juice vary considerably depending on the variety, maturity and origin of the fruit, local climatic conditions, and the manufacturing process. No single component accounts for all observed interactions. Other grapefruit products are also occasionally implicated, including preserves, lyophylised grapefruit juice, powdered whole grapefruit, grapefruit seed extract, and zest. Clinical reports of drug interactions with grapefruit juice are supported by pharmacokinetic studies, each usually involving about 10 healthy volunteers, in which the probable clinical consequences were extrapolated from the observed plasma concentrations. Grapefruit juice inhibits CYP3A4, the cytochrome P450 isoenzyme most often involved in drug metabolism. This increases plasma concentrations of the drugs concerned, creating a risk of overdose and dose-dependent adverse effects. Grapefruit juice also inhibits several other cytochrome P450 isoenzymes, but they are less frequently implicated in interactions with clinical consequences. Drugs interacting with grapefruit and inducing serious clinical consequences (confirmed or very probable) include: immunosuppressants, some statins, benzodiazepines, most calcium channel blockers, indinavir and carbamazepine. There are large inter-individual differences in enzyme efficiency. Along with the variable composition of grapefruit juice, this makes it difficult to predict the magnitude and clinical consequences of drug interactions with grapefruit juice in a given patient. There is increasing evidence that transporter proteins such as organic anion transporters and P-glycoprotein are involved in interactions between drugs and grapefruit juice. In practice, numerous drugs interact with grapefruit juice. Although only a few

Fenton-like reaction: a possible way to efficiently remove illicit drugs and pharmaceuticals from wastewater.

Science.gov (United States)

Mackuľak, Tomáš; Mosný, Michal; Grabic, Roman; Golovko, Oksana; Koba, Olga; Birošová, Lucia

2015-03-01

We analyzed 13 psychoactive pharmaceuticals, illicit drugs and their metabolites in wastewater treatment plant influent and effluent and the possibility of their degradation by biological and chemical processes. Tramadol (413-853 ng/L) and methamphetamine (460-682 ng/L) were the most concentrated compounds in the wastewater in winter and summer, respectively. A significant decrease in the concentration of tramadol in wastewater was measured during the summer. The lowest efficiency was observed for tramadol, venlafaxine, citalopram and oxazepam (∼ 10%) and the highest efficiency was observed for amphetamine and THC-COOH (∼ 80%). The efficiency of compound degradation via the Fenton reaction, a modified Fenton reaction and different degradation (by algae, wood-rotting fungi and enzymes at influent versus effluent) was determined. The Fenton reaction and its modification were efficient at eliminating these substances in comparison with the tested biological processes. Copyright © 2015 Elsevier B.V. All rights reserved.

Effect of ventilation type on radon concentration at places of work

International Nuclear Information System (INIS)

Oksanen, E.

1994-01-01

Indoor radon ( 222 Rn) concentrations were measured at 76 child care facilities and 36 schools in southern Finland. The buildings had three different types of ventilation systems: mechanical air supply and exhaust, mechanical exhaust, and natural ventilation, the first being most common. The effect of the ventilation type on the long-term radon concentration was studied in child care facilities. The radon concentrations were highest in the naturally ventilated buildings. The mechanical air supply and exhaust system maintained the lowest values in cold wintertime. In school buildings both the long-term radon concentration and short-term radon and daughter concentrations were measured. The correlation of the ventilation type and the radon concentration was not obvious in this group of measurements, but the radon concentrations and the equilibrium factors were highest in buildings with natural ventilation. Radon concentrations were generally lower during the working hours than during the one-month period, as expected. (author)

Application of Hill's equation for estimating area under the concentration-time curve (AUC) and use of time to AUC 90% for expressing kinetics of drug disposition.

Science.gov (United States)

Cheng, Hsien C

2009-01-01

Half life and its derived pharmacokinetic parameters are calculated on an assumption that the terminal phase of drug disposition follows a constant rate of disposition. In reality, this assumption may not necessarily be the case. A new method is needed for analyzing PK parameters if the disposition does not follow a first order PK kinetic. Cumulative area under the concentration-time curve (AUC) is plotted against time to yield a hyperbolic (or sigmoidal) AUC-time relationship curve which is then analyzed by Hill's equation to yield AUC(inf), time to achieving AUC50% (T(AUC50%)) or AUC90% (T(AUC90%)), and the Hill's slope. From these parameters, an AUC-time relationship curve can be reconstructed. Projected plasma concentration can be calculated for any time point. Time at which cumulative AUC reaches 90% (T(AUC90%)) can be used as an indicator for expressing how fast a drug is cleared. Clearance is calculated in a traditional manner (i.v. dose/AUC(inf)), and the volume of distribution is proposed to be calculated at T(AUC50%) (0.5 i.v. dose/plasma concentration at T(AUC50%)). This method of estimating AUC is applicable for both i.v. and oral data. It is concluded that the Hill's equation can be used as an alternative method for estimating AUC and analysis of PK parameters if the disposition does not follow a first order kinetic. T(AUC90%) is proposed to be used as an indicator for expressing how fast a drug is cleared from the system.

21 CFR 146.150 - Canned concentrated orange juice.

Science.gov (United States)

2010-04-01

... 21 Food and Drugs 2 2010-04-01 2010-04-01 false Canned concentrated orange juice. 146.150 Section... Fruit Juices and Beverages § 146.150 Canned concentrated orange juice. (a) Canned concentrated orange... labeling of ingredients prescribed for frozen concentrated orange juice by § 146.146, except that it is not...

Highest weight representations of the quantum algebra Uh(gl∞)

International Nuclear Information System (INIS)

Palev, T.D.; Stoilova, N.I.

1997-04-01

A class of highest weight irreducible representations of the quantum algebra U h (gl-∞) is constructed. Within each module a basis is introduced and the transformation relations of the basis under the action of the Chevalley generators are explicitly written. (author). 16 refs

Multi-residue screening of prioritised human pharmaceuticals, illicit drugs and bactericides in sediments and sludge.

Science.gov (United States)

Langford, Katherine H; Reid, Malcolm; Thomas, Kevin V

2011-08-01

A robust multi-residue method was developed for the analysis of a selection of pharmaceutical compounds, illicit drugs and personal care product bactericides in sediments and sludges. Human pharmaceuticals were selected for analysis in Scottish sewage sludge and freshwater sediments based on prescription, physico-chemical and occurrence data. The method was suitable for the analysis of the selected illicit drugs amphetamine, benzoylecgonine, cocaine, and methamphetamine, the pharmaceuticals atenolol, bendroflumethiazide, carbamazepine, citalopram, diclofenac, fluoxetine, ibuprofen, and salbutamol, and the bactericides triclosan and triclocarban in sewage sludge and freshwater sediment. The method provided an overall recovery of between 56 and 128%, RSDs of between 2 and 19% and LODs of between 1 and 50 ng g(-1). Using the methodology the human pharmaceuticals atenolol, carbamazepine and citalopram and the bactericides triclosan and triclocarban were detected in Scottish sewage sludge. The illicit drugs cocaine, its metabolite benzoylecgonine, amphetamine and methamphetamine were not detected in any of the samples analysed. Triclosan and triclocarban were present at the highest concentrations with triclocarban detected in all but one sample and showing a pattern of co-occurrence in both sludge and sediment samples.

Drug utilization of biological drugs in the treatment of chronic Immune-Mediated Inflammatory Diseases (IMIDs: an observational study on Italian patients

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Paolo Faccendini

2017-09-01

Full Text Available Drug utilization of biological drugs in the treatment of chronic Immune-Mediated Inflammatory Diseases (IMIDs: an observational study on Italian patientsObjectives:The aim of this analysis was to provide an estimate of drug utilization indicators (dose escalation and dose tapering related to biologic drugs in the chronic treatment of adult patients with Immune-Mediated Inflammatory Diseases (IMIDs.Methods:We conducted an observational retrospective cohort analysis using the Policlinico di Tor Vergata (PTV database. We considered all biologic drugs dispensed by the PTV hospital pharmacy between January 2010 and December 2015:abatacept, adalimumab, certolizumab, etanercept, golimumab, infliximab (originator and biosimilar, tocilizumab, and ustekinumab were included. Drug dose escalation and dose tapering were calculated and compared with their Defined Daily Dose (DDD.Results:A total of 1803 patients with IMID and biologic drug prescription were analyzed (male: 51.2%. The majority of patients were in the class 36-50 years (n = 612. The median follow-up was 33.8 months (IQR 14.43-56.20. Dermatology was the ward with the largest number of patients (n = 882; 48.9%, followed by rheumatology (n = 619; 34.3% and gastroenterology (n = 302; 16.8%. Dose escalation was observed in 406 patients (22.5%. Infliximab biosimilar (n = 51 was the biological drug with the highest dose escalation rate (86.3%, followed by infliximab originator (n = 28; 60.3% and ustekinumab (37.8%. Etanercept was the biological drug with the lowest dose escalation rate (7.4%, followed by golimumab (12.2% and adalimumab (13.8%. In 677 patients (37.5% a dose tapering was observed. Etanercept showed the highest rate of patients with dose tapering (41.6%, followed by adalimumab (33.6%.Conclusions:The results of this analysis show that dose modification is quite common in PTV clinical practice. Considering the strong focus on the pharmaceutical expenditure and the need of cost containment

One fourth of acutely admitted patients use over-the-counter-drugs 24 hours prior to hospitalisation

DEFF Research Database (Denmark)

Pedersen, Magnus; Brabrand, Mikkel

2014-01-01

INTRODUCTION: Use of over-the-counter (OTC) drugs is increasing and is poorly registered, which can lead to complications. The most commonly used OTC drugs are analgesics, and their usage is highest among elderly patients. Our study investigates the use of OTC drugs 24 hours prior to hospitalisat......INTRODUCTION: Use of over-the-counter (OTC) drugs is increasing and is poorly registered, which can lead to complications. The most commonly used OTC drugs are analgesics, and their usage is highest among elderly patients. Our study investigates the use of OTC drugs 24 hours prior...... to hospitalisation and the effects of this intake. MATERIAL AND METHODS: Junior physicians on call interviewed patients admitted to the medical admission unit at South-West Jutland Hospital in Esbjerg using a modified chart template. Adult patients aged 15 and older admitted during a two-week period in August 2012...

21 CFR 146.145 - Orange juice from concentrate.

Science.gov (United States)

2010-04-01

... 21 Food and Drugs 2 2010-04-01 2010-04-01 false Orange juice from concentrate. 146.145 Section 146... Juices and Beverages § 146.145 Orange juice from concentrate. (a) Orange juice from concentrate is the food prepared by mixing water with frozen concentrated orange juice as defined in § 146.146 or with...

Utility of coloured hair for the detection of drugs and alcohol.

Science.gov (United States)

Agius, Ronald

2014-06-01

The aim of this paper is to assess the utility of coloured hair for the detection of drugs and alcohol in a large statistically significant population. The positivity rate, the 1st, 5th, 50th, 95th, and 99th percentiles of five amphetamines, cannabinoids, cocaine, four opiates, methadone, buprenorphine, seven benzodiazepines, and ethyl glucuronide (EtG) in 9488 non-treated and 1026 cosmetically treated (dyed or bleached) authentic hair samples was compared. Analytical methods used were accredited for forensic purposes at the cut-offs defined by the German driving licence re-granting medical and psychological assessment (MPA) guidelines. Considering only the drug classes for which at least 10 positive samples were detected, the positivity rate in non-treated hair was highest for alcohol (4.50%; measured using EtG at concentrations ≥ 7 pg/mg hair), followed by THC (2.00%), cocaine (1.75%), and amphetamine (0.59%). While the 1st to 99th percentile range was significantly lower for drugs in treated, compared to non-treated hair, no significant change was observed for EtG. Additionally, no significant difference in the positivity rate was observed between treated hair and non-treated hair for both drugs and EtG. This study is the first attempt to evaluate the influence of cosmetic treatment, mainly dying, on the positivity rate for both drugs and EtG in hair samples submitted routinely for abstinence testing and the first to indicate that dyed and eventually bleached hair is not necessarily useless in detecting drugs and/or alcohol consumption, thus making coloured hair analysis still useful, often being the only possibility to prove such misuse. Copyright © 2014 John Wiley & Sons, Ltd.

Composition and Concentration of Phenolic Compounds of ‘Auksis’ Apple Grown on Various Rootstocks

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Kviklys Darius

2017-06-01

Full Text Available The trial was carried out at the Institute of Horticulture, Lithuanian Research Centre for Agriculture and Forestry in 2013-2015. Cv. ‘Auksis’ was tested on 12 rootstocks: B.396, B.9, M.9, M.26, P 22, P 59, P 61, P 62, P 66, P 67, PB.4, and Pure 1. Accumulation of phenolic compounds depended on fruit yield and average fruit weight. On average, significantly lower concentration among rootstocks occurred when apple trees had abundant yield and fruits were smaller. On average chlorogenic acid constituted 50% and total procyanidins 28% of total phenols in ‘Auksis’ fruits. Flavonoid concentration most depended on rootstock and the highest variation was recorded. More than 50% difference occurred between the highest total flavonoid concentration in apples on PB.4 and the lowest on M.9 rootstocks. Low variability of total procyanidin concentration among rootstocks was observed. Differences between the highest and lowest concentration was 15%. Total concentration of phenolic compounds differed among rootstocks by 29-35% depending on the year. Differences in accumulation of phenolic compounds depended on rootstock genotype but not on yield or fruit weight. PB.4 and P 67 rootstocks had the highest, and M.9, P 62 and M.26 had the lowest concentration of total phenol in ‘Auksis’ fruits

Therapeutic drug monitoring of isoniazid and rifampicin during anti-tuberculosis treatment in Auckland, New Zealand.

Science.gov (United States)

Maze, M J; Paynter, J; Chiu, W; Hu, R; Nisbet, M; Lewis, C

2016-07-01

There is uncertainty as to the optimal therapeutic concentrations of anti-tuberculosis drugs to achieve cure. To characterise the use of therapeutic drug monitoring (TDM), and identify risk factors and outcomes for those with concentrations below the drug interval. Patients treated for tuberculosis (TB) who had rifampicin (RMP) or isoniazid (INH) concentrations measured between 1 January 2005 and 31 December 2012 were studied retrospectively. Matched concentrations and drug dosing time were assessed according to contemporary regional drug intervals (RMP > 6 μmol/l, INH > 7.5 μmol/l) and current international recommendations (RMP > 10 μmol/l, INH > 22 μmol/l). Outcomes were assessed using World Health Organization criteria. Of 865 patients, 121 had concentrations of either or both medications. RMP concentrations were within the regional drug intervals in 106/114 (93%) and INH in 91/100 (91%). Concentrations were within international drug intervals for RMP in 76/114 (67%) and INH in 53/100 (53%). Low weight-based dose was the only statistically significant risk factor for concentrations below the drug interval. Of the 35 patients with low concentrations, 21 were cured, 9 completed treatment and 5 transferred out. There were no relapses during follow-up (mean 66.5 months). There were no clinically useful characteristics to guide use of TDM. Many patients had concentrations below international therapeutic intervals, but were successfully treated.

Assessment of simvastatin niosomes for pediatric transdermal drug delivery.

Science.gov (United States)

Zidan, Ahmed S; Hosny, Khaled M; Ahmed, Osama A A; Fahmy, Usama A

2016-06-01

The prevalence of childhood dyslipidemia increases and is considered as an important risk factor for the incidence of cardiovascular disease in the adulthood. To improve dosing accuracy and facilitate the determination of dosing regimens in function of the body weight, the proposed study aims at preparing transdermal niosomal gels of simvastatin as possible transdermal drug delivery system for pediatric applications. Twelve formulations were prepared to screen the influence of formulation and processing variables on critical niosomal characteristics. Nano-sized niosomes with 0.31 μm number-weighted size displayed highest simvastatin release rate with 8.5% entrapment capacity. The niosomal surface coverage by negative charges was calculated according to Langmuir isotherm with n = 0.42 to suggest that the surface association was site-independent, probably producing surface rearrangements. Hypolipidemic activities after transdermal administration of niosomal gels to rats showed significant reduction in cholesterol and triglyceride levels while increasing plasma high-density lipoproteins concentration. Bioavailability estimation in rats revealed an augmentation in simvastatin bioavailability by 3.35 and 2.9 folds from formulation F3 and F10, respectively, compared with oral drug suspension. Hence, this transdermal simvastatin niosomes not only exhibited remarkable potential to enhance its bioavailability and hypolipidemic activity but also considered a promising pediatric antihyperlipidemic formulation.

[Drug expenditures of pensioners in 1997-2000].

Science.gov (United States)

Swistak, Piotr; Błońska-Fajfrowska, Barbara

2003-01-01

The general purpose of the study, carried out in the group of pensioners was to determine the relation between drug prices, household income and amounts of money spent on drugs in the years 1997-2000. The study was based on representative data gathered from annual household budgets review by Polish Statistical Office and data from pharmaceutical market published in 'Vitamina C++' magazine. The used method combined descriptive, comparative, table-descriptive analysis with graphical analysis. During studied period the real value of expenses on drugs in pensioners' households rose by 39.3% and available income decreased by 5.8%. Increased expenses on drugs caused the rise of the proportion of on spending on drugs in total household expenditure. It rose from 3.9% in 1997 to 5.2% in 2000. Throughout this time period the drug prices increased in real terms: the highest growth (approx. 49%) was noticed in patients' co-payment to reimbursed drugs. Despite rise in spending on drugs, due to the increase in drug retail prices and increasing patients co-payment, pensioners in comparison with 1997, could buy only approx. 93% units of reimbursed drugs in 2000. The possibility of buying drugs within OTC group increased by 18%.

Measured density and calculated baricity of custom-compounded drugs for chronic intrathecal infusion.

Science.gov (United States)

Hejtmanek, Michael R; Harvey, Tracy D; Bernards, Christopher M

2011-01-01

To minimize the frequency that intrathecal pumps require refilling, drugs are custom compounded at very high concentrations. Unfortunately, the baricity of these custom solutions is unknown, which is problematic, given baricity's importance in determining the spread of intrathecally administered drugs. Consequently, we measured the density and calculated the baricity of clinically relevant concentrations of multiple drugs used for intrathecal infusion. Morphine, clonidine, bupivacaine, and baclofen were weighed to within 0.0001 g and diluted in volumetric flasks to produce solutions of known concentrations (morphine 1, 10, 25, and 50 mg/mL; clonidine 0.05, 0.5, 1, and 3 mg/mL; bupivacaine 2.5, 5, 10, and 20 mg/mL; baclofen 1, 1.5, 2, and 4 mg/mL). The densities of the solutions were measured at 37°C using the mechanical oscillation method. A "best-fit" curve was calculated for plots of concentration versus density for each drug. All prepared solutions of clonidine and baclofen were hypobaric. Higher concentrations of morphine and bupivacaine were hyperbaric, whereas lower concentrations were hypobaric. The relationship between concentration and density is linear for morphine (r > 0.99) and bupivacaine (r > 0.99) and logarithmic for baclofen (r = 0.96) and clonidine (r = 0.98). This is the first study to examine the relationship between concentration and density for custom drug concentrations commonly used in implanted intrathecal pumps. We calculated an equation that defines the relationship between concentration and density for each drug. Using these equations, clinicians can calculate the density of any solution made from the drugs studied here.

Solid Lipid Nanoparticles of Guggul Lipid as Drug Carrier for Transdermal Drug Delivery

Directory of Open Access Journals (Sweden)

Praveen Kumar Gaur

2013-01-01

Full Text Available Diclofenac sodium loaded solid lipid nanoparticles (SLNs were formulated using guggul lipid as major lipid component and analyzed for physical parameters, permeation profile, and anti-inflammatory activity. The SLNs were prepared using melt-emulsion sonication/low temperature-solidification method and characterized for physical parameters, in vitro drug release, and accelerated stability studies, and formulated into gel. Respective gels were compared with a commercial emulgel (CEG and plain carbopol gel containing drug (CG for ex vivo and in vivo drug permeation and anti-inflammatory activity. The SLNs were stable with optimum physical parameters. GMS nanoparticle 1 (GMN-1 and stearic acid nanoparticle 1 (SAN-1 gave the highest in vitro drug release. Guggul lipid nanoparticle gel 3 (GLNG-3 showed 104.68 times higher drug content than CEG in receptor fluid. The enhancement ratio of GLNG-3 was 39.43 with respect to CG. GLNG-3 showed almost 8.12 times higher Cmax than CEG at 4 hours. The AUC value of GLNG-3 was 15.28 times higher than the AUC of CEG. GLNG-3 showed edema inhibition up to 69.47% in the first hour. Physicochemical properties of major lipid component govern the properties of SLN. SLN made up of guggul lipid showed good physical properties with acceptable stability. Furthermore, it showed a controlled drug release profile along with a promising permeation profile.

Therapeutic drug monitoring of atypical antipsychotic drugs

Directory of Open Access Journals (Sweden)

Grundmann Milan

2014-12-01

Full Text Available Schizophrenia is a severe psychiatric disorder often associated with cognitive impairment and affective, mainly depressive, symptoms. Antipsychotic medication is the primary intervention for stabilization of acute psychotic episodes and prevention of recurrences and relapses in patients with schizophrenia. Typical antipsychotics, the older class of antipsychotic agents, are currently used much less frequently than newer atypical antipsychotics. Therapeutic drug monitoring (TDM of antipsychotic drugs is the specific method of clinical pharmacology, which involves measurement of drug serum concentrations followed by interpretation and good cooperation with the clinician. TDM is a powerful tool that allows tailor-made treatment for the specific needs of individual patients. It can help in monitoring adherence, dose adjustment, minimizing the risk of toxicity and in cost-effectiveness in the treatment of psychiatric disorders. The review provides complex knowledge indispensable to clinical pharmacologists, pharmacists and clinicians for interpretation of TDM results.

Melanin targeting for intracellular drug delivery: Quantification of bound and free drug in retinal pigment epithelial cells.

Science.gov (United States)

Rimpelä, Anna-Kaisa; Hagström, Marja; Kidron, Heidi; Urtti, Arto

2018-05-31

Melanin binding affects drug distribution and retention in pigmented ocular tissues, thereby affecting drug response, duration of activity and toxicity. Therefore, it is a promising possibility for drug targeting and controlled release in the pigmented cells and tissues. Intracellular unbound drug concentrations determine pharmacological and toxicological actions, but analyses of unbound vs. total drug concentrations in pigmented cells are lacking. We studied intracellular binding and cellular drug uptake in pigmented retinal pigment epithelial cells and in non-pigmented ARPE-19 cells with five model drugs (chloroquine, propranolol, timolol, diclofenac, methotrexate). The unbound drug fractions in pigmented cells were 0.00016-0.73 and in non-pigmented cells 0.017-1.0. Cellular uptake (i.e. distribution ratio Kp), ranged from 1.3 to 6300 in pigmented cells and from 1.0 to 25 in non-pigmented cells. Values for intracellular bioavailability, F ic , were similar in both cells types (although larger variation in pigmented cells). In vitro melanin binding parameters were used to predict intracellular unbound drug fraction and cell uptake. Comparison of predictions with experimental data indicates that other factors (e.g. ion-trapping, lipophilicity-related binding to other cell components) also play a role. Melanin binding is a major factor that leads to cellular uptake and unbound drug fractions of a range of 3-4 orders of magnitude indicating that large reservoirs of melanin bound drug can be generated in the cells. Understanding melanin binding has important implications on retinal drug targeting, efficacy and toxicity. Copyright © 2017. Published by Elsevier B.V.

Understanding release kinetics of biopolymer drug delivery microcapsules for biomedical applications

International Nuclear Information System (INIS)

Desai, Salil; Perkins, Jessica; Harrison, Benjamin S.; Sankar, Jag

2010-01-01

Drug delivery and dosage concentrations are considered as major focal points in conventional as well as battlefield emergency medicine. The concept of localizing drug delivery via microcapsules is an evolving field to confine the adverse side effects of high concentration drug doses. This paper focuses on understanding release kinetics through biopolymer microcapsules for time-dependent drug release. Calcium alginate microcapsules were manufactured using a direct-write inkjet technique. Rhodamine 6G was used as the release agent to observe the release kinetics from calcium alginate beads in distilled water. A design of experiments was constructed to compare the effect of the microcapsule diameter and different concentrations of calcium chloride (M) and sodium alginate (%, w/v) solutions on the release kinetics profiles of the microcapsules. This research gives insight to identify favorable sizes of microcapsules and concentrations of sodium alginate and calcium chloride solutions for controlled release behavior of drug delivery microcapsules.

Lung Cancer Screening May Benefit Those at Highest Risk

Science.gov (United States)

People at the highest risk for lung cancer, based on a risk model, may be more likely to benefit from screening with low-dose CT, a new analysis suggests. The study authors believe the findings may better define who should undergo lung cancer screening, as this Cancer Currents blog post explains.

Hydrophobic Drug-Loaded PEGylated Magnetic Liposomes for Drug-Controlled Release

Science.gov (United States)

Hardiansyah, Andri; Yang, Ming-Chien; Liu, Ting-Yu; Kuo, Chih-Yu; Huang, Li-Ying; Chan, Tzu-Yi

2017-05-01

Less targeted and limited solubility of hydrophobic-based drug are one of the serious obstacles in drug delivery system. Thus, new strategies to enhance the solubility of hydrophobic drug and controlled release behaviors would be developed. Herein, curcumin, a model of hydrophobic drug, has been loaded into PEGylated magnetic liposomes as a drug carrier platform for drug controlled release system. Inductive magnetic heating (hyperthermia)-stimulated drug release, in vitro cellular cytotoxicity assay of curcumin-loaded PEGylated magnetic liposomes and cellular internalization-induced by magnetic guidance would be investigated. The resultant of drug carriers could disperse homogeneously in aqueous solution, showing a superparamagnetic characteristic and could inductive magnetic heating with external high-frequency magnetic field (HFMF). In vitro curcumin release studies confirmed that the drug carriers exhibited no significant release at 37 °C, whereas exhibited rapid releasing at 45 °C. However, it would display enormous (three times higher) curcumin releasing under the HFMF exposure, compared with that without HFMF exposure at 45 °C. In vitro cytotoxicity test shows that curcumin-loaded PEGylated magnetic liposomes could efficiently kill MCF-7 cells in parallel with increasing curcumin concentration. Fluorescence microscopy observed that these drug carriers could internalize efficiently into the cellular compartment of MCF-7 cells. Thus, it would be anticipated that the novel hydrophobic drug-loaded PEGylated magnetic liposomes in combination with inductive magnetic heating are promising to apply in the combination of chemotherapy and thermotherapy for cancer therapy.

Tacrolimus concentration/dose ratio as a therapeutic drug monitoring strategy: The influence of gender and comedication

Directory of Open Access Journals (Sweden)

Rančić Nemanja

2015-01-01

Full Text Available Background/Aim. A combination of tacrolimus and other drugs such as corticosteroids has been commonly used immunosuppresive regimens. On the other hand, there is a growing body of evidence that male and female may differ in their response to the equal drug treatment. The aim of the study was to estimated the use of tacrolimus concentration/dose (C/D ratio for the assessment of the influence of gender differences and comedication on tacrolimus exposure in renal transplant recipients. Methods. This prospective case series study included 54 patients, in which the unit of monitoring was outpatient examination (1,872 of the renal transplant patients. The patients were monitored in the period 2010-2014, starting one month after the transplantation. Tacrolimus trough concentrations (TTC were measured by chemiluminescence microparticles immunoassay. Results. TTC and the tacrolimus C/D ratio were significantly lower in the females comparing with the males. Contrary to the males, in the females a significant increase of the tacrolimus daily dose (TDD per body weight and TTC, along with the corticosteroid dose increase, was not accompanied by any significant changes in the tacrolimus C/D ratio; in different corticosteroid doses faster elimination of tacrolimus was found with the exception of the doses > 0.25 mg/kg. In the patients treated with proton pump inhibitors, mainly with pantoprazole TDD per body weight and TTC were significantly higher, while the tacrolimus C/D ratio was significantly lower compared to the patients without this treatment. In the patients treated with calcium channel blockers, TDD per body weight was significantly lower (particularly with amlodipine while the tacrolimus C/D ratio was higher compared to the patients who were not treated by them. Conclusion. A lower tacrolimus exposure was detected in females in comparison to males. When gender differences were considered in the context of different corticosteroid doses, faster

The highest energy cosmic rays, photons and neutrinos

International Nuclear Information System (INIS)

Zas, Enrique

1998-01-01

In these lectures I introduce and discuss aspects of currently active fields of interest related to the production, transport and detection of high energy particles from extraterrestrial sources. I have payed most attention to the highest energies and I have divided the material according to the types of particles which will be searched for with different experimental facilities in planning: hadrons, gamma rays and neutrinos. Particular attention is given to shower development, stochastic acceleration and detection techniques

Prevalence of alcohol and drugs among motorcycle riders killed in road crashes in Norway during 2001-2010.

Science.gov (United States)

Christophersen, Asbjørg S; Gjerde, Hallvard

2015-07-01

The aim of the study was to examine the prevalence of alcohol and drugs in blood samples from motorcycle riders who died in road crashes in Norway from 2001 to 2010. An additional aim was to compare the prevalence of alcohol and drugs in blood samples from fatally injured motorcycle riders and car drivers who died during the same time period. Blood samples from motorcycle riders who died within 24h after the accident (n=207, 63% of all killed riders), were analysed for alcohol, psychoactive drugs (medicinal and illicit drugs). The cut-off concentrations for alcohol and drugs findings in blood samples (i.e., the drug concentrations above which a finding was regarded as positive) were set according to the legislative limits under the Norwegian Road Traffic Act. Results were assessed in relation to age, sex, time of the day and week, and single versus multiple-vehicle accidents. Alcohol or drugs were found in 27.1 percent of all investigated riders. For riders killed in single or multiple-vehicle accidents, alcohol or drugs were found in 44.6 and 15.3 percent, respectively. Alcohol was the most frequently found substance for all age groups and most prevalent in samples from riders below 25 years who died in single-vehicle accidents (45.8 percent). Drugs were most often found among riders between 25 and 34 years (19.6 percent in total and 25.9% for those killed in single-vehicle crashes). The prevalence of alcohol or drugs was highest among riders killed in single-vehicle accidents during weekend days and nights (60.9 and 65.2 percent). Alcohol and drugs were less often found in samples from killed motorcycles riders than in samples from car and van drivers (40.2 percent). For single-vehicle accidents, the total prevalence of alcohol or drugs among killed motorcycles riders and car drivers was 44.6 percent and 63.8 percent, respectively. The same pattern of alcohol and drugs was found among the two groups, except that the prevalence among motorcycle riders was lower

Analyzing a low NO[sub x] concentric combustion system

Energy Technology Data Exchange (ETDEWEB)

Kotler, V.R.; Eremeev, A.V.

1992-05-01

Discusses concentric combustion technology developed by Combustion Engineering, Inc. (USA) to reduce NO[sub x] emissions from pulverized coal-fired boilers. The major innovation consists in arranging existing independent secondary air burners into three pairs of concentric combustion burners. Using high-deflection angle concentric combustion burners, higher oxygen concentration near the boiler walls, reduced erosion and lower probability of slag deposition on the heat shield are achieved. The technology was tested at the 165 MW Valmont power plant and 350 MW Cherokee power plant. Reduction of 55.7% (to 0.294 kg/GJ) in NO[sub x] emissions with a boiler efficiency of 86.35% was achieved. Highest NO[sub x] reduction efficiency was observed at full load (highest tertiary air supply). Burner design, performance, relations of NO[sub x] emissions and tertiary air blast as well as fuel entrainment prior to and after upgrading are given. Methods of reducing slag deposition in boilers are considered. 2 refs.

Effects of low concentrations of Regorafenib and Sorafenib on human HCC cell AFP, migration, invasion and growth in vitro

Science.gov (United States)

Carr, Brian Irving; D’Alessandro, Rosalba; Refolo, Maria Grazia; Iacovazzi, Palma Aurelia; Lippolis, Catia; Messa, Caterina; Cavallini, Aldo; Correale, Mario; Di Carlo, Antonio

2012-01-01

Sorafenib was shown in clinical trial to enhance survival in hepatocellular carcinoma (HCC) patients, but with minimal tumor shrinkage. To correlate several indices of HCC growth at various drug concentrations, HCC cells were grown in various low concentrations of two multi-kinase inhibitors, Regorafenib (Stivarga) and Sorafenib (Nexavar) and their effects were examined on alpha-fetoprotein (AFP), cell growth, migration and invasion. In two AFP positive human HCC cell lines, AFP was inhibited at 0.1–1µM drug concentrations. Cell migration and invasion were also inhibited at similar low drug concentrations. However, 10-fold higher drug concentrations were required to inhibit cell growth in both AFP positive and negative cells. To investigate this concentration discrepancy of effects, cells were then grown for prolonged times and sub-cultured in low drug concentrations and then their growth was re-tested. The growth in these drug-exposed cells was found to be slower than cells without prior drug exposure and they were also more sensitive to subsequent drug challenge. Evidence was also found for changes in cell signaling pathways in these slow-growth cells. Low multi-kinase inhibitor concentrations thus modulate several aspects of HCC cell biology. PMID:23169148

Setting priorities for a research agenda to combat drug-resistant tuberculosis in children.

Science.gov (United States)

Velayutham, B; Nair, D; Ramalingam, S; Perez-Velez, C M; Becerra, M C; Swaminathan, S

2015-12-21

Numerous knowledge gaps hamper the prevention and treatment of childhood drug-resistant tuberculosis (TB). Identifying research priorities is vital to inform and develop strategies to address this neglected problem. To systematically identify and rank research priorities in childhood drug-resistant TB. Adapting the Child Health and Nutrition Research Initiative (CHNRI) methodology, we compiled 53 research questions in four research areas, then classified the questions into three research types. We invited experts in childhood drug-resistant TB to score these questions through an online survey. A total of 81 respondents participated in the survey. The top-ranked research question was to identify the best combination of existing diagnostic tools for early diagnosis. Highly ranked treatment-related questions centred on the reasons for and interventions to improve treatment outcomes, adverse effects of drugs and optimal treatment duration. The prevalence of drug-resistant TB was the highest-ranked question in the epidemiology area. The development type questions that ranked highest focused on interventions for optimal diagnosis, treatment and modalities for treatment delivery. This is the first effort to identify and rank research priorities for childhood drug-resistant TB. The result is a resource to guide research to improve prevention and treatment of drug-resistant TB in children.

Remote controlled capsules in human drug absorption (HDA) studies.

Science.gov (United States)

Wilding, Ian R; Prior, David V

2003-01-01

The biopharmaceutical complexity of today's new drug candidates provides significant challenges for pharmaceutical scientists in terms of both candidate selection and optimizing subsequent development strategy. In addition, life cycle management of marketed drugs has become an important income stream for pharmaceutical companies, but the selection of least risk/highest benefit strategies is far from simple. The proactive adoption of human drug absorption (HDA) studies using remote controlled capsules offers the pharmaceutical scientist significant guidance for planning a route through the maze of product development. This review examines the position of HDA studies in drug development, using a variety of case histories and an insightful update on remote controlled capsules to achieve site-specific delivery.

Origin of the highest energy cosmic rays

Energy Technology Data Exchange (ETDEWEB)

Biermann, Peter L.; Ahn, Eun-Joo; Medina-Tanco, Gustavo; Stanev, Todor

2000-06-01

Introducing a simple Galactic wind model patterned after the solar wind we show that back-tracing the orbits of the highest energy cosmic events suggests that they may all come from the Virgo cluster, and so probably from the active radio galaxy M87. This confirms a long standing expectation. Those powerful radio galaxies that have their relativistic jets stuck in the interstellar medium of the host galaxy, such as 3C147, will then enable us to derive limits on the production of any new kind of particle, expected in some extensions of the standard model in particle physics. New data from HIRES will be crucial in testing the model proposed here.

Can medical students calculate drug doses? | Harries | Southern ...

African Journals Online (AJOL)

... with calculations when the drug concentration was expressed either as a ratio or a percentage. Conclusion: Our findings support calls for the standardised labelling of drugs in solution and for dosage calculation training in the medical curriculum. Keywords: drug dosage calculations, clinical competence, medication errors

A Drug Combination Screen Identifies Drugs Active against Amoxicillin-Induced Round Bodies of In Vitro Borrelia burgdorferi Persisters from an FDA Drug Library.

Science.gov (United States)

Feng, Jie; Shi, Wanliang; Zhang, Shuo; Sullivan, David; Auwaerter, Paul G; Zhang, Ying

2016-01-01

Although currently recommended antibiotics for Lyme disease such as doxycycline or amoxicillin cure the majority of the patients, about 10-20% of patients treated for Lyme disease may experience lingering symptoms including fatigue, pain, or joint and muscle aches. Under experimental stress conditions such as starvation or antibiotic exposure, Borrelia burgdorferi can develop round body forms, which are a type of persister bacteria that appear resistant in vitro to customary first-line antibiotics for Lyme disease. To identify more effective drugs with activity against the round body form of B. burgdorferi, we established a round body persister model induced by exposure to amoxicillin (50 μg/ml) and then screened the Food and Drug Administration drug library consisting of 1581 drug compounds and also 22 drug combinations using the SYBR Green I/propidium iodide viability assay. We identified 23 drug candidates that have higher activity against the round bodies of B. burgdorferi than either amoxicillin or doxycycline. Eleven individual drugs scored better than metronidazole and tinidazole which have been previously described to be active against round bodies. In this amoxicillin-induced round body model, some drug candidates such as daptomycin and clofazimine also displayed enhanced activity which was similar to a previous screen against stationary phase B. burgdorferi persisters not exposure to amoxicillin. Additional candidate drugs active against round bodies identified include artemisinin, ciprofloxacin, nifuroxime, fosfomycin, chlortetracycline, sulfacetamide, sulfamethoxypyridazine and sulfathiozole. Two triple drug combinations had the highest activity against amoxicillin-induced round bodies and stationary phase B. burgdorferi persisters: artemisinin/cefoperazone/doxycycline and sulfachlorpyridazine/daptomycin/doxycycline. These findings confirm and extend previous findings that certain drug combinations have superior activity against B. burgdorferi

A New Class III Antiarrhythmic Drug Niferidil Prolongs Action Potentials in Guinea Pig Atrial Myocardium via Inhibition of Rapid Delayed Rectifier.

Science.gov (United States)

Abramochkin, Denis V; Kuzmin, Vladislav S; Rosenshtraukh, Leonid V

2017-12-01

A new class III antiarrhythmic drug niferidil (RG-2) has been introduced as a highly effective therapy for cases of persistent atrial fibrillation, but ionic mechanisms of its action are poorly understood. In the present study, the effects of niferidil on action potential (AP) waveform and potassium currents responsible for AP repolarization were investigated in guinea pig atrial myocardium. APs were recorded with sharp glass microelectrodes in multicellular atrial preparations. Whole-cell patch-clamp technique was used to measure K + currents in isolated myocytes. In multicellular atrial preparations, 10 -8  M niferidil effectively prolonged APs by 15.2 ± 2.8% at 90% repolarization level. However, even the highest tested concentrations, 10 -6  M and 10 -5  M failed to prolong APs more than 32.5% of control duration. The estimated concentration of niferedil for half-maximal AP prolongation was 1.13 × 10 -8  M. Among the potassium currents responsible for AP repolarization phase, I K1 was found to be almost insensitive to niferidil. However, another inward rectifier, I KACh , was effectively suppressed by micromolar concentrations of niferidil with IC 50  = 9.2 × 10 -6  M. I KATP was much less sensitive to the drug with IC 50  = 2.26 × 10 -4  M. The slow component of delayed rectifier, I Ks , also demonstrated low sensitivity to niferidil-the highest used concentration, 10 -4  M, decreased peak I Ks density to 46.2 ± 5.5% of control. Unlike I Ks , the rapid component of delayed rectifier, I Kr , appeared to be extremely sensitive to niferidil. The IC 50 was 1.26 × 10 -9  M. I Kr measured in ventricular myocytes was found to be less sensitive to niferidil with IC 50  = 3.82 × 10 -8  M. Niferidil prolongs APs in guinea pig atrial myocardium via inhibition of I Kr .

Radionuclide concentrations in wild waterfowl using the test reactor area radioactive leaching pond

International Nuclear Information System (INIS)

Halford, D.K.; Millard, J.B.; Markham, O.D.

1978-01-01

Waterfowl use the Test Reactor Area (TRA) Radioactive Leaching Pond on the Idaho National Engineering Laboratory Site (INEL Site) as a resting area. Daily observations of waterfowl were made to determine species composition and numbers. Eight ducks and one coot were collected from the TRA pond during 1976 and 1977. Seven background samples were also collected. Each bird was dissected and tissue samples were analyzed for gamma-emitting radionuclides. Duck tissues contained 25 radionuclides. Average and maximum radionuclide concentrations were highest in gut followed by feathers, liver, and muscle, Chromium-51 had the highest concentrations of all radionuclides identified 130,000 pCi/g (4800 Bq/g) in the gut and 37,500 pCi/g (1390 Bq/g) on the feathres). Neodymium-147 had the highest concentration on feathers of any radionuclide (104,000 pCi/g, 3850 Bq/g). Cesium-137 was the predominant radionuclide in muscle with a maximum concentration of 4,070 pCi/g (150 Bq/g). The ducks had lower radionuclide concentrations in the edible tissues than in the non-edible tissues. Potential whole-body and thyroid dose commitments to man consuming contaminated ducks were calculated using muscle concentrations of Cs-134, Cs-137, and I-131. Although assumptions used for dose calculations maximized the dose commitment to man, results indicated that consumption of contaminated duck tissue is not a radiation hazard to humans. Even the highest dose commitments were below the limits recommended for individuals of the general population by the Internatioal Commission on Radiological Protection (ICRP). The highest potential dose commitment to man would result from the consumption of an American coot known to have spent 20 days on the TRA pond. The average dose commitment to man would be 20 mrem

A new derivation of the highest-weight polynomial of a unitary lie algebra

International Nuclear Information System (INIS)

P Chau, Huu-Tai; P Van, Isacker

2000-01-01

A new method is presented to derive the expression of the highest-weight polynomial used to build the basis of an irreducible representation (IR) of the unitary algebra U(2J+1). After a brief reminder of Moshinsky's method to arrive at the set of equations defining the highest-weight polynomial of U(2J+1), an alternative derivation of the polynomial from these equations is presented. The method is less general than the one proposed by Moshinsky but has the advantage that the determinantal expression of the highest-weight polynomial is arrived at in a direct way using matrix inversions. (authors)

Alcohol and drug use in early adolescence.

Science.gov (United States)

Hotton, Tina; Haans, Dave

2004-05-01

This analysis presents the prevalence of substance use among young adolescents. The extent to which factors such as peer behaviour, parenting practices and school commitment and achievement are associated with drinking to intoxication and other drug use is investigated. The data are from the 1998/99 National Longitudinal Survey of Children and Youth. Analysis is based on a cross-sectional file from 4,296 respondents aged 12 to 15. Prevalence estimates for alcohol and drug use were calculated by sex. Logistic regression models were fitted to estimate the odds of drinking to intoxication and drug use, adjusted for socio-demographic factors, peer and parent substance use, parenting practices, school commitment/attachment, emotional health and religious attendance. In general, drinking to intoxication and drug use were more common among 14- and 15-year-olds than among 12- and 13-year-olds. The odds of drinking to intoxication and drug use were highest among adolescents whose friends used alcohol or drugs or were often in trouble, who reported low commitment to school, or whose parents had a hostile and ineffective parenting style.

Intensive care unit drug costs in the context of total hospital drug expenditures with suggestions for targeted cost containment efforts.

Science.gov (United States)

Altawalbeh, Shoroq M; Saul, Melissa I; Seybert, Amy L; Thorpe, Joshua M; Kane-Gill, Sandra L

2018-04-01

To assess costs of intensive care unit (ICU) related pharmacotherapy relative to hospital drug expenditures, and to identify potential targets for cost-effectiveness investigations. We offer the unique advantage of comparing ICU drug costs with previously published data a decade earlier to describe changes over time. Financial transactions for all ICU patients during fiscal years (FY) 2009-2012 were retrieved from the hospital's data repository. ICU drug costs were evaluated for each FY. ICU departments' charges were also retrieved and calculated as percentages of total ICU charges. Albumin, prismasate (dialysate), voriconazole, factor VII and alteplase denoted the highest percentages of ICU drug costs. ICU drug costs contributed to an average of 31% (SD 1.0%) of the hospital's total drug costs. ICU drug costs per patient day increased by 5.8% yearly versus 7.8% yearly for non-ICU drugs. This rate was higher for ICU drugs costs at 12% a decade previous. Pharmacy charges contributed to 17.7% of the total ICU charges. Growth rates of costs per year have declined but still drug expenditures in the ICU are consistently a significant driver in this resource intensive environment with a high impact on hospital drug expenditures. Copyright © 2017 Elsevier Inc. All rights reserved.

A high content screening assay to predict human drug-induced liver injury during drug discovery.

Science.gov (United States)

Persson, Mikael; Løye, Anni F; Mow, Tomas; Hornberg, Jorrit J

2013-01-01

Adverse drug reactions are a major cause for failures of drug development programs, drug withdrawals and use restrictions. Early hazard identification and diligent risk avoidance strategies are therefore essential. For drug-induced liver injury (DILI), this is difficult using conventional safety testing. To reduce the risk for DILI, drug candidates with a high risk need to be identified and deselected. And, to produce drug candidates without that risk associated, risk factors need to be assessed early during drug discovery, such that lead series can be optimized on safety parameters. This requires methods that allow for medium-to-high throughput compound profiling and that generate quantitative results suitable to establish structure-activity-relationships during lead optimization programs. We present the validation of such a method, a novel high content screening assay based on six parameters (nuclei counts, nuclear area, plasma membrane integrity, lysosomal activity, mitochondrial membrane potential (MMP), and mitochondrial area) using ~100 drugs of which the clinical hepatotoxicity profile is known. We find that a 100-fold TI between the lowest toxic concentration and the therapeutic Cmax is optimal to classify compounds as hepatotoxic or non-hepatotoxic, based on the individual parameters. Most parameters have ~50% sensitivity and ~90% specificity. Drugs hitting ≥2 parameters at a concentration below 100-fold their Cmax are typically hepatotoxic, whereas non-hepatotoxic drugs typically hit based on nuclei count, MMP and human Cmax, we identified an area without a single false positive, while maintaining 45% sensitivity. Hierarchical clustering using the multi-parametric dataset roughly separates toxic from non-toxic compounds. We employ the assay in discovery projects to prioritize novel compound series during hit-to-lead, to steer away from a DILI risk during lead optimization, for risk assessment towards candidate selection and to provide guidance of safe

The Experience Elicited by Hallucinogens Presents the Highest Similarity to Dreaming within a Large Database of Psychoactive Substance Reports

Science.gov (United States)

Sanz, Camila; Zamberlan, Federico; Erowid, Earth; Erowid, Fire; Tagliazucchi, Enzo

2018-01-01

Ever since the modern rediscovery of psychedelic substances by Western society, several authors have independently proposed that their effects bear a high resemblance to the dreams and dreamlike experiences occurring naturally during the sleep-wake cycle. Recent studies in humans have provided neurophysiological evidence supporting this hypothesis. However, a rigorous comparative analysis of the phenomenology (“what it feels like” to experience these states) is currently lacking. We investigated the semantic similarity between a large number of subjective reports of psychoactive substances and reports of high/low lucidity dreams, and found that the highest-ranking substance in terms of the similarity to high lucidity dreams was the serotonergic psychedelic lysergic acid diethylamide (LSD), whereas the highest-ranking in terms of the similarity to dreams of low lucidity were plants of the Datura genus, rich in deliriant tropane alkaloids. Conversely, sedatives, stimulants, antipsychotics, and antidepressants comprised most of the lowest-ranking substances. An analysis of the most frequent words in the subjective reports of dreams and hallucinogens revealed that terms associated with perception (“see,” “visual,” “face,” “reality,” “color”), emotion (“fear”), setting (“outside,” “inside,” “street,” “front,” “behind”) and relatives (“mom,” “dad,” “brother,” “parent,” “family”) were the most prevalent across both experiences. In summary, we applied novel quantitative analyses to a large volume of empirical data to confirm the hypothesis that, among all psychoactive substances, hallucinogen drugs elicit experiences with the highest semantic similarity to those of dreams. Our results and the associated methodological developments open the way to study the comparative phenomenology of different altered states of consciousness and its relationship with non-invasive measurements of brain physiology. PMID

The Experience Elicited by Hallucinogens Presents the Highest Similarity to Dreaming within a Large Database of Psychoactive Substance Reports

Directory of Open Access Journals (Sweden)

Camila Sanz

2018-01-01

Full Text Available Ever since the modern rediscovery of psychedelic substances by Western society, several authors have independently proposed that their effects bear a high resemblance to the dreams and dreamlike experiences occurring naturally during the sleep-wake cycle. Recent studies in humans have provided neurophysiological evidence supporting this hypothesis. However, a rigorous comparative analysis of the phenomenology (“what it feels like” to experience these states is currently lacking. We investigated the semantic similarity between a large number of subjective reports of psychoactive substances and reports of high/low lucidity dreams, and found that the highest-ranking substance in terms of the similarity to high lucidity dreams was the serotonergic psychedelic lysergic acid diethylamide (LSD, whereas the highest-ranking in terms of the similarity to dreams of low lucidity were plants of the Datura genus, rich in deliriant tropane alkaloids. Conversely, sedatives, stimulants, antipsychotics, and antidepressants comprised most of the lowest-ranking substances. An analysis of the most frequent words in the subjective reports of dreams and hallucinogens revealed that terms associated with perception (“see,” “visual,” “face,” “reality,” “color”, emotion (“fear”, setting (“outside,” “inside,” “street,” “front,” “behind” and relatives (“mom,” “dad,” “brother,” “parent,” “family” were the most prevalent across both experiences. In summary, we applied novel quantitative analyses to a large volume of empirical data to confirm the hypothesis that, among all psychoactive substances, hallucinogen drugs elicit experiences with the highest semantic similarity to those of dreams. Our results and the associated methodological developments open the way to study the comparative phenomenology of different altered states of consciousness and its relationship with non-invasive measurements of brain

The highest global concentrations and increased abundance of oceanic plastic debris in the North Pacific: Evidence from seabirds

Science.gov (United States)

Robards, Martin D.; Gould, Patrick J.; Coe, James M.; Rogers, Donald B.

1997-01-01

Plastic pollution has risen dramatically with an increase in production of plastic resin during the past few decades. Plastic production in the United States increased from 2.9 million tons in I960 to 47.9 million tons in 1985 (Society of the Plastics Industry 1986). This has been paralleled by a significant increase in the concentration of plastic particles in oceanic surface waters of the North Pacific from the 1970s to the late 1980s (Day and Shaw 1987; Day et al. 1990a). Research during the past few decades has indicated two major interactions between marine life and oceanic plastic: entanglement and ingestion (Laist 1987). Studies in the last decade have documented the prevalence of plastic in the diets of many seabird species in the North Pacific and the need for further monitoring of those species and groups that ingest the most plastic (Day et al. 1985).

21 CFR 146.146 - Frozen concentrated orange juice.

Science.gov (United States)

2010-04-01

... 21 Food and Drugs 2 2010-04-01 2010-04-01 false Frozen concentrated orange juice. 146.146 Section... Fruit Juices and Beverages § 146.146 Frozen concentrated orange juice. (a) Frozen concentrated orange juice is the food prepared by removing water from the juice of mature oranges as provided in § 146.135...

Quantitative analysis of microbicide concentrations in fluids, gels and tissues using confocal Raman spectroscopy.

Directory of Open Access Journals (Sweden)

Oranat Chuchuen

Full Text Available Topical vaginal anti-HIV microbicides are an important focus in female-based strategies to prevent the sexual transmission of HIV. Understanding microbicide pharmacokinetics is essential to development, characterization and implementation of efficacious microbicide drug delivery formulations. Current methods to measure drug concentrations in tissue (e.g., LC-MS/MS, liquid chromatography coupled with tandem mass spectrometry are highly sensitive, but destructive and complex. This project explored the use of confocal Raman spectroscopy to detect microbicide drugs and to measure their local concentrations in fluids, drug delivery gels, and tissues. We evaluated three candidate microbicide drugs: tenofovir, Dapivirine and IQP-0528. Measurements were performed in freshly excised porcine buccal tissue specimens, gel vehicles and fluids using two Horiba Raman microscopes, one of which is confocal. Characteristic spectral peak calibrations for each drug were obtained using serial dilutions in the three matrices. These specific Raman bands demonstrated strong linear concentration dependences in the matrices and were characterized with respect to their unique vibrational signatures. At least one specific Raman feature was identified for each drug as a marker band for detection in tissue. Sensitivity of detection was evaluated in the three matrices. A specific peak was also identified for tenofovir diphosphate, the anti-HIV bioactive product of tenofovir after phosphorylation in host cells. Z-scans of drug concentrations vs. depth in excised tissue specimens, incubated under layers of tenofovir solution in a Transwell assay, showed decreasing concentration with depth from the surface into the tissue. Time-dependent concentration profiles were obtained from tissue samples incubated in the Transwell assay, for times ranging 30 minutes - 6 hours. Calibrations and measurements from tissue permeation studies for tenofovir showed good correlation with gold

Quantitative Analysis of Microbicide Concentrations in Fluids, Gels and Tissues Using Confocal Raman Spectroscopy

Science.gov (United States)

Chuchuen, Oranat; Henderson, Marcus H.; Sykes, Craig; Kim, Min Sung; Kashuba, Angela D. M.; Katz, David F.

2013-01-01

Topical vaginal anti-HIV microbicides are an important focus in female-based strategies to prevent the sexual transmission of HIV. Understanding microbicide pharmacokinetics is essential to development, characterization and implementation of efficacious microbicide drug delivery formulations. Current methods to measure drug concentrations in tissue (e.g., LC-MS/MS, liquid chromatography coupled with tandem mass spectrometry) are highly sensitive, but destructive and complex. This project explored the use of confocal Raman spectroscopy to detect microbicide drugs and to measure their local concentrations in fluids, drug delivery gels, and tissues. We evaluated three candidate microbicide drugs: tenofovir, Dapivirine and IQP-0528. Measurements were performed in freshly excised porcine buccal tissue specimens, gel vehicles and fluids using two Horiba Raman microscopes, one of which is confocal. Characteristic spectral peak calibrations for each drug were obtained using serial dilutions in the three matrices. These specific Raman bands demonstrated strong linear concentration dependences in the matrices and were characterized with respect to their unique vibrational signatures. At least one specific Raman feature was identified for each drug as a marker band for detection in tissue. Sensitivity of detection was evaluated in the three matrices. A specific peak was also identified for tenofovir diphosphate, the anti-HIV bioactive product of tenofovir after phosphorylation in host cells. Z-scans of drug concentrations vs. depth in excised tissue specimens, incubated under layers of tenofovir solution in a Transwell assay, showed decreasing concentration with depth from the surface into the tissue. Time-dependent concentration profiles were obtained from tissue samples incubated in the Transwell assay, for times ranging 30 minutes - 6 hours. Calibrations and measurements from tissue permeation studies for tenofovir showed good correlation with gold standard LC-MS/MS data

X-ray Spectroscopy for Quality Control of Chemotherapy Drugs

International Nuclear Information System (INIS)

Greaves, E. D.; Barros, H.; Bermudez, J.; Sajo-Bohus, L.; Angeli-Greaves, M.

2007-01-01

We develop a method, employing Compton peak standardization and the use of matrix-matched spiked samples with Total Reflection X-ray Fluorescence (TXRF), for the determination of platinum plasma concentrations of patients undergoing chemotherapy with Pt-bearing drugs. Direct blood plasma analysis attains Pt detection limits of 70 ng/ml. Measurement results of prescribed drug doses are compared to achieved blood Pt concentrations indicating a lack of expected correlations. Direct analysis of Pt-containing infused drugs from a variety of suppliers indicates cases of abnormal concentrations which raises quality control issues. We demonstrate the potential usefulness of the method for pharmacokinetic studies or for routine optimization and quality control of Pt chemotherapy treatments

Emerging Frontiers in Drug Delivery.

Science.gov (United States)

Tibbitt, Mark W; Dahlman, James E; Langer, Robert

2016-01-27

Medicine relies on the use of pharmacologically active agents (drugs) to manage and treat disease. However, drugs are not inherently effective; the benefit of a drug is directly related to the manner by which it is administered or delivered. Drug delivery can affect drug pharmacokinetics, absorption, distribution, metabolism, duration of therapeutic effect, excretion, and toxicity. As new therapeutics (e.g., biologics) are being developed, there is an accompanying need for improved chemistries and materials to deliver them to the target site in the body, at a therapeutic concentration, and for the required period of time. In this Perspective, we provide an historical overview of drug delivery and controlled release followed by highlights of four emerging areas in the field of drug delivery: systemic RNA delivery, drug delivery for localized therapy, oral drug delivery systems, and biologic drug delivery systems. In each case, we present the barriers to effective drug delivery as well as chemical and materials advances that are enabling the field to overcome these hurdles for clinical impact.

mtct regimen choice, drug resistance and the treatment of hiv

African Journals Online (AJOL)

risk of transmission is highest during labour and delivery, ... will have a major impact on controlling perinatally acquired HIV infection. ... could result in the development of drug resistance with potential .... dosing, pharmacokinetics and safety.

Tocopheryl pullulan-based self assembling nanomicelles for anti-cancer drug delivery

Energy Technology Data Exchange (ETDEWEB)

Wang, Jingyun, E-mail: wangjingyun67@dlut.edu.cn [School of Life Science and Biotechnology, Dalian University of Technology, Dalian 116024 (China); Cui, Shuang [School of Life Science and Biotechnology, Dalian University of Technology, Dalian 116024 (China); Bao, Yongming, E-mail: biosci@dlut.edu.cn [School of Life Science and Biotechnology, Dalian University of Technology, Dalian 116024 (China); Xing, Jishuang [School of Life Science and Biotechnology, Dalian University of Technology, Dalian 116024 (China); Hao, Wenbo [Department of Physics and Chemistry, Heihe University, Heihe 164300 (China)

2014-10-01

Amphiphilic α-tocopherol pullulan polymers (PUTC1, PUTC2, and PUTC3) with different degrees of substitution were synthesized as new carriers for anticancer drugs. The polymers easily self-assembled into nanomicelles through dialysis method. The critical micelle concentrations (CMCs) were 38.0, 8.0, and 4.3 mg/L for PUTC1, PUTC2, and PUTC3, respectively. 10-Hydroxycamptothecin (HCPT) used as a model drug was successfully loaded into the PUTC nanomicelles. Transmission electron microscopy images demonstrated that HCPT-loaded PUTC nanomicelles were almost spherical and had sizes ranging within 171.5–257.8 nm that increased with increased HCPT-loading content, as determined by dynamic laser scattering. The highest encapsulation efficiency of HCPT in PUTC nanomicelles reached 98.3%. The in vitro release of HCPT from PUTC micelles demonstrated sustained release for over 80 h. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assays showed that blank PUTC micelles were nontoxic to normal cells and that the HCPT-loaded PUTC2 nanomicelles showed higher cytotoxicity than the free drug, which was attributed to the enhanced cellular uptake of drug-loaded nanomicelles. Biodistribution experiments showed that PUTC micelles provided an excellent approach to rapid drug transport into cell nuclei. Moreover, the cellular uptake of micelles was found to be an energy-dependent and actin polymerization-associated endocytic process by endocytosis inhibition experiments. These results suggested that PUTC nanomicelles had considerable potential as a drug carrier for drug intracellular delivery in cancer therapy. - Highlights: • Tocopheryl pullulan-based (PUTC) self-assembling nanomicelles were fabricated. • These micelles showed low CMC and dispersed uniformly with regular spherical shape. • High entrapment efficiency and in vitro sustained release of HCPT in PUTC micelles • HCPT–PUTC micelles accumulated in cell nuclei and showed higher anticancer activity. �

Tocopheryl pullulan-based self assembling nanomicelles for anti-cancer drug delivery

International Nuclear Information System (INIS)

Wang, Jingyun; Cui, Shuang; Bao, Yongming; Xing, Jishuang; Hao, Wenbo

2014-01-01

Amphiphilic α-tocopherol pullulan polymers (PUTC1, PUTC2, and PUTC3) with different degrees of substitution were synthesized as new carriers for anticancer drugs. The polymers easily self-assembled into nanomicelles through dialysis method. The critical micelle concentrations (CMCs) were 38.0, 8.0, and 4.3 mg/L for PUTC1, PUTC2, and PUTC3, respectively. 10-Hydroxycamptothecin (HCPT) used as a model drug was successfully loaded into the PUTC nanomicelles. Transmission electron microscopy images demonstrated that HCPT-loaded PUTC nanomicelles were almost spherical and had sizes ranging within 171.5–257.8 nm that increased with increased HCPT-loading content, as determined by dynamic laser scattering. The highest encapsulation efficiency of HCPT in PUTC nanomicelles reached 98.3%. The in vitro release of HCPT from PUTC micelles demonstrated sustained release for over 80 h. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assays showed that blank PUTC micelles were nontoxic to normal cells and that the HCPT-loaded PUTC2 nanomicelles showed higher cytotoxicity than the free drug, which was attributed to the enhanced cellular uptake of drug-loaded nanomicelles. Biodistribution experiments showed that PUTC micelles provided an excellent approach to rapid drug transport into cell nuclei. Moreover, the cellular uptake of micelles was found to be an energy-dependent and actin polymerization-associated endocytic process by endocytosis inhibition experiments. These results suggested that PUTC nanomicelles had considerable potential as a drug carrier for drug intracellular delivery in cancer therapy. - Highlights: • Tocopheryl pullulan-based (PUTC) self-assembling nanomicelles were fabricated. • These micelles showed low CMC and dispersed uniformly with regular spherical shape. • High entrapment efficiency and in vitro sustained release of HCPT in PUTC micelles • HCPT–PUTC micelles accumulated in cell nuclei and showed higher anticancer activity. �

Efficacy Coefficients Determined Using Nail Permeability and Antifungal Activity in Keratin-Containing Media Are Useful for Predicting Clinical Efficacies of Topical Drugs for Onychomycosis.

Directory of Open Access Journals (Sweden)

Yoshiki Matsuda

Full Text Available Onychomycosis is difficult to treat topically due to the deep location of the infection under the densely keratinized nail plate. In order to obtain an in vitro index that is relevant to the clinical efficacy of topical anti-onychomycosis drugs, we profiled five topical drugs: amorolfine, ciclopirox, efinaconazole, luliconazole, and terbinafine, for their nail permeabilities, keratin affinities, and anti-dermatophytic activities in the presence of keratin. Efinaconazole and ciclopirox permeated full-thickness human nails more deeply than luliconazole. Amorolfine and terbinafine did not show any detectable permeation. The free-drug concentration of efinaconazole in a 5% human nail keratin suspension was 24.9%, which was significantly higher than those of the other drugs (1.1-3.9%. Additionally, efinaconazole was released from human nail keratin at a greater proportion than the other drugs. The MICs of the five drugs for Trichophyton rubrum were determined at various concentrations of keratin (0-20% in RPMI 1640 medium. The MICs of ciclopirox were not affected by keratin, whereas those of efinaconazole were slightly increased and those of luliconazole and terbinafine were markedly increased in the presence of 20% keratin. Efficacy coefficients were calculated using the nail permeation flux and MIC in media without or with keratin. Efinaconazole showed the highest efficacy coefficient, which was determined using MIC in media with keratin. The order of efficacy coefficients determined using MIC in keratin-containing media rather than keratin-free media was consistent with that of complete cure rates in previously reported clinical trials. The present study revealed that efficacy coefficients determined using MIC in keratin-containing media are useful for predicting the clinical efficacies of topical drugs. In order to be more effective, topical drugs have to possess higher efficacy coefficients.

Interaction of charged amphiphilic drugs with phosphatidylcholine vesicles studied by NMR

International Nuclear Information System (INIS)

Eriksson, L.E.G.

1987-01-01

Small unilamellar vesicles from egg phosphatidylcholine in NaCl solutions were exposed to some amphiphilic pharmaca. The aromatic drugs (chlorpromazine, dibucaine, tetracaine, imipramine and propranolol) were in their cationic form of the amines. By 1 H- and 31 P-NMR the membrane signals were observed. In particular, the N-methyl choline proton signals were followed upon drug addition. The intrinsic chemical shift difference (0.02 ppm) between the inner (upfield) and outer choline signals was influenced by the drug concentration. Packing properties of the lipid head groups and ring current shift probably contributed. At very high drug concentration, the vesicles are destroyed. A transformation into a micellar state with a high sample viscosity took place in a narrow concentration range of drug. The anion effects of Cl - were studied from the 35 Cl-NMR linewidth at 9.8 and 39.1 MHz. A continuous increase in the signal linewidth followed upon drug addition to the vesicles. Only chlorpromazine produced a broadening in the absence of vesicles (NaCl blank). The linewidth reflected a critical micelle concentration of this drug around 7 mM in 0.1 M NaCl. The 35 Cl-NMR experiments demonstrated the existence of an anionic counterion effect. This phenomenon should be accounted for when quantitatively analysing drug-membrane interactions in electrostatic terms. (Auth.)

Fabrication of drug nanoparticles by evaporative precipitation of nanosuspension.

Science.gov (United States)

Kakran, M; Sahoo, N G; Li, L; Judeh, Z; Wang, Y; Chong, K; Loh, L

2010-01-04

Evaporative precipitation of nanosuspension (EPN) was used to fabricate nanoparticles of a poorly water-soluble antimalarial drug, artemisinin (ART), with the aim of enhancing its dissolution rate. We investigated the nanoparticle fabrication of ART via a full factorial experimental design considering the effects of drug concentration and solvent to antisolvent ratio on the physical, morphological and dissolution properties of ART. Characterization of the original ART powder and EPN prepared ART nanoparticles was carried out by scanning electron microscopy, differential scanning calorimetry (DSC), X-ray diffraction (XRD) and dissolution tester. DSC and XRD studies suggested that the crystallinity of EPN prepared ART nanoparticles decreased with increasing drug concentration and ratio of solvent to antisolvent. The particle diameters of EPN prepared ART nanoparticles were found to be 100-360 nm. The dissolution of EPN prepared ART nanoparticles markedly increased as compared to the original ART powder. A percent dissolution surface-response model was used to elucidate the significant and direct relationships between drug concentration and solvent to antisolvent ratio on one hand and percent dissolution on the other hand. The best dissolution percent was found to be 75.9%, at the drug concentration of 15 mg/mL and solvent to antisolvent ratio (by volume) of 1:20.

Radon and radon-daughter concentrations in air in the vicinity of the Anaconda Uranium Mill

International Nuclear Information System (INIS)

Momeni, M.H.; Lindstrom, J.B.; Dungey, C.E.; Kisieleski, W.E.

1979-11-01

Radon concentration, working level, and meteorological variables were measured continuously from June 1977 through June 1978 at three stations in the vicinity of the Anaconda Uranium Mill with measurements integrated to hourly intervals. Both radon and daughters show strong variations associated with low wind velocities and stable atmospheric conditions, and diurnal variations associated with thermal inversions. Average radon concentration shows seasonal dependence with highest concentrations observed during fall and winter. Comparison of radon concentrations and working levels between three stations shows strong dependence on wind direction and velocity. Radon concentrations and working-level distributions for each month and each station were analyzed. The average maximum, minimum, and modal concentration and working levels were estimated with observed frequencies. The highest concentration is 11,000 pCi/m 3 on the tailings. Working-level variations parallel radon variations but lag by less than one hour. The highest working levels were observed at night when conditions of higher secular radioactive equilibrium for radon daughters exist. Background radon concentration was measured at two stations, each located about 25 km from the mill, and the average is 408 pCi/m 3 . Average working-level background is 3.6 x 10 -3

The current status of community drug testing via the analysis of drugs and drug metabolites in sewage

Directory of Open Access Journals (Sweden)

Malcolm J. Reid

2011-12-01

Full Text Available Over the past few years the analysis of drug residues in sewage has been promoted as a means of estimating the level of drug use in communities. Measured drug residue concentrations in the sewage are used to determine the load (total mass of the drug being used by the entire community. Knowledge of the size or population of the community then allows for the calculation of drug-use relative to population (typically drug-mass/day/1000 inhabitants which facilitates comparisons between differing communities or populations. Studies have been performed in many European countries, including Norway, as well as in the US and Australia. The approach has successfully estimated the use of cocaine, amphetamine, methamphetamine, MDMA, cannabis, nicotine and alcohol. The analysis of biomarkers of drug use in sewage has great potential to support and complement existing techniques for estimating levels of drug use, and as such has been identified as a promising development by the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA; www.emcdda.europa.eu/wastewater-analysis. The approach is not without its challenges, and ongoing collaboration across Europe aims at agreeing upon best-practice and harmonising the methods being used. In Norway development is being performed through the NFR RUSMIDDEL funded DrugMon (www.niva.no/drugmon project that has led to the development of many new techniques, significantly improved our understanding of the uncertainties associated with the approach and allowed the coordination of Europe wide collaboration which has included all important intercalibration exercises. Application of the technique can provide evidence-based and real-time estimates of collective drug use with the resulting data used to improve the much needed estimates of drug use and dependency.

21 CFR 146.154 - Concentrated orange juice with preservative.

Science.gov (United States)

2010-04-01

... 21 Food and Drugs 2 2010-04-01 2010-04-01 false Concentrated orange juice with preservative. 146... Canned Fruit Juices and Beverages § 146.154 Concentrated orange juice with preservative. (a) Concentrated orange juice with preservative complies with the requirements for composition and labeling of optional...

Correlation Of Giant Nuclei With Cloud Droplet Concentration

Science.gov (United States)

Jha, V.; Hudson, J. G.; Noble, S.

2011-12-01

The effect of giant nuclei (GN; larger than 1 micrometer particles produced by wind on the ocean surface) on warm rain has been debated for decades. During RICO (Rain in Cumulus over the Ocean) Hudson et al. (2011) found a negative correlation (R) between CCN concentrations at 1% supersaturation (S) and large cloud droplet concentrations (Fig. 1A). This reversal from positive R for CCN with total (or small) cloud droplet concentrations (left side of Fig. 1A) was explained by the greater competition for condensate, which thus limits droplet sizes when CCN concentrations are higher. The negative R increased in magnitude with altitude, and the droplet size where the maximum negative R occurred increased with altitude (Fig. 1A). However, at all altitudes this negative R decreased in magnitude for even larger cloud and drizzle drops (right side of Fig. 1A except highest altitude). The decrease in magnitude of the negative R was greater for increasing drop sizes at higher altitudes. Thus, at the higher altitudes, R for CCN with large drizzle drops was of low negative magnitude and even positive at the highest RICO altitudes. The disparity between CCN and drizzle drop concentrations precluded a causal relationship. But the high R between GN and drizzle drop concentrations at the highest altitudes (Fig. 1B) and the comparable concentrations indicated that GN were engendering drizzle. This is supported by the increasing R with altitude of the GN-drizzle drop R (right side of Fig. 1B). The conclusion of a GN-drizzle connection is also supported by the fact that CCN concentrations should inhibit drizzle. This analysis of Hudson et al. (2011) is here expanded to include correlations of CCN concentrations at lower S with cloud and drizzle drop concentrations to investigate intermediate relationships; i.e., between large nuclei (i.e., 0.1-1 micrometer; critical S 0.1-0.01%) and drizzle drop concentrations. A shortcoming of Hudson et al. (2011) was the small number of high

Surfactants enhance recovery of poorly soluble drugs during microdialysis sampling

DEFF Research Database (Denmark)

Koplin, Sebastian; Kumpugdee-Vollrath, Mont; Bauer-Brandl, Annette

2017-01-01

Aim of this project was to investigate the applicability of a recently developed in vitro microdialysis-sampling approach in connection with a dissolution-/permeation (D/P) system, especially the impact of surfactants within the perfusion fluid. The D/P-system is based on side-by-side chambers...... drug-dissolution (-release) and drug permeation. Furthermore, it should allow quantification of the unbound (free) drug concentration. In the first step, it was assessed, if the addition of the anionic surfactant sodium dodecyl sulphate (SDS) to the perfusate of the microdialysis system affects...... celecoxib, i.e. the fraction of drug, which is not associated with taurocholate surfactant micelles. In buffer, the measured concentrations matched the overall CXB concentrations. By the use of SDS-containing perfusates microdialysis sampling enabled reliable quantification of minute amounts of free CXB...

Cell culture media impact on drug product solution stability.

Science.gov (United States)

Purdie, Jennifer L; Kowle, Ronald L; Langland, Amie L; Patel, Chetan N; Ouyang, Anli; Olson, Donald J

2016-07-08

To enable subcutaneous administration of monoclonal antibodies, drug product solutions are often needed at high concentrations. A significant risk associated with high drug product concentrations is an increase in aggregate level over the shelf-life dating period. While much work has been done to understand the impact of drug product formulation on aggregation, there is limited understanding of the link between cell culture process conditions and soluble aggregate growth in drug product. During cell culture process development, soluble aggregates are often measured at harvest using cell-free material purified by Protein A chromatography. In the work reported here, cell culture media components were evaluated with respect to their impact on aggregate levels in high concentration solution drug product during accelerated stability studies. Two components, cysteine and ferric ammonium citrate, were found to impact aggregate growth rates in our current media (version 1) leading to the development of new chemically defined media and concentrated feed formulations. The new version of media and associated concentrated feeds (version 2) were evaluated across four cell lines producing recombinant IgG4 monoclonal antibodies and a bispecific antibody. In all four cell lines, the version 2 media reduced aggregate growth over the course of a 12 week accelerated stability study compared with the version 1 media, although the degree to which aggregate growth decreased was cell line dependent. © 2016 American Institute of Chemical Engineers Biotechnol. Prog., 32:998-1008, 2016. © 2016 American Institute of Chemical Engineers.

Chitosan microspheres in novel drug delivery systems.

Science.gov (United States)

Mitra, Analava; Dey, Baishakhi

2011-07-01

The main aim in the drug therapy of any disease is to attain the desired therapeutic concentration of the drug in plasma or at the site of action and maintain it for the entire duration of treatment. A drug on being used in conventional dosage forms leads to unavoidable fluctuations in the drug concentration leading to under medication or overmedication and increased frequency of dose administration as well as poor patient compliance. To minimize drug degradation and loss, to prevent harmful side effects and to increase drug bioavailability various drug delivery and drug targeting systems are currently under development. Handling the treatment of severe disease conditions has necessitated the development of innovative ideas to modify drug delivery techniques. Drug targeting means delivery of the drug-loaded system to the site of interest. Drug carrier systems include polymers, micelles, microcapsules, liposomes and lipoproteins to name some. Different polymer carriers exert different effects on drug delivery. Synthetic polymers are usually non-biocompatible, non-biodegradable and expensive. Natural polymers such as chitin and chitosan are devoid of such problems. Chitosan comes from the deacetylation of chitin, a natural biopolymer originating from crustacean shells. Chitosan is a biocompatible, biodegradable, and nontoxic natural polymer with excellent film-forming ability. Being of cationic character, chitosan is able to react with polyanions giving rise to polyelectrolyte complexes. Hence chitosan has become a promising natural polymer for the preparation of microspheres/nanospheres and microcapsules. The techniques employed to microencapsulate with chitosan include ionotropic gelation, spray drying, emulsion phase separation, simple and complex coacervation. This review focuses on the preparation, characterization of chitosan microspheres and their role in novel drug delivery systems.

Effect of the anticarcinogenic drug 6-mercaptopurine on mineral metabolism

International Nuclear Information System (INIS)

Amemiya, K.

1987-01-01

The effect of 6-mercaptopurine (6-MP) on mineral metabolism was investigated using rats and mice. A single 6-mercaptopurine injection in pregnant rats on day 11 of gestation proved to be highly teratogenic. At term, fetuses from 6-MP injected dams had lower livers zinc concentrations than non-injected or vehicle injected controls while dams showed no differences in liver zinc. Fetuses from dams injected with 6-MP and fed supplemental levels of zinc had a lower frequency of malformations and had higher hepatic zinc concentrations than fetuses from dams fed less zinc with drug injection. Non-pregnant mice injected with 6-MP had higher zinc concentrations compared to controls. In addition, iron, copper and calcium concentrations were higher in the livers of 6-MP injected mice than in controls, indicating that the drug affected several elements. Hepatic concentrations of metallothionein (MT) were also elevated in 6-MP injected mice, suggesting that the change in zinc concentrations associated with drug administration was the result of a drug induction of MT. Dams injected with 6-MP on day 13 of pregnancy had livers which retained more of an absorbed dose of 65 zinc than non-injected dams. Plasma from these drug injected dams also retained less of the absorbed dose than control dams. In contrast, day 14 from dams injected with 6-MP, retained less of an absorbed dose than control embryos

Parallel screening of FDA-approved antineoplastic drugs for identifying sensitizers of TRAIL-induced apoptosis in cancer cells

International Nuclear Information System (INIS)

Taylor, David J; Parsons, Christine E; Han, Haiyong; Jayaraman, Arul; Rege, Kaushal

2011-01-01

Tumor Necrosis Factor-α Related Apoptosis Inducing Ligand (TRAIL) and agonistic antibodies to death receptor 4 and 5 are promising candidates for cancer therapy due to their ability to induce apoptosis selectively in a variety of human cancer cells, while demonstrating little cytotoxicity in normal cells. Although TRAIL and agonistic antibodies to DR4 and DR5 are considered safe and promising candidates in cancer therapy, many malignant cells are resistant to DR-mediated, TRAIL-induced apoptosis. In the current work, we screened a small library of fifty-five FDA and foreign-approved anti-neoplastic drugs in order to identify candidates that sensitized resistant prostate and pancreatic cancer cells to TRAIL-induced apoptosis. FDA-approved drugs were screened for their ability to sensitize TRAIL resistant prostate cancer cells to TRAIL using an MTT assay for cell viability. Analysis of variance was used to identify drugs that exhibited synergy with TRAIL. Drugs demonstrating the highest synergy were selected as leads and tested in different prostate and pancreatic cancer cell lines, and one immortalized human pancreatic epithelial cell line. Sequential and simultaneous dosing modalities were investigated and the annexin V/propidium iodide assay, in concert with fluorescence microscopy, was employed to visualize cells undergoing apoptosis. Fourteen drugs were identified as having synergy with TRAIL, including those whose TRAIL sensitization activities were previously unknown in either prostate or pancreatic cancer cells or both. Five leads were tested in additional cancer cell lines of which, doxorubicin, mitoxantrone, and mithramycin demonstrated synergy in all lines. In particular, mitoxantrone and mithramycin demonstrated significant synergy with TRAIL and led to reduction of cancer cell viability at concentrations lower than 1 μM. At these low concentrations, mitoxantrone demonstrated selectivity toward malignant cells over normal pancreatic epithelial cells

Parallel screening of FDA-approved antineoplastic drugs for identifying sensitizers of TRAIL-induced apoptosis in cancer cells

Directory of Open Access Journals (Sweden)

Taylor David J

2011-11-01

Full Text Available Abstract Background Tumor Necrosis Factor-α Related Apoptosis Inducing Ligand (TRAIL and agonistic antibodies to death receptor 4 and 5 are promising candidates for cancer therapy due to their ability to induce apoptosis selectively in a variety of human cancer cells, while demonstrating little cytotoxicity in normal cells. Although TRAIL and agonistic antibodies to DR4 and DR5 are considered safe and promising candidates in cancer therapy, many malignant cells are resistant to DR-mediated, TRAIL-induced apoptosis. In the current work, we screened a small library of fifty-five FDA and foreign-approved anti-neoplastic drugs in order to identify candidates that sensitized resistant prostate and pancreatic cancer cells to TRAIL-induced apoptosis. Methods FDA-approved drugs were screened for their ability to sensitize TRAIL resistant prostate cancer cells to TRAIL using an MTT assay for cell viability. Analysis of variance was used to identify drugs that exhibited synergy with TRAIL. Drugs demonstrating the highest synergy were selected as leads and tested in different prostate and pancreatic cancer cell lines, and one immortalized human pancreatic epithelial cell line. Sequential and simultaneous dosing modalities were investigated and the annexin V/propidium iodide assay, in concert with fluorescence microscopy, was employed to visualize cells undergoing apoptosis. Results Fourteen drugs were identified as having synergy with TRAIL, including those whose TRAIL sensitization activities were previously unknown in either prostate or pancreatic cancer cells or both. Five leads were tested in additional cancer cell lines of which, doxorubicin, mitoxantrone, and mithramycin demonstrated synergy in all lines. In particular, mitoxantrone and mithramycin demonstrated significant synergy with TRAIL and led to reduction of cancer cell viability at concentrations lower than 1 μM. At these low concentrations, mitoxantrone demonstrated selectivity toward

[Are there any sex/gender differences in drug use and drug addiction?].

Science.gov (United States)

Mendrek, Adrianna

responsiveness of the dopaminergic system to drugs of abuse, has been shown to differ between males and females and it has been shown to be modulated by sex steroid hormones, especially estrogen. For example, female rats exhibit greater motivation to self-administer cocaine than male rats and their motivation is the highest during elevated levels of estrogen. All these psychological, socio-cultural and biological factors that contribute to sex/gender difference in drug use and drug dependence, should be considered while evaluating and treating individuals with drug addiction problem.

Population pharmacokinetics and limited sampling strategy for first-line tuberculosis drugs and moxifloxacin

NARCIS (Netherlands)

Magis-Escurra, C.; Later-Nijland, H. M. J.; Alffenaar, J. W. C.; Broeders, J.; Burger, D. M.; van Crevel, R.; Boeree, M. J.; Donders, A. R. T.; van Altena, R.; van der Werf, T. S.; Aarnoutse, R. E.

Therapeutic drug monitoring (TDM) of tuberculosis (TB) drugs currently focuses on peak plasma concentrations, yet total exposure [area under the 24-h concentration-time curve (AUC(0-24))] is probably most relevant to the efficacy of these drugs. We therefore assessed population AUC(0-24) data for

Investigations on the viscoelastic performance of pressure sensitive adhesives in drug-in-adhesive type transdermal films.

Science.gov (United States)

Wolff, Hans-Michael; Irsan; Dodou, Kalliopi

2014-08-01

We aimed to investigate the effect of solubility parameter and drug concentration on the rheological behaviour of drug-in-adhesive films intended for transdermal application. Films were prepared over a range of drug concentrations (5%, 10% and 20% w/w) using ibuprofen, benzoic acid, nicotinic acid and lidocaine as model drugs in acrylic (Duro-Tak 87-4287 and Duro-Tak 87900A) or silicone (Bio-PSA 7-4301 and Bio-PSA 7-4302) pressure sensitive adhesives (PSAs). Saturation status of films was determined using light microscopy. Viscoelastic parameters were measured in rheology tests at 32°C. Subsaturated films had lower viscoelastic moduli whereas saturated films had higher moduli than the placebo films and/or a concentration-dependent increase in their modulus. Saturation concentration of each drug in the films was reflected by decreasing/increasing viscoelastic patterns. The viscoelastic windows (VWs) of the adhesive and drug-in-adhesive films clearly depicted the effect of solubility parameter differences, molar concentration of drug in the adhesive film and differences in PSA chemistry. Drug solubility parameters and molar drug concentrations have an impact on rheological patterns and thus on the adhesive performance of tested pressure sensitive adhesives intended for use in transdermal drug delivery systems. Use of the Flory equation in its limiting form was appropriate to predict drug solubility in the tested formulations.

Amount of self-reported illicit drug use compared to quantitative hair test results in community-recruited young drug users in Amsterdam

NARCIS (Netherlands)

Welp, Esther A. E.; Bosman, Ingrid; Langendam, Miranda W.; Totté, Maja; Maes, Robert A. A.; van Ameijden, Erik J. C.

2003-01-01

To assess the dose-effect relationship between self-reported drug intake and the concentration of drugs and/or their metabolites in hair and to examine factors that may mediate this relationship. A cohort study among young drug users (YDU) in Amsterdam, the Netherlands, which began in July 2000. At

The fifty highest cited papers in anterior cruciate ligament injury.

Science.gov (United States)

Vielgut, Ines; Dauwe, Jan; Leithner, Andreas; Holzer, Lukas A

2017-07-01

The anterior cruciate ligament (ACL) is one of the most common injured knee ligaments and at the same time, one of the most frequent injuries seen in the sport orthopaedic practice. Due to the clinical relevance of ACL injuries, numerous papers focussing on this topic including biomechanical-, basic science-, clinical- or animal studies, were published. The purpose of this study was to determine the most frequently cited scientific articles which address this subject, establish a ranking of the 50 highest cited papers and analyse them according to their characteristics. The 50 highest cited articles related to Anterior Cruciate Ligament Injury were searched in Thomson ISI Web of Science® by the use of defined search terms. All types of scientific papers with reference to our topic were ranked according to the absolute number of citations and analyzed for the following characteristics: journal title, year of publication, number of citations, citation density, geographic origin, article type and level of evidence. The 50 highest cited articles had up to 1624 citations. The top ten papers on this topic were cited 600 times at least. Most papers were published in the American Journal of Sports Medicine. The publication years spanned from 1941 to 2007, with the 1990s and 2000s accounting for half of the articles (n = 25). Seven countries contributed to the top 50 list, with the USA having by far the most contribution (n = 40). The majority of articles could be attributed to the category "Clinical Science & Outcome". Most of them represent a high level of evidence. Scientific articles in the field of ACL injury are highly cited. The majority of these articles are clinical studies that have a high level of evidence. Although most of the articles were published between 1990 and 2007, the highest cited articles in absolute and relative numbers were published in the early 1980s. These articles contain well established scoring- or classification systems. The

Therapeutic drug monitoring of aminoglycosides in neonates

NARCIS (Netherlands)

Touw, Daniël J; Westerman, Elsbeth M; Sprij, Arwen J

2009-01-01

The efficacy and toxicity of aminoglycosides show a strong direct positive relationship with blood drug concentrations, therefore, therapy with aminoglycosides in adults is usually guided by therapeutic drug monitoring. Dosing regimens in adults have evolved from multiple daily dosing to

Selective exploitation of large pike Esox lucius-Effects on mercury concentrations in fish populations

International Nuclear Information System (INIS)

Sharma, Chhatra Mani; Borgstrom, Reidar; Huitfeldt, Jorgen Sinkaberg; Rosseland, Bjorn Olav

2008-01-01

The present study outlines two main trends of mercury transfer patterns through the fish community: 1) the Hg concentrations increase with increase in the trophic level, with top predators having the highest concentrations, and 2) a fast growth rate may dilute the concentrations of Hg in fish muscle tissue (growth biodilution). In 2004, an extensive reduction in number of large pike (Esox lucius L.), was initiated by selective gillnet fishing in Lake Arungen, Norway, in order to increase the pike recruitment due to an expected reduction in cannibalism. In this connection, total mercury (THg) concentrations in the fish community were studied both before (2003) and after (2005) the removal of large pike. The δ 15 N signatures and stomach content analyses indicated that pike and perch (Perca fluviatilis L.) occupied the highest trophic position, while roach (Rutilus rutilus (L.)) was at the lower level, and rudd (Scardinius erythrophthalmus L.) at the lowest. The piscivores, pike and perch, had the highest concentrations of THg. The biomagnification rate of THg through the food web in the fish community was 0.163 ( per milleδ 15 N), with the highest uptake rate (0.232) in perch. A significant decrease in THg concentrations was found in all fish species in 2005 compared to 2003. Removal of the top predators in an Hg contaminated lake might thus be an important management tool for reducing Hg levels in fish, thereby reducing health risk to humans

Doxorubicin-loaded QuadraSphere microspheres: plasma pharmacokinetics and intratumoral drug concentration in an animal model of liver cancer.

Science.gov (United States)

Lee, Kwang-Hun; Liapi, Eleni A; Cornell, Curt; Reb, Philippe; Buijs, Manon; Vossen, Josephina A; Ventura, Veronica Prieto; Geschwind, Jean-Francois H

2010-06-01

The purpose of this study was to evaluate, in vitro and in vivo, doxorubicin-loaded poly (vinyl alcohol-sodium acrylate) copolymer microspheres [QuadraSphere microspheres (QSMs)] for transcatheter arterial delivery in an animal model of liver cancer. Doxorubicin loading efficiency and release profile were first tested in vitro. In vivo, 15 rabbits, implanted with a Vx-2 tumor in the liver, were divided into three groups of five rabbits each, based on the time of euthanasia. Twenty-five milligrams of QSMs was diluted in 10 ml of a 10 mg/ml doxorubicin solution and 10 ml of nonionic contrast medium for a total volume of 20 ml. One milliliter of a drug-loaded QSM solution containing 5 mg of doxorubicin was injected into the tumor feeding artery. Plasma doxorubicin and doxorubicinol concentrations, and intratumoral and peritumoral doxorubicin tissue concentrations, were measured. Tumor specimens were pathologically evaluated to record tumor necrosis. As a control, one animal was blandly embolized with plain QSMs in each group. In vitro testing of QSM doxorubicin loadability and release over time showed 82-94% doxorubicin loadability within 2 h and 6% release within the first 6 h after loading, followed by a slow release pattern. In vivo, the doxorubicin plasma concentration declined at 40 min. The peak doxorubicin intratumoral concentration was observed at 3 days and remained detectable till the study's end point (7 days). Mean percentage tumor cell death in the doxorubicin QSM group was 90% at 7 days and 60% in the bland QSM embolization group. In conclusion, QSMs can be efficiently loaded with doxorubicin. Initial experiments with doxorubicin-loaded QSMs show a safe pharmacokinetic profile and effective tumor killing in an animal model of liver cancer.

Doxorubicin-Loaded QuadraSphere Microspheres: Plasma Pharmacokinetics and Intratumoral Drug Concentration in an Animal Model of Liver Cancer

International Nuclear Information System (INIS)

Lee, Kwang-Hun; Liapi, Eleni A.; Cornell, Curt; Reb, Philippe; Buijs, Manon; Vossen, Josephina A.; Ventura, Veronica Prieto; Geschwind, Jean-Francois H.

2010-01-01

The purpose of this study was to evaluate, in vitro and in vivo, doxorubicin-loaded poly (vinyl alcohol-sodium acrylate) copolymer microspheres [QuadraSphere microspheres (QSMs)] for transcatheter arterial delivery in an animal model of liver cancer. Doxorubicin loading efficiency and release profile were first tested in vitro. In vivo, 15 rabbits, implanted with a Vx-2 tumor in the liver, were divided into three groups of five rabbits each, based on the time of euthanasia. Twenty-five milligrams of QSMs was diluted in 10 ml of a 10 mg/ml doxorubicin solution and 10 ml of nonionic contrast medium for a total volume of 20 ml. One milliliter of a drug-loaded QSM solution containing 5 mg of doxorubicin was injected into the tumor feeding artery. Plasma doxorubicin and doxorubicinol concentrations, and intratumoral and peritumoral doxorubicin tissue concentrations, were measured. Tumor specimens were pathologically evaluated to record tumor necrosis. As a control, one animal was blandly embolized with plain QSMs in each group. In vitro testing of QSM doxorubicin loadability and release over time showed 82-94% doxorubicin loadability within 2 h and 6% release within the first 6 h after loading, followed by a slow release pattern. In vivo, the doxorubicin plasma concentration declined at 40 min. The peak doxorubicin intratumoral concentration was observed at 3 days and remained detectable till the study's end point (7 days). Mean percentage tumor cell death in the doxorubicin QSM group was 90% at 7 days and 60% in the bland QSM embolization group. In conclusion, QSMs can be efficiently loaded with doxorubicin. Initial experiments with doxorubicin-loaded QSMs show a safe pharmacokinetic profile and effective tumor killing in an animal model of liver cancer.

The frequency of drugs in randomly selected drivers in Denmark

DEFF Research Database (Denmark)

Simonsen, Kirsten Wiese; Steentoft, Anni; Hels, Tove

is the Danish legal limit. The percentage of drivers positive for medicinal drugs above the Danish legal concentration limit was 0.4%; while, 0.3% of the drivers tested positive for one or more illicit drug at concentrations exceeding the Danish legal limit. Tetrahydrocannabinol, cocaine, and amphetamine were...... the most frequent illicit drugs detected above the limit of quantitation (LOQ); while, codeine, tramadol, zopiclone, and benzodiazepines were the most frequent legal drugs. Middle aged men (median age 47.5 years) dominated the drunk driving group, while the drivers positive for illegal drugs consisted......Introduction Driving under the influence of alcohol and drugs is a global problem. In Denmark as well as in other countries there is an increasing focus on impaired driving. Little is known about the occurrence of psychoactive drugs in the general traffic. Therefore the European commission...

Tacrolimus interaction with nafcillin resulting in significant decreases in tacrolimus concentrations: A case report.

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Wungwattana, Minkey; Savic, Marizela

2017-04-01

Tacrolimus (TAC) is subject to many drug interactions as a result of its metabolism primarily via CYP450 isoenzyme 3A4. Numerous case reports of TAC and CYP3A4 inducers and inhibitors have been described including antimicrobials, calcium channel antagonists, and antiepileptic drugs. We present the case of a 13-year-old patient with cystic fibrosis and a history of liver transplantation, where subtherapeutic TAC concentrations were suspected to be a result of concomitant TAC and nafcillin (NAF) therapy. The observed drug interaction occurred on two separate hospital admissions, during both of which the patient exhibited therapeutic TAC concentrations prior to exposure to NAF, a CYP3A4 inducer. Upon discontinuation of NAF, TAC concentrations recovered in both instances. This case represents a drug-drug interaction between TAC and NAF that has not previously been reported to our knowledge. Despite the lack of existing reports of interaction between these two agents, this case highlights the importance of therapeutic drug monitoring and assessing for any potential drug-drug or drug-food interactions in patients receiving TAC therapy. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Investigation on physical behavior of styrene wood-polymer in different concentrations of monomer

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maryam ghorbani

2016-09-01

Full Text Available This research was conducted to study the effect of different concentrations of styrene lumen monomer on the physical properties of beech wood. Physical test samples were prepared according to ASTM-D1037 standard and treated with vacuum-pressure method at five concentration levels; 0, 40, 60, 80 and 100 percent of soluble monomer. For polymerization, treated samples were heated in oven for two 24-hour period at 90 and 103ºC respectively. Monomer and polymer absorption, density variation, water absorption, swelling and anti-swelling efficiency (ASE were determined. According to the results, Monomer and polymer absorption were increment by monomer concentration increase, and they were reported 38.2% and 26% in highest level. With polymer absorption enhancement, density of wood increased from 0/63g/cm³ in control to 0/91g/cm³ in the highest monomer concentration level that reduces pores in wood-polymer structure. Absorbed polymer enhancement decreased hydrophilicity and dimensional changes of treated samples, so that water absorption and swelling volume of the samples saturated with 100% concentration of monomer were decreased 64% and 45.3% after the longest immersion time. Highest Anti-swelling efficiency of Styrene-saturated samples was determined 56.15% in the maximum concentration level of treatment.

The occurrence of pharmaceuticals, personal care products, endocrine disruptors and illicit drugs in surface water in South Wales, UK.

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Kasprzyk-Hordern, Barbara; Dinsdale, Richard M; Guwy, Alan J

2008-07-01

The presence and fate of 56 pharmaceuticals, personal care products, endocrine disruptors and illicit drugs (PPCPs) were investigated in the South Wales region of the UK. Two contrasting rivers: River Taff and River Ely were chosen for this investigation and were monitored for a period of 10 months. The impact of the factors affecting the levels of concentration of PPCPs and illicit drugs in surface water such as surrounding area, proximity to wastewater effluent and weather conditions, mainly rainfall was also investigated. Most PPCPs were frequently found in river water at concentrations reaching single microgL(-1) and their levels depended mainly on the extent of water dilution resulting from rainfall. Discharge of treated wastewater effluent into the river course was found to be the main cause of water contamination with PPCPs. The most frequently detected PPCPs represent the group of pharmaceuticals dispensed at the highest levels in the Welsh community. These were antibacterial drugs (trimethoprim, erythromycin-H(2)O and amoxicillin), anti-inflammatories/analgesics (paracetamol, tramadol, codeine, naproxen, ibuprofen and diclofenac) and antiepileptic drugs (carbamazepine and gabapentin). Only four PPCPs out of 56 (simvastatin, pravastatin, digoxin and digoxigenin) were not quantified over the course of the study. Several PPCPs were found to be both ubiquitous and persistent in the aqueous environment (e.g. erythromycin-H(2)O, codeine, carbamazepine, gabapentin and valsartan). The calculated average daily loads of PPCPs indicated that in total almost 6 kg of studied PPCPs are discharged daily into the studied rivers. The illicit drugs studied were found in rivers at low levels of ng L(-1). Average daily loads of amphetamine, cocaine and its main metabolite benzoylecgonine were as follows: 8, 1.2 and 39 gday(-1), respectively. Their frequent occurrence in surface water is primarily associated with their high illegal usage and is strongly associated with the

NSAIDs: can the presence of infectious agent influence the choice of analgesic drug?

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О. А. Podpletnya

2017-08-01

Full Text Available Purpose. Considering the significant prevalence of comorbid pathology there is a high probability of NSAID use in patients with concomitant infection. In view of this screening of antimicrobial properties of their main groups was conducted for the purpose of selecting the most promising ones for further in-depth study. Materials and methods. The study of microorganisms’ sensitivity was conducted using standard research methods – the method of "wells" and by determining the antibacterial properties of drugs, using tablets, based on the ability of the drug to diffuse into agar, used for sowing the test-culture. As the test cultures S. aureus, S. mutans, S. pyogenes, P. aeruginosa, E. Coli, isolated from patients who were treated in hospital were used. Predominant blocker of COX-1 (acetylsalicylic acid, ASA, nonselective blockers of COX-1 and COX-2 (ketorolac, diclofenac sodium, ibuprofen, mefenamic acid, dexketoprofen, predominant blockers of COX-2 (meloxicam and nimesulide, selective blockers of COX-2 (celecoxib, selective blockers of COX-3 (COX-1 in the brain paracetamol and metamizole were tested. Results. The studies found that most of the tested NSAIDs have antimicrobial activity. Leader drugs in expressiveness of antimicrobial effects are drugs that have sufficient COX-1 (3 - activity: ASA, diclofenac, dexketoprofen, metamizole, and lesser extent – paracetamol. Tested NSAIDs showed the highest activity against gram-positive coccal flora, mostly affecting S. Pyogenes. Blockers of COX-3 paracetamol and metamizole, unlike other studied drugs, showed stronger antipseudomonal (both – moderate and antistaphylococcal action (metamizole. Conclusions. NSAIDs with antimicrobial activity can potentially increase the activity of antiinfectious therapy. At the same time, the antimicrobial activity of NSAIDs, theoretically, can promote microbial resistance because of existence of microorganisms in a medium with subthreshold concentrations of drugs

Fatal poisoning in drug addicts in the Nordic countries

DEFF Research Database (Denmark)

Steentoft, Anni; Teige, Brita; Ceder, Gunnel

2001-01-01

The study includes medicolegally examined fatal poisonings among drug addicts in 1997 in the five Nordic countries: Denmark, Finland, Iceland, Norway and Sweden, and the results are compared to a similar investigation from 1991. A common definition of ‘‘drug addict’’ was applied...... by the participating countries. The highest death rate by poisoning in drug addicts was observed in Denmark, where it was 6.54 per 105 inhabitants, followed by Norway with 6.35, Sweden with 2.21, Finland with 1.63 and Iceland with 1.20 per 105 inhabitants. All countries showed a higher death rate in 1997 than in 1991...

Effect of liposomes on rheological and syringeability properties of hyaluronic acid hydrogels intended for local injection of drugs.

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El Kechai, Naila; Bochot, Amélie; Huang, Nicolas; Nguyen, Yann; Ferrary, Evelyne; Agnely, Florence

2015-06-20

The aim of this work was to thoroughly study the effect of liposomes on the rheological and the syringeability properties of hyaluronic acid (HA) hydrogels intended for the local administration of drugs by injection. Whatever the characteristics of the liposomes added (neutral, positively or negatively charged, with a corona of polyethylene glycol chains, size), the viscosity and the elasticity of HA gels increased in a lipid concentration-dependent manner. Indeed, liposomes strengthened the network formed by HA chains due to their interactions with this polymer. The nature and the resulting effects of these interactions depended on liposome composition and concentration. The highest viscosity and elasticity were observed with liposomes covered by polyethylene glycol chains while neutral liposomes displayed the lowest effect. Despite their high viscosity at rest, all the formulations remained easily injectable through needles commonly used for local injections thanks to the shear-thinning behavior of HA gels. The present study demonstrates that rheological and syringeability tests are both necessary to elucidate the behavior of such systems during and post injection. In conclusion, HA liposomal gels appear to be a promising and versatile formulation platform for a wide range of applications in local drug delivery when an injection is required. Copyright © 2015 Elsevier B.V. All rights reserved.

Effect of honokiol on the induction of drug-metabolizing enzymes in human hepatocytes

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Cho YY

2014-11-01

Full Text Available Yong-Yeon Cho,1 Hyeon-Uk Jeong,1 Jeong-Han Kim,2 Hye Suk Lee1 1College of Pharmacy, The Catholic University of Korea, Bucheon, Korea; 2Department of Agricultural Biotechnology, Seoul National University, Seoul, Korea Abstract: Honokiol, 2-(4-hydroxy-3-prop-2-enyl-phenyl-4-prop-2-enyl-phenol, an active component of Magnolia officinalis and Magnolia grandiflora, exerts various pharmacological activities such as antitumorigenic, antioxidative, anti-inflammatory, neurotrophic, and antithrombotic effects. To investigate whether honokiol acts as a perpetrator in drug interactions, messenger ribonucleic acid (mRNA levels of phase I and II drug-metabolizing enzymes, including cytochrome P450 (CYP, UDP-glucuronosyltransferase (UGT, and sulfotransferase 2A1 (SULT2A1, were analyzed by real-time reverse transcription polymerase chain reaction following 48-hour honokiol exposure in three independent cryopreserved human hepatocyte cultures. Honokiol treatment at the highest concentration tested (50 µM increased the CYP2B6 mRNA level and CYP2B6-catalyzed bupropion hydroxylase activity more than two-fold in three different hepatocyte cultures, indicating that honokiol induces CYP2B6 at higher concentrations. However, honokiol treatment (0.5–50 µM did not significantly alter the mRNA levels of phase I enzymes (CYP1A2, CYP3A4, CYP2C8, CYP2C9, and CYP2C19 or phase II enzymes (UGT1A1, UGT1A4, UGT1A9, UGT2B7, and SULT2A1 in cryopreserved human hepatocyte cultures. CYP1A2-catalyzed phenacetin O-deethylase and CYP3A4-catalyzed midazolam 1'-hydroxylase activities were not affected by 48-hour honokiol treatment in cryopreserved human hepatocytes. These results indicate that honokiol is a weak CYP2B6 inducer and is unlikely to increase the metabolism of concomitant CYP2B6 substrates and cause pharmacokinetic-based drug interactions in humans. Keywords: honokiol, human hepatocytes, drug interactions, cytochrome P450, UDP-glucuronosyltransferases

Reforming private drug coverage in Canada: inefficient drug benefit design and the barriers to change in unionized settings.

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O'Brady, Sean; Gagnon, Marc-André; Cassels, Alan

2015-02-01

Prescription drugs are the highest single cost component for employees' benefits packages in Canada. While industry literature considers cost-containment for prescription drug costs to be a priority for insurers and employers, the implementation of cost-containment measures for private drug plans in Canada remains more of a myth than a reality. Through 18 semi-structured phone interviews conducted with experts from private sector companies, unions, insurers and plan advisors, this study explores the reasons behind this incapacity to implement cost-containment measures by examining how private sector employers negotiate drug benefit design in unionized settings. Respondents were asked questions on how employee benefits are negotiated; the relationships between the players who influence drug benefit design; the role of these players' strategies in influencing plan design; the broad system that underpins drug benefit design; and the potential for a universal pharmacare program in Canada. The study shows that there is consensus about the need to educate employees and employers, more collaboration and data-sharing between these two sets of players, and for external intervention from government to help transform established norms in terms of private drug plan design. Copyright © 2014 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.

Modelling Formation of a Drug Reservoir in the Stratum Corneum and Its Impact on Drug Monitoring Using Reverse Iontophoresis

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Yvonne Paulley

2010-01-01

Full Text Available Reverse iontophoresis is a relatively new technique for non-invasive drug monitoring in the body. It involves a small electrical current being passed through the skin to facilitate the movement of small charged ions and polar molecules on the skin's surface where the amount of drug can then be measured and hence an accurate estimate of the blood concentration can be made. In vivo studies for several molecules show that initially large amounts of drug are extracted from the body, which are unrelated to the magnitude of the blood concentration; over time the fluxes of extraction decrease to a level proportional to the steady state blood concentration. This suggests that, at first, the drug is being extracted from some source other than the blood; one such candidate for this source is the dead cells which form the stratum corneum. In this paper, we construct two related mathematical models; the first describes the formation of the drug reservoir in the stratum corneum as a consequence of repeated drug intake and natural death of skin cells in the body. The output from this model provides initial conditions for the model of reverse iontophoresis in which charged ions from both the blood and the stratum corneum reservoir compete for the electric current. Model parameters are estimated from data collected for lithium monitoring. Our models will improve interpretation of reverse iontophoretic data by discriminating the subdermal from the skin contribution to the fluxes of extraction. They also suggest that analysis of the skin reservoir might be a valuable tool to investigate patients' exposure to chemicals including therapeutic drugs.

Microencapsulation of protein drugs for drug delivery: strategy, preparation, and applications.

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Ma, Guanghui

2014-11-10

Bio-degradable poly(lactide) (PLA)/poly(lactide-glycolide) (PLGA) and chitosan microspheres (or microcapsules) have important applications in Drug Delivery Systems (DDS) of protein/peptide drugs. By encapsulating protein/peptide drugs in the microspheres, the serum drug concentration can be maintained at a higher constant value for a prolonged time, or injection formulation can be changed to orally or mucosally administered formulation. PLA/PLGA and chitosan are most often used in injection formulation and oral formulation. However, in the preparation and applications of PLA/PLGA and chitosan microspheres containing protein/peptide drugs, the problems of broad size distribution and poor reproducibility of microspheres, and deactivation of protein during the preparation, storage and release, are still big challenges. In this article, the techniques for control of the diameter of microspheres and microcapsules will be introduced at first, then the strategies about how to maintain the bioactivity of protein drugs during preparation and drug release will be reviewed and developed in our research group. The membrane emulsification techniques including direct membrane emulsification and rapid membrane emulsification processes were developed to prepare uniform-sized microspheres, the diameter of microspheres can be controlled from submicron to 100μm by these two processes, and the reproducibility of products can be guaranteed. Furthermore, compared with conventional stirring method, the big advantages of membrane emulsification process were that the uniform microspheres with much higher encapsulation efficiency can be obtained, and the release behavior can be adjusted by selecting microsphere size. Mild membrane emulsification condition also can prevent the deactivation of proteins, which frequently occurred under high shear force in mechanical stirring, sonification, and homogenization methods. The strategies for maintaining the bioactivity of protein drug were

Variable aromatase inhibitor plasma concentrations do not correlate with circulating estrogen concentrations in post-menopausal breast cancer patients.

Science.gov (United States)

Hertz, Daniel L; Speth, Kelly A; Kidwell, Kelley M; Gersch, Christina L; Desta, Zeruesenay; Storniolo, Anna Maria; Stearns, Vered; Skaar, Todd C; Hayes, Daniel F; Henry, N Lynn; Rae, James M

2017-10-01

The aromatase inhibitors (AI) exemestane (EXE), letrozole (LET), and anastrozole suppress estrogen biosynthesis, and are effective treatments for estrogen receptor (ER)-positive breast cancer. Prior work suggests that anastrozole blood concentrations are associated with the magnitude of estrogen suppression. The objective of this study was to determine whether the magnitude of estrogen suppression, as determined by plasma estradiol (E2) concentrations, in EXE or LET treated patients is associated with plasma AI concentrations. Five hundred post-menopausal women with ER-positive breast cancer were enrolled in the prospective Exemestane and Letrozole Pharmacogenetic (ELPh) Study conducted by the COnsortium on BReast cancer phArmacogomics (COBRA) and randomly assigned to either drug. Estrogen concentrations were measured at baseline and after 3 months of AI treatment and drug concentrations were measured after 1 or 3 months. EXE or LET concentrations were compared with 3-month E2 concentration or the change from baseline to 3 months using several complementary statistical procedures. Four-hundred patients with on-treatment E2 and AI concentrations were evaluable (EXE n = 200, LET n = 200). Thirty (7.6%) patients (EXE n = 13, LET n = 17) had 3-month E2 concentrations above the lower limit of quantification (LLOQ) (median: 4.75; range: 1.42-63.8 pg/mL). EXE and LET concentrations were not associated with on-treatment E2 concentrations or changes in E2 concentrations from baseline (all p > 0.05). Steady-state plasma AI concentrations do not explain variability in E2 suppression in post-menopausal women receiving EXE or LET therapy, in contrast with prior evidence in anastrozole treated patients.

Hepatic transporter drug-drug interactions: an evaluation of approaches and methodologies.

Science.gov (United States)

Williamson, Beth; Riley, Robert J

2017-12-01

Drug-drug interactions (DDIs) continue to account for 5% of hospital admissions and therefore remain a major regulatory concern. Effective, quantitative prediction of DDIs will reduce unexpected clinical findings and encourage projects to frontload DDI investigations rather than concentrating on risk management ('manage the baggage') later in drug development. A key challenge in DDI prediction is the discrepancies between reported models. Areas covered: The current synopsis focuses on four recent influential publications on hepatic drug transporter DDIs using static models that tackle interactions with individual transporters and in combination with other drug transporters and metabolising enzymes. These models vary in their assumptions (including input parameters), transparency, reproducibility and complexity. In this review, these facets are compared and contrasted with recommendations made as to their application. Expert opinion: Over the past decade, static models have evolved from simple [I]/k i models to incorporate victim and perpetrator disposition mechanisms including the absorption rate constant, the fraction of the drug metabolised/eliminated and/or clearance concepts. Nonetheless, models that comprise additional parameters and complexity do not necessarily out-perform simpler models with fewer inputs. Further, consideration of the property space to exploit some drug target classes has also highlighted the fine balance required between frontloading and back-loading studies to design out or 'manage the baggage'.

High prevalence of drug-resistant tuberculosis, Republic of Lithuania, 2002

DEFF Research Database (Denmark)

Dewan, P; Sosnovskaja, A; Thomsen, V

2005-01-01

BACKGROUND: Nations of the former Soviet Union have the world's highest reported levels of resistance to anti-tuberculosis drugs. We conducted the first national survey of anti-tuberculosis drug resistance in the Republic of Lithuania. METHODS: We tested Mycobacterium tuberculosis isolates from all...... isolates, 475 (41%) were resistant to at least one first-line drug, and 263 (23%) were resistant to at least INH and RMP (MDR); this included 76/818 (9.3%) from new patients and 187/345 (54%) from previously treated patients. Of 52 MDR isolates randomly selected for extended testing at an international...

Response of Sphagnum mosses to increased CO2 concentration and nitrogen deposition

International Nuclear Information System (INIS)

Jauhiainen, J.

1998-01-01

The main objective of this work was to study the effects of different CO 2 concentration and N deposition rates on Sphagna adapted to grow along a nutrient availability gradient (i.e. ombrotrophy-mesotrophy-eutrophy). The study investigated: (i) the effects of various longterm CO 2 concentrations on the rate of net photosynthesis in Sphagna, (ii) the effects of the CO 2 and N treatments on the moss density, shoot dry masses, length increment and dry mass production in Sphagna, (iii) the concentrations of the major nutrients in Sphagna after prolonged exposure to the CO 2 and N treatments, and (iv) species dependent differences in potential NH 4 + and NO 3 - uptake rates. The internal nutrient concentration of the capitulum and the production of biomass were effected less by the elevated CO 2 concentrations because the availability of N was a controlling factor. In addition responses to the N treatments were related to ecological differences between the Sphagna species. Species with a high tolerance of N availability were able to acclimatise to the increased N deposition rates. The data suggests a high nutrient status is less significant than the adaptation of the Sphagna to their ecological niche (e.g. low tolerance of meso-eutrophic S. warnstorfii to high N deposition rate). At the highest N deposition rate the ombrotrophic S. fuscum had the highest increase in tissue N concentration among the Sphagna studied. S. fuscum almost died at the highest N deposition rate because of the damaging effects of N to the plant's metabolism. Ombrotrophic hummock species such as S. fuscum, were also found to have the highest potential N uptake rate (on density of dry mass basis) compared to lawn species. The rate of net photosynthesis was initially increased with elevated CO 2 concentrations, but photosynthesis was down regulated with prolonged exposure to CO 2 . The water use efficiency in Sphagna appeared not to be coupled with exposure to the long-term CO 2 concentration. The

Evaluations of in vitro metabolism, drug-drug interactions mediated by reversible and time-dependent inhibition of CYPs, and plasma protein binding of MMB4 DMS.

Science.gov (United States)

Hong, S Peter; Lusiak, Bozena D; Burback, Brian L; Johnson, Jerry D

2013-01-01

1,1'-Methylenebis[4-[(hydroxyimino)methyl]-pyridinium] (MMB4) dimethanesulfonate (DMS) is a bisquaternary pyridinium aldoxime that reactivates acetylcholinesterase inhibited by organophosphorus nerve agent. Drug metabolism and plasma protein binding for MMB4 DMS were examined using various techniques and a wide range of species. When (14)C-MMB4 DMS was incubated in liver microsomes, 4-pyridine aldoxime (4-PA) and an additional metabolite were detected in all species tested. Identity of the additional metabolite was postulated to be isonicotinic acid (INA) based on liquid chromatography with a tandem mass spectrometry analysis, which was confirmed by comparison with authentic INA. Formation of INA was dependent on species, with the highest level found in monkey liver microsomes. The MMB4 DMS exhibited reversible inhibition in a concentration-dependent manner toward cytochrome P450 1A2 (CYP1A2), CYP2C9, CYP2C19, CYP2D6, and CYP3A4 in human liver microsomes showing the highest inhibition for CYP2D6. Human recombinant CYPs were used to evaluate inhibitory curves more adequately and determine detailed kinetic constants for reversible inhibition and potential time-dependent inhibition (TDI). The MMB4 DMS exhibited reversible inhibition toward human-recombinant CYP2D6 with an inhibition constant (K i) value of 66.6 µmol/L. Based on the k inact/K I values, MMB4 DMS was found to exhibit the most potent TDI toward CYP2D6. The MMB4 DMS at 5 different concentrations was incubated in plasma for 5 hours using an equilibrium dialysis device. For all species tested, there were no concentration-dependent changes in plasma protein binding, ranging from 10% to 17%. These results suggest that MMB4 was not extensively bound to plasma protein, and there were no overt species-related differences in the extent of MMB4 bound to plasma protein.

Can the genotype or phenotype of two polymorphic drug metabolising cytochrome P450-enzymes identify oral lichenoid drug eruptions?

DEFF Research Database (Denmark)

Kragelund, Camilla; Hansen, Claus; Reibel, Jesper

2010-01-01

Lichenoid drug eruptions (LDE) in the oral cavity are adverse drug reactions (ADR) that are impossible to differentiate from oral lichen planus (OLP) as no phenotypic criteria exist. Impaired function of polymorphic cytochrome 450-enzymes (CYPs) may cause increased plasma concentration of some...

Illicit drugs and the environment--a review.

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Pal, Raktim; Megharaj, Mallavarapu; Kirkbride, K Paul; Naidu, Ravi

2013-10-01

Illicit drugs and their metabolites are the latest group of emerging pollutants. Determination of their concentration in environment (such as water bodies, soil, sediment, air) is an indirect tool to estimate the community level consumption of illicit drug and to evaluate potential ecotoxicological impacts from chronic low level exposure. They enter the wastewater network as unaltered drugs and/or their active metabolites by human excretion after illegal consumption or by accidental or deliberate disposal from clandestine drug laboratories. This article critically reviews the occurrence and concentration levels of illicit drugs and their metabolites in different environmental compartments (e.g., wastewater, surface waters, groundwater, drinking water, and ambient air) and their potential impact on the ecosystem. There is limited published information available on the presence of illicit drugs in the environment, reports are available mainly from European countries, UK, USA, and Canada but there is a lack of information from the remainder of the world. Although the environmental concentrations are not very high, they can potentially impact the human health and ecosystem functioning. Cocaine, morphine, amphetamine, and MDMA have potent pharmacological activities and their presence as complex mixtures in water may cause adverse effect on aquatic organisms and human health. However, there is no current regulation demanding the determination of occurrence of these emerging pollutants in treated wastewater, surface water, drinking water, or atmosphere. Thus, critical investigation on distribution pattern of this new group of emerging contaminant and their potential harmful impact on our environment needs immediate attention. Copyright © 2012. Published by Elsevier B.V.

Investigation of the mechanisms of action behind Electromotive Drug Administration (EMDA).

Science.gov (United States)

Kos, Bor; Vásquez, Juan Luis; Miklavčič, Damijan; Hermann, Gregers G G; Gehl, Julie

2016-01-01

Bladder cancer is a cause of considerable morbidity worldwide. Electromotive Drug Administration is a method that combines intravesical chemotherapy with local electric field application. Electroporation has been suggested among other mechanisms as having a possible role in the therapy, so the goal of the present study was to investigate the electric fields present in the bladder wall during the treatment to determine which mechanisms might be involved. Electromotive Drug Administration involves applying intravesical mitomycin C with direct current of 20 mA delivered through a catheter electrode for 30 min. For numerical electric field computation we built a 3-D nonhomogeneous patient specific model based on CT images and used finite element method simulations to determine the electric fields in the whole body. Results indicate that highest electric field in the bladder wall was 37.7 V/m. The mean electric field magnitude in the bladder wall was 3.03 V/m. The mean magnitude of the current density in the bladder wall was 0.61 A/m(2). The present study shows that electroporation is not the mechanism of action in EMDA. A more likely explanation of the mechanism of action is iontophoretic forces increasing the mitomycin C concentration in the bladder wall.

Selective serotonin reuptake inhibitors and venlafaxine in pregnancy: Changes in drug disposition.

Directory of Open Access Journals (Sweden)

Andreas Austgulen Westin

Full Text Available Pregnancy may cause changes in drug disposition. The clinical consequences may be profound and even counterintuitive; in some cases pregnant women may need more than twice their usual drug dose in order to maintain therapeutic drug levels. For antidepressants, evidence on drug disposition in pregnancy is scarce. The aim of this study was to determine the effects of pregnancy on serum levels of selective serotonin reuptake inhibitors (SSRIs and venlafaxine in a large and naturalistic patient material, in order to provide tentative dose recommendations for pregnant women.Using patient data from two routine therapeutic drug monitoring (TDM services in Norway with linkage to the national birth registry, dose-adjusted serum drug concentrations of SSRIs and venlafaxine during pregnancy were compared to the women's own baseline (non-pregnant values, using a linear mixed model.Overall, the TDM databases contained 196,726 serum concentration measurements from 54,393 women. After data linkage and drug selection (SSRIs or venlafaxine only, we identified 367 analyses obtained from a total of 290 pregnancies in 281 women, and 420 baseline observations from the same women. Serum concentrations in the third trimester were significantly lower than baseline for paroxetine (-51%; 95% confidence interval [CI], -66%, -30%; p<0.001, fluvoxamine (-56%; CI, -75%, -23%; p = 0.004 and citalopram (-24%; CI, -38%, -7%; p = 0,007, and higher than baseline for sertraline (+68%; CI, +37%, +106%; p<0.001. For escitalopram, fluoxetine and venlafaxine concentrations did not change significantly.For paroxetine and fluvoxamine the pronounced decline in maternal drug serum concentrations in pregnancy may necessitate a dose increase of about 100% during the third trimester in order to maintain stable concentrations. For fluoxetine, venlafaxine, citalopram, escitalopram and sertraline, the present study indicates that dose adjustments are generally not necessary during pregnancy.

Highest recorded electrical conductivity and microstructure in polypropylene-carbon nanotubes composites and the effect of carbon nanofibers addition

Science.gov (United States)

Ramírez-Herrera, C. A.; Pérez-González, J.; Solorza-Feria, O.; Romero-Partida, N.; Flores-Vela, A.; Cabañas-Moreno, J. G.

2018-04-01

In the last decade, numerous investigations have been devoted to the preparation of polypropylene-multiwalled carbon nanotubes (PP/MWCNT) nanocomposites having enhanced properties, and in particular, high electrical conductivities (> 1 S cm-1). The present work establishes that the highest electrical conductivity in PP/MWCNT nanocomposites is limited by the amount of nanofiller content which can be incorporated in the polymer matrix, namely, about 20 wt%. This concentration of MWCNT in PP leads to a maximum electrical conductivity slightly lower than 8 S cm-1, but only by assuring an adequate combination of dispersion and spatial distribution of the carbon nanotubes. The realization of such an optimal microstructure depends on the characteristics of the production process of the PP/MWCNT nanocomposites; in our experiments, involving composite fabrication by melt mixing and hot pressing, a second re-processing cycle is shown to increase the electrical conductivity values by up to two orders of magnitude, depending on the MWCNT content of the nanocomposite. A modest increase of the highest electrical conductivity obtained in nanocomposites with 21.5 wt% MWCNT content has been produced by the combined use of carbon nanofibers (CNF) and MWCNT, so that the total nanofiller content was increased to 30 wt% in the nanocomposite with PP—15 wt% MWCNT—15 wt%CNF.

Radon and radon-daughter concentrations in air in the vicinity of the Anaconda Uranium Mill

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Momeni, M H; Lindstrom, J B; Dungey, C E; Kisieleski, W E

1979-11-01

Radon concentration, working level, and meteorological variables were measured continuously from June 1977 through June 1978 at three stations in the vicinity of the Anaconda Uranium Mill with measurements integrated to hourly intervals. Both radon and daughters show strong variations associated with low wind velocities and stable atmospheric conditions, and diurnal variations associated with thermal inversions. Average radon concentration shows seasonal dependence with highest concentrations observed during fall and winter. Comparison of radon concentrations and working levels between three stations shows strong dependence on wind direction and velocity. Radon concentrations and working-level distributions for each month and each station were analyzed. The average maximum, minimum, and modal concentration and working levels were estimated with observed frequencies. The highest concentration is 11,000 pCi/m/sup 3/ on the tailings. Working-level variations parallel radon variations but lag by less than one hour. The highest working levels were observed at night when conditions of higher secular radioactive equilibrium for radon daughters exist. Background radon concentration was measured at two stations, each located about 25 km from the mill, and the average is 408 pCi/m/sup 3/. Average working-level background is 3.6 x 10/sup -3/.

Reference Brain/Blood Concentrations of Citalopram, Duloxetine, Mirtazapine and Sertraline

DEFF Research Database (Denmark)

Nedahl, Michael; Johansen, Sys Stybe; Linnet, Kristian

2018-01-01

Postmortem blood samples may not accurately reflect antemortem drug concentrations, as the levels of some drugs increase due to postmortem redistribution (PMR). The brain has been suggested as an alternative sampling site. The anatomically secluded site of the brain limits redistribution and prol.......85), whereas the median citalopram/N-desmethylcitalopram ratio was higher in brain (9.1) than blood (4.1). The results of this study may serve as reference concentrations in brain for forensic cases....

Highest Resolution Gaspra Mosaic

Science.gov (United States)

1992-01-01

This picture of asteroid 951 Gaspra is a mosaic of two images taken by the Galileo spacecraft from a range of 5,300 kilometers (3,300 miles), some 10 minutes before closest approach on October 29, 1991. The Sun is shining from the right; phase angle is 50 degrees. The resolution, about 54 meters/pixel, is the highest for the Gaspra encounter and is about three times better than that in the view released in November 1991. Additional images of Gaspra remain stored on Galileo's tape recorder, awaiting playback in November. Gaspra is an irregular body with dimensions about 19 x 12 x 11 kilometers (12 x 7.5 x 7 miles). The portion illuminated in this view is about 18 kilometers (11 miles) from lower left to upper right. The north pole is located at upper left; Gaspra rotates counterclockwise every 7 hours. The large concavity on the lower right limb is about 6 kilometers (3.7 miles) across, the prominent crater on the terminator, center left, about 1.5 kilometers (1 mile). A striking feature of Gaspra's surface is the abundance of small craters. More than 600 craters, 100-500 meters (330-1650 feet) in diameter are visible here. The number of such small craters compared to larger ones is much greater for Gaspra than for previously studied bodies of comparable size such as the satellites of Mars. Gaspra's very irregular shape suggests that the asteroid was derived from a larger body by nearly catastrophic collisions. Consistent with such a history is the prominence of groove-like linear features, believed to be related to fractures. These linear depressions, 100-300 meters wide and tens of meters deep, are in two crossing groups with slightly different morphology, one group wider and more pitted than the other. Grooves had previously been seen only on Mars's moon Phobos, but were predicted for asteroids as well. Gaspra also shows a variety of enigmatic curved depressions and ridges in the terminator region at left. The Galileo project, whose primary mission is the

Gaspra - Highest Resolution Mosaic

Science.gov (United States)

1992-01-01

This picture of asteroid 951 Gaspra is a mosaic of two images taken by the Galileo spacecraft from a range of 5,300 kilometers (3,300 miles), some 10 minutes before closest approach on October 29, 1991. The Sun is shining from the right; phase angle is 50 degrees. The resolution, about 54 meters/pixel, is the highest for the Gaspra encounter and is about three times better than that in the view released in November 1991. Additional images of Gaspra remain stored on Galileo's tape recorder, awaiting playback in November. Gaspra is an irregular body with dimensions about 19 x 12 x 11 kilometers (12 x 7.5 x 7 miles). The portion illuminated in this view is about 18 kilometers (11 miles) from lower left to upper right. The north pole is located at upper left; Gaspra rotates counterclockwise every 7 hours. The large concavity on the lower right limb is about 6 kilometers (3.7 miles) across, the prominent crater on the terminator, center left, about 1.5 kilometers (1 mile). A striking feature of Gaspra's surface is the abundance of small craters. More than 600 craters, 100-500 meters (330-1650 feet) in diameter are visible here. The number of such small craters compared to larger ones is much greater for Gaspra than for previously studied bodies of comparable size such as the satellites of Mars. Gaspra's very irregular shape suggests that the asteroid was derived from a larger body by nearly catastrophic collisions. Consistent with such a history is the prominence of groove-like linear features, believed to be related to fractures. These linear depressions, 100-300 meters wide and tens of meters deep, are in two crossing groups with slightly different morphology, one group wider and more pitted than the other. Grooves had previously been seen only on Mars's moon Phobos, but were predicted for asteroids as well. Gaspra also shows a variety of enigmatic curved depressions and ridges in the terminator region at left. The Galileo project, whose primary mission is the

Alpha-1-antitrypsin deficiency in Madeira (Portugal): the highest prevalence in the world.

Science.gov (United States)

Spínola, Carla; Bruges-Armas, Jácome; Pereira, Conceição; Brehm, António; Spínola, Hélder

2009-10-01

Alpha-1-antitrypsin (AAT) deficiency is a common genetic disease which affects both lung and liver. Early diagnosis can help asymptomatic patients to adjust their lifestyle choices in order to reduce the risk of Chronic Obstructive Pulmonary Disease (COPD). The determination of this genetic deficiency prevalence in Madeira Island (Portugal) population is important to clarify susceptibility and define the relevance of performing genetic tests for AAT on individuals at risk for COPD. Two hundred samples of unrelated individuals from Madeira Island were genotyped for the two most common AAT deficiency alleles, PI*S and PI*Z, using Polymerase Chain Reaction-Mediated Site-Directed Mutagenesis. Our results show one of the highest frequencies for both mutations when compared to any already studied population in the world. In fact, PI*S mutation has the highest prevalence (18%), and PI*Z mutation (2.5%) was the third highest worldwide. The frequency of AAT deficiency genotypes in Madeira (PI*ZZ, PI*SS, and PI*SZ) is estimated to be the highest in the world: 41 per 1000. This high prevalence of AAT deficiency on Madeira Island reveals an increased genetic susceptibility to COPD and suggests a routine genetic testing for individuals at risk.

Pulmonary toxicity of cytostatic drugs: cell kinetics

International Nuclear Information System (INIS)

Witschi, H.; Godfrey, G.; Frome, E.; Lindenschmidt, R.C.

1987-01-01

Mice were treated with three cytostatic drugs: cyclophosphamide, busulfan, or 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). The alveolar labeling index was measured following drug administration with a pulse of 3 H-labeled thymidine and autoradiography. In cyclophosphamide-treated animals, peak alveolar cell proliferation was seen 5 days after injection of the drug. In animals treated with busulfan or BCNU, proliferation was even more delayed (occurring 2-3 weeks after administration). In contrast, with oleic acid, the highest alveolar cell labeling was found 2 days after intravenous administration. In animals exposed to a cytostatic drug, proliferation of type II alveolar cells was never a prominent feature whereas in animals treated with oleic acid there was an initial burst of type II cell proliferation. It is concluded that the patterns of pulmonary repair vary between chemicals designed to interfere with DNA replication as compared to agents which produce acute lung damage such as oleic acid

Quantitation of methylglyoxal bis(guanylhydrazone) in blood plasma and leukemia cells of patients receiving the drug.

Science.gov (United States)

Seppänen, P; Alhonen-Hongisto, L; Siimes, M; Jänne, J

1980-11-15

Methylglyoxal bis(guanylhydrazone), a cytostatic compound which apparently interferes with the metabolism and/or functions of the natural polyamines (spermidine and spermine), was effectively taken up by cultured human lymphocytic leukemia cells, rapidly resulting in the formation of a concentration gradient of up to 1,000-fold across the cell membrane in cells grown in the presence of micromolar concentrations of the drug. For an anti-proliferative effect on the leukemia cells, an intracellular concentration of more than 0.5 mM was required. The uptake of methylglyoxal bis(guanylhydrazone) was critically dependent on the growth rate of the leukemia cells. Low intracellular concentrations of the drug were present in cells growing slowly, whereas in rapidly dividing cells the intracellular concentration of the drug approached 5mM. When given as repeated intravenous infusions to two leukemic children, methylglyoxal bis(guanylhydrazone) exhibited sharp and transient peaks of plasma concentration, the drug having an apparent half-life in plasma of only 1-2 h. However, as in cultured cells, the drug was rapidly concentrated in the leukemia cells, reaching concentrations that were distinctly anti-proliferative. In contrast to the rapid disappearance of methylglyoxal bis(guanylhydrazone) from plasma, the circulation leukemia cells retained the drug for a period of several days with only minimal decrease in the initial concentrations. Methylglyoxal bis(guanylhydrazone) was given to the patients for 1 to 2 months as intravenous infusions, the timing of which was determined by regular assays of the drug concentrations in the leukemia cells. In agreement with the results obtained with the cultured cells, and intracellular concentration of about 0.5 to 1mM was apparently required for growth-inhibitory action to occur. Regular determination of the cellular drug concentrations indicated that methylglyoxal bis(quanylhydrazone) could be given as weekly infusions. This treatment

Physicochemical characterization of in situ drug-polymer nanocomplex formed between zwitterionic drug and ionomeric material in aqueous solution

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Salamanca, Constain H., E-mail: chsalamanca@icesi.edu.co [Pharmaceutical physical chemistry laboratory, Department of Pharmacy, Faculty of Natural Sciences, ICESI University, Cali (Colombia); Castillo, Duvan F.; Villada, Juan D. [Pharmaceutical physical chemistry laboratory, Department of Pharmacy, Faculty of Natural Sciences, ICESI University, Cali (Colombia); Rivera, Gustavo R. [SIT Biotech GmbH, BMZ 2 Otto-Hahn-Str. 15, 44227 Dortmund (Germany)

2017-03-01

Biocompatible polymeric materials with the potential to form functional structures, in association with different therapeutic molecules, in physiological media, represent a great potential for biological and pharmaceutical applications. Therefore, here the formation of a nano-complex between a synthetic cationic polymer and model drug (ampicillin trihydrate) was studied. The formed complex was characterized by size and zeta potential measurements, using dynamic light scattering and capillary electrophoresis. Moreover, the chemical and thermodynamically stability of these complexes were studied. The ionomeric material, here referred as EuCl, was obtained by equimolar reaction between Eudragit E and HCl. The structural characterization was carried out by potentiometric titration, FTIR spectroscopy, and DSC. The effect of pH, time, polymer concentration and ampicillin/polymer molar ratio over the hydrodynamic diameter and zeta potential were established. The results show that EuCl ionomer in aqueous media presents two different populations of nanoparticles; one of this tends to form flocculated aggregates in high pH and concentrations, by acquiring different conformations in solution by changing from a compact to an extended conformation. Moreover, the formation of an in situ interfacial polymer-drug complex was demonstrated, this could slightly reduce the hydrolytic degradation of the drug while affecting its solubility, mainly under acidic conditions. - Highlights: • The EuCl ionomer in aqueous media presents two different populations of nanoparticle, corresponding to proximally 15 nm and 150 nm. • The EuCl ionomer in aqueous media may form different structure depending on the pH and polymer concentration, which tends to form flocculated aggregates in high pH and concentrations. • The formation of an in situ interfacial polymer-drug complex was demonstrated, which could slightly reduce the hydrolytic degradation of the drug and affecting its solubility in

Drug interactions: volatile anesthetics and opioids.

Science.gov (United States)

Glass, P S; Gan, T J; Howell, S; Ginsberg, B

1997-09-01

Multiple drugs are used to provide anesthesia. Volatile anesthetics are commonly combined with opioids. Several studies have demonstrated that small doses of opioid (i.e., within the analgesic range) result in a marked reduction in minimum alveolar concentration (MAC) of the volatile anesthetic that will prevent purposeful movement in 50% of patients at skin incision). Further increases in opioid dose provide only a further small reduction in MAC. Thus, a ceiling effect of the opioid is observed at a MAC value of the volatile anesthetic equal to its MAC awake. Recovery from anesthesia when an opioid is combined with a volatile anesthetic is dependent on the rate of decrease of both drugs to their respective concentrations that are associated with adequate spontaneous ventilation and awakening. Through an understanding of the pharmacodynamic interaction of volatile anesthetics with opioids and the pharmacokinetic processes responsible for the recovery from drug effect, optimal dosing schemes can thus be developed. A review of these pharmacodynamic and pharmacokinetic principles that will allow clinicians to administer drugs to provide a more optimal anesthetic is provided.

A comparison of alcohol and drug use by random motor vehicle drivers in Brazil and Norway.

Science.gov (United States)

Gjerde, Hallvard; Sousa, Tanara R; De Boni, Raquel; Christophersen, Asbjørg S; Limberger, Renata P; Zancanaro, Ivomar; Oiestad, Elisabeth L; Normann, Per T; Mørland, Jørg; Pechansky, Flavio

2014-05-01

A large proportion of road traffic crashes are related to driving under the influence (DUI) of alcohol or drugs. The aim of this study was to compare the use of alcohol, illegal drugs and psychoactive medicinal drugs among random drivers in Brazil and Norway, two countries with the same legal limit for drunk driving, but with marked differences in legislation history, enforcement and penalties for DUI, and to discuss any differences found. Roadside surveys were conducted on Fridays and Saturdays between noon and midnight. Samples of oral fluid were collected for analysis of drugs, whereas alcohol was determined by breath testing or by analysis of oral fluid. High participation rates of 94-97% were obtained in both countries. The weighted prevalence of driving with alcohol concentrations in breath or oral fluid equivalent to blood alcohol concentrations (BAC) above 0.2g/L was 2.7% (95% CI 2.2-3.3) in Brazil and 0.2% (95% CI 0.0-0.5) in Norway. Stimulants (amphetamines or cocaine) were found in samples from 1.0% (95% CI 0.7-1.4) of drivers in Brazil and 0.3% (95% CI 0.1-0.7) in Norway. The prevalence of amphetamines was highest among Brazilian truck drivers (3.6%; 95% CI 2.0-6.4). Tetrahydrocannabinol was found in samples from 0.5% (95% CI 0.3-0.8) of drivers in Brazil and 1.0% (95% CI 0.6-1.5) in Norway, whereas benzodiazepines or zopiclone were found in 1.0% (95% CI 0.7-1.4) and 1.7% (95% CI 1.2-2.4) of the samples from Brazil and Norway, respectively. The difference in the prevalence of alcohol may be related to the fact that Norway has implemented steps to reduce drunk driving since 1936, whereas Brazil has attempted to do the same for only a few years. Differences for drugs may be related to different patterns in the use of stimulants, cannabis and medicines. Copyright © 2014 Elsevier B.V. All rights reserved.

Wet microcontact printing (µCP) for micro-reservoir drug delivery systems

International Nuclear Information System (INIS)

Lee, Hong-Pyo; Ryu, WonHyoung

2013-01-01

When micro-reservoir-type drug delivery systems are fabricated, loading solid drugs in drug reservoirs at microscale is often a non-trivial task. This paper presents a simple and effective solution to load a small amount of drug solution at microscale using ‘wet’ microcontact printing (µCP). In this wet µCP, a liquid solution containing drug molecules (methylene blue and tetracycline HCl) dissolved in a carrier solvent was transferred to a target surface (drug reservoir) by contact printing process. In particular, we have investigated the dependence of the quantity and morphology of transferred drug molecules on the stamp size, concentration, printing times, solvent types and surfactant concentration. It was also found that the repetition of printing using a non-volatile solvent such as polyethylene glycol (PEG) as a drug carrier material actually increased the transferred amount of drug molecules in proportion to the printing times based on asymmetric liquid bridge formation. Utilizing this wet µCP, drug delivery devices containing different quantity of drugs in micro-reservoirs were fabricated and their performance as controlled drug delivery devices was demonstrated. (paper)

Nonlinearities in Drug Release Process from Polymeric Microparticles: Long-Time-Scale Behaviour

Directory of Open Access Journals (Sweden)

Elena Simona Bacaita

2012-01-01

Full Text Available A theoretical model of the drug release process from polymeric microparticles (a particular type of polymer matrix, through dispersive fractal approximation of motion, is built. As a result, the drug release process takes place through cnoidal oscillations modes of a normalized concentration field. This indicates that, in the case of long-time-scale evolutions, the drug particles assemble in a lattice of nonlinear oscillators occur macroscopically, through variations of drug concentration. The model is validated by experimental results.

Directional clustering in highest energy cosmic rays

International Nuclear Information System (INIS)

Goldberg, Haim; Weiler, Thomas J.

2001-01-01

An unexpected degree of small-scale clustering is observed in highest-energy cosmic ray events. Some directional clustering can be expected due to purely statistical fluctuations for sources distributed randomly in the sky. This creates a background for events originating in clustered sources. We derive analytic formulas to estimate the probability of random cluster configurations, and use these formulas to study the strong potential of the HiRes, Auger, Telescope Array and EUSO-OWL-AirWatch facilities for deciding whether any observed clustering is most likely due to nonrandom sources. For a detailed comparison to data, our analytical approach cannot compete with Monte Carlo simulations, including experimental systematics. However, our derived formulas do offer two advantages: (i) easy assessment of the significance of any observed clustering, and most importantly, (ii) an explicit dependence of cluster probabilities on the chosen angular bin size

Exploring the cultural dimensions of the right to the highest ...

African Journals Online (AJOL)

The right to enjoying the highest attainable standard of health is incorporated in many international and regional human rights instruments. This right contains both freedoms and entitlements, including the freedom to control one's own health and body and the right to an accessible system of health care, goods and services.

Lack of cross-reactivity of Ambien (zolpidem) with drugs in standard urine drug screens.

Science.gov (United States)

Piergies, A A; Sainati, S; Roth-Schechter, B

1997-04-01

To determine in healthy volunteers (men and women; 18 to 40 years old) the potential cross-reactivity of Ambien (zolpidem) and/or its metabolites with drugs that are screened by the Syva EMIT II and the Abbott ADx urine drug screens assays. Open-label, fixed-treatment sequence of 1 night each of treatment with zolpidem (10 mg) and temazepam (15 mg). Clinical Pharmacology Unit within a teaching hospital. Over a 24-hour period, presence or absence of positive results on the Syva EMIT II or the Abbott ADx urine drug assay system, each performed at two different laboratory assay sites. Following ingestion of zolpidem, no subject had any positive response in either laboratory to the Syva EMIT II or the Abbott ADx urine drug screen assays at 0, 4, 8, 12, and 24 hours postdose. During the same time period, all subjects had measurable zolpidem plasma concentrations at 1.5 and 8 hours postdose, with mean concentrations of 115.2 ng/mL and 30.1 ng/mL, respectively (in agreement with its half-life of 2.5 hours). The positive response rate at 10 hours after ingestion of Restoril (temazepam) among the four laboratory/assay combinations ranged from 36.8% to 73.7%, a range that is within the reported response rates for these tests. These data indicate that zolpidem will not cross-react in standard urine drug screens with benzodiazepines, opiates, barbiturates, cocaine, cannabinoids, or amphetamines.

Evidence on the cost of breast cancer drugs is required for rational decision making.

Science.gov (United States)

Berghuis, Anne Margreet Sofie; Koffijberg, Hendrik; Terstappen, Leonardus Wendelinus Mathias Marie; Sleijfer, Stefan; IJzerman, Maarten Joost

2018-01-01

For rational decision making, assessing the cost-effectiveness and budget impact of new drugs and comparing the costs of drugs already on the market is required. In addition to value frameworks, such as the American Society of Clinical Oncology Value Framework and the European Society of Medical Oncology-Magnitude of Clinical benefit Scale, this also requires a transparent overview of actual drug prices. While list prices are available, evidence on treatment cost is not. This paper aims to synthesise evidence on the reimbursement and costs of high-cost breast cancer drugs in The Netherlands (NL). A literature review was performed to identify currently reimbursed breast cancer drugs in the NL. Treatment costs were determined by multiplying list prices with the average length of treatment and dosing schedule. Comparing list prices to the estimated treatment cost resulted in substantial differences in the ranking of costliness of the drugs. The average mean treatment length was unknown for 11/31 breast cancer drugs (26.2%). The differences in the 15 highest-cost drugs were largest for Bevacizumab, Lapatinib and everolimus, with list prices of €541, €158, €1,168 and estimated treatment cost of €174,400, €18,682 and €31,207, respectively. The lowest-cost (patented) targeted drug is €1,818 more expensive than the highest-cost (off-patent) generic drug according to the estimated drug treatment cost. A lack of evidence on the reimbursement and cost of high-cost breast cancer drugs complicates rapid and transparent evidence synthesis, necessary to focus strategies aiming to limit the increasing healthcare costs. Interestingly, the findings show that off-patent generics (such as paclitaxel or doxorubicin), although substantially cheaper than patented drugs, are still relatively costly. Extending standardisation and increasing European and national regulations on presenting information on costs per cancer drug is highly recommended.

Quantitative Analysis of Therapeutic Drugs in Dried Blood Spot Samples by Paper Spray Mass Spectrometry: An Avenue to Therapeutic Drug Monitoring

Science.gov (United States)

Manicke, Nicholas Edward; Abu-Rabie, Paul; Spooner, Neil; Ouyang, Zheng; Cooks, R. Graham

2011-09-01

A method is presented for the direct quantitative analysis of therapeutic drugs from dried blood spot samples by mass spectrometry. The method, paper spray mass spectrometry, generates gas phase ions directly from the blood card paper used to store dried blood samples without the need for complex sample preparation and separation; the entire time for preparation and analysis of blood samples is around 30 s. Limits of detection were investigated for a chemically diverse set of some 15 therapeutic drugs; hydrophobic and weakly basic drugs, such as sunitinib, citalopram, and verapamil, were found to be routinely detectable at approximately 1 ng/mL. Samples were prepared by addition of the drug to whole blood. Drug concentrations were measured quantitatively over several orders of magnitude, with accuracies within 10% of the expected value and relative standard deviation (RSD) of around 10% by prespotting an internal standard solution onto the paper prior to application of the blood sample. We have demonstrated that paper spray mass spectrometry can be used to quantitatively measure drug concentrations over the entire therapeutic range for a wide variety of drugs. The high quality analytical data obtained indicate that the technique may be a viable option for therapeutic drug monitoring.

Species differences in drug glucuronidation: Humanized UDP-glucuronosyltransferase 1 mice and their application for predicting drug glucuronidation and drug-induced toxicity in humans.

Science.gov (United States)

Fujiwara, Ryoichi; Yoda, Emiko; Tukey, Robert H

2018-02-01

More than 20% of clinically used drugs are glucuronidated by a microsomal enzyme UDP-glucuronosyltransferase (UGT). Inhibition or induction of UGT can result in an increase or decrease in blood drug concentration. To avoid drug-drug interactions and adverse drug reactions in individuals, therefore, it is important to understand whether UGTs are involved in metabolism of drugs and drug candidates. While most of glucuronides are inactive metabolites, acyl-glucuronides that are formed from compounds with a carboxylic acid group can be highly toxic. Animals such as mice and rats are widely used to predict drug metabolism and drug-induced toxicity in humans. However, there are marked species differences in the expression and function of drug-metabolizing enzymes including UGTs. To overcome the species differences, mice in which certain drug-metabolizing enzymes are humanized have been recently developed. Humanized UGT1 (hUGT1) mice were created in 2010 by crossing Ugt1-null mice with human UGT1 transgenic mice in a C57BL/6 background. hUGT1 mice can be promising tools to predict human drug glucuronidation and acyl-glucuronide-associated toxicity. In this review article, studies of drug metabolism and toxicity in the hUGT1 mice are summarized. We further discuss research and strategic directions to advance the understanding of drug glucuronidation in humans. Copyright © 2017 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.

Mercury in United Kingdom topsoils; concentrations, pools, and Critical Limit exceedances

Energy Technology Data Exchange (ETDEWEB)

Tipping, E., E-mail: et@ceh.ac.uk [Centre for Ecology and Hydrology, Lancaster Environment Centre, Library Avenue, Bailrigg, Lancaster LA1 4AP (United Kingdom); Poskitt, J.M.; Lawlor, A.J.; Wadsworth, R.A. [Centre for Ecology and Hydrology, Lancaster Environment Centre, Library Avenue, Bailrigg, Lancaster LA1 4AP (United Kingdom); Norris, D.A.; Hall, J.R. [Centre for Ecology and Hydrology, Bangor, Gwynedd LL57 2UW (United Kingdom)

2011-12-15

The median total mercury concentration in 898 UK rural topsoils, sampled between 1998 and 2008, was 0.095 {mu}g g{sup -1}. Approximate adjustment for unreactive metal produced an estimate of 0.052 {mu}g g{sup -1} for reactive Hg. The highest concentrations were in the north and west, where organic-rich soils with low bulk densities dominate, but the spatial pattern was quite different if soil Hg pools (mg m{sup -2}) were considered, the highest values being near to the industrial north of England and London. Possible toxic effects of Hg were best evaluated by comparison with soil Critical Limits expressed as ratios of Hg to soil organic matter, or soil solution Hg{sup 2+} concentrations, estimated by chemical speciation modelling. Only a few percent of the rural UK soils showed exceedance, and this also applied to rural soils from the whole of Europe. UK urban and industrial soils had higher Hg concentrations and more cases of exceedance. - Highlights: > Concentrations of Hg in rural soils are highest near to industrial areas and London. > Mercury is strongly associated with soil organic matter. > Only a few percent of UK rural soils have Hg levels higher than Critical Limits. > Critical Limit exceedances are found for 15-30% of urban and industrial soils. - Mercury contents of 898 UK and 868 European rural soils are largely lower than Critical Limit values, but appreciable numbers of soils in UK urban and industrial areas show exceedance.

Cannabis use: a perspective in relation to the proposed UK drug-driving legislation.

Science.gov (United States)

Wolff, Kim; Johnston, Atholl

2014-01-01

With regard to THC (Δ(9)-tetrahydrocannabinol), the main psychoactive constituent identified in the plant Cannabis sativa L, several facts are indisputable. Cannabis remains the most commonly used drug in the UK among those who reported driving under the influence of illegal drugs in the previous 12 months. There is a significant dose-related decrement in driving performance following cannabis use; raised blood THC concentrations are significantly associated with increased traffic crash and death risk. When cannabis and alcohol are detected together, there is a greater risk to road safety than when either drug is used alone. Patterns of use are important when interpreting blood concentration data: Smoking infrequently a single cannabis cigarette leads to peak plasma THC concentrations (21-267 µg/L) causing acute intoxication. In habitual, daily users, plasma THC concentrations range from 1.0 to 11.0 µg/L and are maintained by sequestration of the drug from the tissues. These facts undoubtedly make setting thresholds for drug-driving legislation difficult but there is clearly a case for cannabis. Determining minimum blood THC concentrations at which a driver becomes sufficiently impaired to be unable to safely drive a vehicle is of particular concern given the increasing medicinal use of the drug. Internationally legislation for driving under the influence of drugs (DUID) is based on either a proof of impairment or a per se approach. For the latter this can be either zero-tolerance or based on concentration limits such as those used for alcohol. The different approaches are considered against current scientific evidence. Copyright © 2013 John Wiley & Sons, Ltd.

Number and type of psychotropic drugs on the Scandinavian market in 1950-1977

DEFF Research Database (Denmark)

Hemminki, E; Pesonen, T; Hansen, E H

1981-01-01

This article describes the number and types of psychotropic drugs on the market in Denmark, Finland, Norway, and Sweden from 1950-1977. The total number of drugs on the market in each country depended greatly on how psychotropic drugs were defined, but trends with time and differences between...... the countries were less affected by this definition. The number of drugs was highest in Finland and lowest in Norway. In all countries, the number of drugs increased from 1950 to the mid-1960s, most abruptly in Finland. They then quickly decreased in Finland and Sweden, but remained fairly constant in Denmark...... numbers of combination drugs contributed greatly to the wide differences in the number of drugs. From the medical point of view, far too many drugs were on the market in that period....

The activity concentration of radiocesium in mushrooms from locality Stare Ransko

International Nuclear Information System (INIS)

Kunova, V.; Dvorak, P.; Benova, K.

2006-01-01

In this paper, activity concentrations of radiocesium in mushrooms from Stare Ransko (Czech Republic) in the years 2003 - 2004 are presented. The highest activity concentrations of 137 Cs measured by gamma-spectrometry was 6 040 Bq/kg (on a dry mass basis) in Xerocomus badius. The lowest activity concentration of 137 Cs was < 2.4 Bq/kg in Lycoperdon perlatum. (authors)

Examining the Spatial Distribution of Law Enforcement Encounters among People Who Inject Drugs after Implementation of Mexico’s Drug Policy Reform

OpenAIRE

Gaines, Tommi L.; Beletsky, Leo; Arredondo, Jaime; Werb, Daniel; Rangel, Gudelia; Vera, Alicia; Brouwer, Kimberly

2014-01-01

In 2009, Mexico decriminalized the possession of small amounts of illicit drugs for personal use in order to refocus law enforcement resources on drug dealers and traffickers. This study examines the spatial distribution of law enforcement encounters reported by people who inject drugs (PWID) in Tijuana, Mexico to identify concentrated areas of policing activity after implementation of the new drug policy. Mapping the physical location of law enforcement encounters provided by PWID (n = 461) ...

Drug delivery system and breast cancer cells

Science.gov (United States)

Colone, Marisa; Kaliappan, Subramanian; Calcabrini, Annarica; Tortora, Mariarosaria; Cavalieri, Francesca; Stringaro, Annarita

2016-06-01

Recently, nanomedicine has received increasing attention for its ability to improve the efficacy of cancer therapeutics. Nanosized polymer therapeutic agents offer the advantage of prolonged circulation in the blood stream, targeting to specific sites, improved efficacy and reduced side effects. In this way, local, controlled delivery of the drug will be achieved with the advantage of a high concentration of drug release at the target site while keeping the systemic concentration of the drug low, thus reducing side effects due to bioaccumulation. Various drug delivery systems such as nanoparticles, liposomes, microparticles and implants have been demonstrated to significantly enhance the preventive/therapeutic efficacy of many drugs by increasing their bioavailability and targetability. As these carriers significantly increase the therapeutic effect of drugs, their administration would become less cost effective in the near future. The purpose of our research work is to develop a delivery system for breast cancer cells using a microvector of drugs. These results highlight the potential uses of these responsive platforms suited for biomedical and pharmaceutical applications. At the request of all authors of the paper an updated version was published on 12 July 2016. The manuscript was prepared and submitted without Dr. Francesca Cavalieri's contribution and her name was added without her consent. Her name has been removed in the updated and re-published article.

Tenofovir alafenamide (TAF) does not deplete mitochondrial DNA in human T-cell lines at intracellular concentrations exceeding clinically relevant drug exposures.

Science.gov (United States)

Stray, Kirsten M; Park, Yeojin; Babusis, Darius; Callebaut, Christian; Cihlar, Tomas; Ray, Adrian S; Perron, Michel

2017-04-01

HIV-infected patients treated with certain nucleoside reverse transcriptase inhibitors (NRTIs) have experienced adverse effects due to drug-related mitochondrial toxicity. Tenofovir alafenamide (TAF) is a novel prodrug of the NRTI tenofovir (TFV) with an improved safety profile compared to tenofovir disoproxil fumarate (TDF). Prior in vitro studies have demonstrated that the parent nucleotide TFV has no significant effects on mtDNA synthesis. This study investigated whether clinically relevant TAF and TDF exposures affect mtDNA content in human lymphocytes. First, activated or resting peripheral blood mononuclear cells (PBMCs), as well as MT-2 and Jurkat T-cell lines, were continuously treated with ddC for 10 days to establish their susceptibility to mtDNA depletion. PBMCs had low sensitivity to NRTI-mediated mtDNA depletion in vitro. In contrast, ddC treatment of rapidly dividing MT-2 and Jurkat cells resulted in a dose-dependent decrease in mtDNA. Therefore, these two T-cell lines were selected for evaluating TAF and TDF treatment effects. MT-2 and Jurkat cells were pulse-treated with TAF or TDF every 24 h for 10 days to mimic pharmacologically relevant drug exposures. Pulse treatment of cells with 3.3 μM TAF or 1.1 μM TDF for 10 days resulted in 2- to 7-fold greater steady-state intracellular TFV-diphosphate (TFV-DP) levels than those observed clinically in TAF- or TDF-treated patients. At these concentrations, no significant TAF- (106.7% and 84.1% of control; p = 0.77 and 0.12 for MT-2 and Jurkat, respectively) or TDF- (100.6% and 91.0% of control; p = 0.91 and 0.37, respectively) associated reduction in mtDNA content was observed compared with untreated control cells. This study demonstrates that, despite delivering higher intracellular levels of TFV-DP than TDF, TAF does not inhibit mtDNA synthesis in vitro at concentrations exceeding the clinically relevant intracellular drug exposures. Thus, TAF has a low potential for mitochondrial toxicity in

Impact of orphan drugs on Latvian budget.

Science.gov (United States)

Logviss, Konstantins; Krievins, Dainis; Purvina, Santa

2016-05-11

Number of orphan medicinal products on the market and number of rare disease patients, taking these usually expensive products, are increasing. As a result, budget impact of orphan drugs is growing. This factor, along with the cost-effectiveness of orphan drugs, is often considered in the reimbursement decisions, directly affecting accessibility of rare disease therapies. The current study aims to assess the budget impact of orphan drugs in Latvia. Our study covered a 5-year period, from 2010 to 2014. Impact of orphan drugs on Latvian budget was estimated from the National Health Service's perspective. It was calculated in absolute values and relative to total pharmaceutical market and total drug reimbursement budget. A literature review was performed for comparison with other European countries. Orphan drug annual expenditure ranged between EUR 2.065 and 3.065 million, with total 5-year expenditure EUR 12.467 million. It constituted, on average, 0.84 % of total pharmaceutical market and 2.14 % of total drug reimbursement budget, respectively. Average annual per patient expenditures varied widely, from EUR 1 534 to EUR 580 952. The most costly treatment was enzyme replacement therapy (Elaprase) for MPS II. Glivec had the highest share (34 %) of the total orphan drug expenditure. Oncological drugs represented more than a half of the total orphan drug expenditure, followed by drugs for metabolic and endocrine conditions and medicines for cardiopulmonary diseases. Three indications: Ph+ CML, MPS II, and PAH accounted for nearly 90 % of the total orphan drug expenditure. Budget impact of orphan drugs in Latvia is very small. It increased slightly over a period of five years, due to the slight increase in the number of patients and the number of orphan drugs reimbursed. Current Latvian drug reimbursement system is not sufficient for most orphan drugs.

Risk factors contributing to a low darunavir plasma concentration

NARCIS (Netherlands)

Daskapan, Alper; Stienstra, Ymkje; Kosterink, Jos G.W.; Bierman, Wouter F.W.; van der Werf, Tjip S.; Touw, Daan J.; Alffenaar, Jan Willem C.

Darunavir is an efficacious drug; however, pharmacokinetic variability has been reported. The objective of this study was to find predisposing factors for low darunavir plasma concentrations in patients starting the once- or twice-daily dosage. Darunavir plasma concentrations from January 2010 till

Microdialysis as a tool for drug quantification in the bronchioles of anaesthetized pigs

DEFF Research Database (Denmark)

Rottbøll, Lisa Amanda Holm; Friis, Christian

2014-01-01

through a tracheostomy into the distal bronchioles using an insertion tube. Intravenously administered inulin served as a marker of extracellular fluid contamination of PELF. Concentrations of free drug in MD fractions were compared to total and non-protein-bound drug concentrations in plasma. Rising...... equipment, the danofloxacin concentrations in PELF were consistent within the different administration groups. The described MD method for drug quantification in PELF is easily accessible and provides repeatable results. However, trace amount of inulin was detected in the MD fractions, suggesting a local...

Modulating effect of the nootropic drug, piracetam on stress- and subsequent morphine-induced prolactin secretion in male rats.

Science.gov (United States)

Matton, A.; Engelborghs, S.; Bollengier, F.; Finné, E.; Vanhaeist, L.

1996-01-01

1. The effect of the nootropic drug, piracetam on stress- and subsequent morphine-induced prolactin (PRL) secretion was investigated in vivo in male rats, by use of a stress-free blood sampling and drug administration method by means of a permanent indwelling catheter in the right jugular vein. 2. Four doses of piracetam were tested (20, 100, 200 and 400 mg kg-1), being given intraperitoneally 1 h before blood sampling; control rats received saline instead. After a first blood sample, rats were subjected to immobilization stress and received morphine, 6 mg kg-1, 90 min later. 3. Piracetam had no effect on basal plasma PRL concentration. 4. While in the non-piracetam-treated rats, stress produced a significant rise in plasma PRL concentration, in the piracetam-pretreated rats PRL peaks were attenuated, especially in the group given 100 mg kg-1 piracetam, where plasma PRL concentration was not significantly different from basal values. The dose-response relationship showed a U-shaped curve; the smallest dose had a minor inhibitory effect and the highest dose had no further effect on the PRL rise. 5. In unrestrained rats, morphine led to a significant elevation of plasma PRL concentration. After the application of immobilization stress it lost its ability to raise plasma PRL concentration in the control rats, but not in the piracetam-treated rats. This tolerance was overcome by piracetam in a significant manner but with a reversed dose-response curve; i.e. the smaller the dose of piracetam, the higher the subsequent morphine-induced PRL peak. 6. There is no simple explanation for the mechanism by which piracetam induces these contradictory effects. Interference with the excitatory amino acid system, which is also involved in opiate action, is proposed speculatively as a possible mediator of the effects of piracetam. PMID:8821540

The Research Progress of Targeted Drug Delivery Systems

Science.gov (United States)

Zhan, Jiayin; Ting, Xizi Liang; Zhu, Junjie

2017-06-01

Targeted drug delivery system (DDS) means to selectively transport drugs to targeted tissues, organs, and cells through a variety of drugs carrier. It is usually designed to improve the pharmacological and therapeutic properties of conventional drugs and to overcome problems such as limited solubility, drug aggregation, poor bio distribution and lack of selectivity, controlling drug release carrier and to reduce normal tissue damage. With the characteristics of nontoxic and biodegradable, it can increase the retention of drug in lesion site and the permeability, improve the concentration of the drug in lesion site. at present, there are some kinds of DDS using at test phase, such as slow controlled release drug delivery system, targeted drug delivery systems, transdermal drug delivery system, adhesion dosing system and so on. This paper makes a review for DDS.

Five year results of an international proficiency testing programme for measurement of antifungal drug concentrations

NARCIS (Netherlands)

Lempers, V.J.C.; Alffenaar, J.W.C.; Touw, D.J.; Burger, D.M.; Uges, D.R.A.; Aarnoutse, R.E.; Brüggemann, R.J.M.

2014-01-01

OBJECTIVES: Since 2007 the Dutch Association for Quality Assessment in Therapeutic Drug Monitoring (KKGT) has organized an international interlaboratory proficiency testing (PT) programme for measurement of antifungal drugs in plasma. We describe the 5 year results of the laboratories' performance.

Evaluation of Chlorinated Hydrocarbon Concentrations in Tehran’s Districts Drinking Water

Directory of Open Access Journals (Sweden)

Alireza Pardakhti

2012-01-01

Full Text Available In this study Tehran’s drinking water was evaluated for the presence of chlorinated hydrocarbons during spring and summer of 2009. Chlorinated hydrocarbons are an important class of environmental pollutants that cause adverse health effects on human’s kidney, liver and central nervous systems. In this study six water districts were selected for taking drinking water samples in the city of Tehran as well as one location outside the city limits. The samples were analyzed by GC/MS using EPA method 8260. The average concentrations of 1,1-dichloroethylene, 1,2 Dichloromethane, Tetra chloromethane, Trichloroethylene and tetra chloroethylene were determined during a 7 month period and the results were 0.04ppb, 0.52ppb, 0.01ppb, 0.24ppb, 0.03ppb respectively. The highest concentration of chlorinated hydrocarbon observed in Tehran’s drinking water was Trichloroethylene and the lowest concentration was Tetra chloromethane. Districts 5 and 6 showed the highest concentrations of chlorinated hydrocarbons in the city of Tehran.

Essential and toxic element concentrations in monofloral honeys from southern Croatia.

Science.gov (United States)

Bilandžić, Nina; Tlak Gajger, Ivana; Kosanović, Marina; Čalopek, Bruno; Sedak, Marija; Solomun Kolanović, Božica; Varenina, Ivana; Luburić, Đurđica Božić; Varga, Ines; Đokić, Maja

2017-11-01

The concentrations of 24 elements in seven honey types (multifloral, heather, common heather, bearberry, sage, mandarin orange-blossom and honeydew) collected in southern Mediterranean regions of Croatia were determined using ICP-MS. Significant differences were found in the concentrations of Ag, As, Ba, Cu, Co, Fe, K, Mg, Mn, Mo, Na, Ni, Se, Sb, U and Th (p<0.05, all) among honeys. The highest element concentrations were determined in honeydew honeys, with the exception of multifloral (Ca, Cr, Mo, Se), common heather (Mg, Na), bearberry (Ba, Fe, Pb) and sage (Ag) honeys. Among the floral honeys, the highest concentrations were found in multifloral honey (Al, As, Be, Ca, Cr, Mn, Mo, Ni, Se, Th and U), common heather (Co, K, Mg, Na, V), sage (Ag, Cd, Cu), and bearberry (Ba, Fe, Pb, Sb, Zn). The results contribute to the evidence supporting the role of botanical origin on the elemental composition of honey. Copyright © 2017 Elsevier Ltd. All rights reserved.

Drug overdose surveillance using hospital discharge data.

Science.gov (United States)

Slavova, Svetla; Bunn, Terry L; Talbert, Jeffery

2014-01-01

We compared three methods for identifying drug overdose cases in inpatient hospital discharge data on their ability to classify drug overdoses by intent and drug type(s) involved. We compared three International Classification of Diseases, Ninth Revision, Clinical Modification code-based case definitions using Kentucky hospital discharge data for 2000-2011. The first definition (Definition 1) was based on the external-cause-of-injury (E-code) matrix. The other two definitions were based on the Injury Surveillance Workgroup on Poisoning (ISW7) consensus recommendations for national and state poisoning surveillance using the principal diagnosis or first E-code (Definition 2) or any diagnosis/E-code (Definition 3). Definition 3 identified almost 50% more drug overdose cases than did Definition 1. The increase was largely due to cases with a first-listed E-code describing a drug overdose but a principal diagnosis that was different from drug overdose (e.g., mental disorders, or respiratory or circulatory system failure). Regardless of the definition, more than 53% of the hospitalizations were self-inflicted drug overdoses; benzodiazepines were involved in about 30% of the hospitalizations. The 2011 age-adjusted drug overdose hospitalization rate in Kentucky was 146/100,000 population using Definition 3 and 107/100,000 population using Definition 1. The ISW7 drug overdose definition using any drug poisoning diagnosis/E-code (Definition 3) is potentially the highest sensitivity definition for counting drug overdose hospitalizations, including by intent and drug type(s) involved. As the states enact policies and plan for adequate treatment resources, standardized drug overdose definitions are critical for accurate reporting, trend analysis, policy evaluation, and state-to-state comparison.

Drug Overdose Surveillance Using Hospital Discharge Data

Science.gov (United States)

Bunn, Terry L.; Talbert, Jeffery

2014-01-01

Objectives We compared three methods for identifying drug overdose cases in inpatient hospital discharge data on their ability to classify drug overdoses by intent and drug type(s) involved. Methods We compared three International Classification of Diseases, Ninth Revision, Clinical Modification code-based case definitions using Kentucky hospital discharge data for 2000–2011. The first definition (Definition 1) was based on the external-cause-of-injury (E-code) matrix. The other two definitions were based on the Injury Surveillance Workgroup on Poisoning (ISW7) consensus recommendations for national and state poisoning surveillance using the principal diagnosis or first E-code (Definition 2) or any diagnosis/E-code (Definition 3). Results Definition 3 identified almost 50% more drug overdose cases than did Definition 1. The increase was largely due to cases with a first-listed E-code describing a drug overdose but a principal diagnosis that was different from drug overdose (e.g., mental disorders, or respiratory or circulatory system failure). Regardless of the definition, more than 53% of the hospitalizations were self-inflicted drug overdoses; benzodiazepines were involved in about 30% of the hospitalizations. The 2011 age-adjusted drug overdose hospitalization rate in Kentucky was 146/100,000 population using Definition 3 and 107/100,000 population using Definition 1. Conclusion The ISW7 drug overdose definition using any drug poisoning diagnosis/E-code (Definition 3) is potentially the highest sensitivity definition for counting drug overdose hospitalizations, including by intent and drug type(s) involved. As the states enact policies and plan for adequate treatment resources, standardized drug overdose definitions are critical for accurate reporting, trend analysis, policy evaluation, and state-to-state comparison. PMID:25177055

In vitro killing of Escherichia coli, Staphylococcus pseudintermedius and Pseudomonas aeruginosa by enrofloxacin in combination with its active metabolite ciprofloxacin using clinically relevant drug concentrations in the dog and cat.

Science.gov (United States)

Blondeau, J M; Borsos, S; Blondeau, L D; Blondeau, B J

2012-03-23

Enrofloxacin is a fluoroquinolone antibacterial agent used to treat infections in companion animals. Enrofloxacin's antimicrobial spectrum includes Gram positive and Gram-negative bacteria and demonstrates concentration-dependent bacteriocidal activity. In dogs and cats, enrofloxacin is partially metabolized to ciprofloxacin and both active agents circulate simultaneously in treated animals at ratios of approximately 60-70% enrofloxacin to 30-40% ciprofloxacin. We were interested in determining the killing of companion animal isolates of Escherichia coli, Staphylococcus pseudintermedius and Pseudomonas aeruginosa by enrofloxacin and ciprofloxacin combined using clinically relevant drug concentrations and ratios. For E. coli isolates exposed to 2.1 and 4.1μg/ml of enrofloxacin/ciprofloxacin at 50:50, 60:40 and 70:30 ratios, a 1.7-2.5log(10) reduction (94-99% kill) was seen following 20min of drug exposure; 0.89-1.7log(10) (92-99% kill) of S. pseudintermedius following 180min of drug exposure; 0.85-3.4log(10) (98-99% kill) of P. aeruginosa following 15min of drug exposure. Killing of S. pseudintermedius was enhanced in the presence of enrofloxacin whereas killing of P. aeruginosa was enhanced in the presence of ciprofloxacin. Antagonism was not seen when enrofloxacin and ciprofloxacin were used in kill assays. The unique feature of partial metabolism of enrofloxacin to ciprofloxacin expands the spectrum of enhanced killing of common companion animal pathogens. Copyright © 2011 Elsevier B.V. All rights reserved.

A New Drug Release Method in Early Development of Transdermal Drug Delivery Systems

Directory of Open Access Journals (Sweden)

Bing Cai

2012-01-01

Full Text Available In vitro drug release tests are a widely used tool to measure the variance between transdermal product performances and required by many authorities. However, the result cannot provide a good estimation of the in vivo drug release. In the present work, a new method for measuring drug release from patches has been explored and compared with the conventional USP apparatus 2 and 5 methods. Durogesic patches, here used as a model patch, were placed on synthetic skin simulator and three moisture levels (29, 57, 198 μL cm−2 were evaluated. The synthetic skin simulators were collected after 1, 2, 3, 4, 6, and 24 hours and extracted with pH 1.0 hydrochloric acid solution. The drug concentrations in the extractions were measured by isocratic reverse phase high-pressure liquid chromatography. The results showed that, with the increasing moisture level on the synthetic skin simulator, the drug release rate increased. In comparison with the conventional USP method, the drug release results performed by the new method were in more correlation to the release rate claimed in the product label. This new method could help to differentiate the drug release rates among assorted formulations of transdermal drug delivery systems in the early stage of development.

Spread of anti-malarial drug resistance: Mathematical model with implications for ACT drug policies

Directory of Open Access Journals (Sweden)

Dondorp Arjen M

2008-11-01

Full Text Available Abstract Background Most malaria-endemic countries are implementing a change in anti-malarial drug policy to artemisinin-based combination therapy (ACT. The impact of different drug choices and implementation strategies is uncertain. Data from many epidemiological studies in different levels of malaria endemicity and in areas with the highest prevalence of drug resistance like borders of Thailand are certainly valuable. Formulating an appropriate dynamic data-driven model is a powerful predictive tool for exploring the impact of these strategies quantitatively. Methods A comprehensive model was constructed incorporating important epidemiological and biological factors of human, mosquito, parasite and treatment. The iterative process of developing the model, identifying data needed, and parameterization has been taken to strongly link the model to the empirical evidence. The model provides quantitative measures of outcomes, such as malaria prevalence/incidence and treatment failure, and illustrates the spread of resistance in low and high transmission settings. The model was used to evaluate different anti-malarial policy options focusing on ACT deployment. Results The model predicts robustly that in low transmission settings drug resistance spreads faster than in high transmission settings, and treatment failure is the main force driving the spread of drug resistance. In low transmission settings, ACT slows the spread of drug resistance to a partner drug, especially at high coverage rates. This effect decreases exponentially with increasing delay in deploying the ACT and decreasing rates of coverage. In the high transmission settings, however, drug resistance is driven by the proportion of the human population with a residual drug level, which gives resistant parasites some survival advantage. The spread of drug resistance could be slowed down by controlling presumptive drug use and avoiding the use of combination therapies containing drugs with

Cultural energy analyses of dairy cattle receiving different concentrate levels

International Nuclear Information System (INIS)

Koknaroglu, Hayati

2010-01-01

Purpose of this study was to conduct cultural energy analyses of dairy cows receiving different levels of concentrate. Data were acquired by conducting a survey on 132 dairy farms selected by the stratified random sampling method. Dairy cattle farms were divided into three groups according to concentrate level and were analyzed. Accordingly concentrate levels were assigned as low (LLC) ( 50%, 44 farms). Cultural energy used for feed for cows was calculated by multiplying each ingredient with corresponding values of ingredients from literature. Transportation energy was also included in the analysis. Total cultural energy expended was highest for LLC (P < 0.05). Cultural energy expended for feed constituted more than half of the total cultural energy and was highest for LLC (P < 0.05). Cultural energy expended per kg milk and per Mcal protein energy was higher for LLC (P < 0.05). Efficiency defined as Mcal input/Mcal output was better for ILC and was worse for LLC (P < 0.05) and HLC was intermediate thus not differing from other groups. Results show that cultural energy use efficiency does not linearly increases as concentrate level increases and increasing concentrate level does not necessarily mean better efficiency. Thus optimum concentrate level not interfering cows performance should be sought for sustainable dairy production.

The effect of initial cell concentration on xylose fermentation by Pichia stipitis

Science.gov (United States)

Frank K. Agbogbo; Guillermo Coward-Kelly; Mads Torry-Smith; Kevin Wenger; Thomas W. Jeffries

2007-01-01

Xylose was fermented using Pichia stipitis CBS 6054 at different initial cell concentrations. A high initial cell concentration increased the rate of xylose utilization, ethanol formation, and the ethanol yield. The highest ethanol concentration of 41.0 g/L and a yield of 0.38 g/g was obtained using an initial cell concentration of 6.5 g/L. Even though more xylitol was...

The effect of environmental parameters to dust concentration in air-conditioned space

Science.gov (United States)

Ismail, A. M. M.; Manssor, N. A. S.; Nalisa, A.; Yahaya, N.

2017-08-01

Malaysia has a wet and hot climate, therefore most of the spaces are air conditioned. The environment might affect dust concentration inside a space and affect the indoor air quality (IAQ). The main objective of this study is to study the dust concentration collected inside enclosed air-conditioned space. The measurement was done physically at four selected offices and two classrooms using a number of equipment to measure the dust concentration and environmental parameters which are temperature and relative air humidity. It was found that the highest dust concentration produced in office (temperature of 24.7°C, relative humidity of 66.5%) is 0.075 mg/m3, as compared to classroom, the highest dust concentration produced is 0.060 mg/m3 office (temperature of 25.9°C, relative humidity of 64.0%). However, both measurements show that value still within the safety level set by DOSH Malaysia (2005-2010) and ASHRAE 62.2 2016. The office contained higher dust concentration compared to classroom because of frequent movement transpires daily due to the functional of the offices.

Polypharmacology of Approved Anticancer Drugs.

Science.gov (United States)

Amelio, Ivano; Lisitsa, Andrey; Knight, Richard A; Melino, Gerry; Antonov, Alexey V

2017-01-01

The major drug discovery efforts in oncology have been concentrated on the development of selective molecules that are supposed to act specifically on one anticancer mechanism by modulating a single or several closely related drug targets. However, a bird's eye view on data from multiple available bioassays implies that most approved anticancer agents do, in fact, target many more proteins with different functions. Here we will review and systematize currently available information on the targets of several anticancer drugs along with revision of their potential mechanisms of action. Polypharmacology of the current antineoplastic agents suggests that drug clinical efficacy in oncology can be achieved only via modulation of multiple cellular mechanisms. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

[Characteristics of the development of drug addiction and toxicomania in adolescents].

Science.gov (United States)

Lukacher, G Ia; Makshantseva, N V

1988-01-01

The study involved 152 adolescents which had abused narcotic and toxic substances once, occasionally or regularly. Males aged 15 to 16 years displayed highest occurrence rate of the abuse. Drug addiction and toxicomania were established in 6% of subjects. Volatile stuff and tranquilizers were most frequent in use. Microsocial adversities were experienced by all the subjects. Besides, an "altered background" is characteristic of drug addicts and toxicomania patients. The fact of narcotic and toxic substances usage as euphorigenic agents deserves due attention of narcologists, pedagogues, sociologists. Biologically conditioned risk factors conducive to drug addiction and toxicomania should be investigated.

Photocatalytic degradation kinetics and mechanism of antivirus drug-lamivudine in TiO{sub 2} dispersion

Energy Technology Data Exchange (ETDEWEB)

An, Taicheng, E-mail: antc99@gig.ac.cn [State Key Laboratory of Organic Geochemistry and Guangdong Key Laboratory of Environmental Resources Utilization and Protection, Guangzhou Institute of Geochemistry, Chinese Academy of Sciences, Guangzhou 510640 (China); An, Jibin [State Key Laboratory of Organic Geochemistry and Guangdong Key Laboratory of Environmental Resources Utilization and Protection, Guangzhou Institute of Geochemistry, Chinese Academy of Sciences, Guangzhou 510640 (China); College of Petrochemical Technology, Lanzhou University of Technology, Lanzhou 730050 (China); Graduate School of Chinese Academy of Sciences, Beijing 100049 (China); Yang, Hai [State Key Laboratory of Organic Geochemistry and Guangdong Key Laboratory of Environmental Resources Utilization and Protection, Guangzhou Institute of Geochemistry, Chinese Academy of Sciences, Guangzhou 510640 (China); Graduate School of Chinese Academy of Sciences, Beijing 100049 (China); Li, Guiying [State Key Laboratory of Organic Geochemistry and Guangdong Key Laboratory of Environmental Resources Utilization and Protection, Guangzhou Institute of Geochemistry, Chinese Academy of Sciences, Guangzhou 510640 (China); Feng, Huixia [College of Petrochemical Technology, Lanzhou University of Technology, Lanzhou 730050 (China); Nie, Xiangping [Institute of Hydrobiology, Jinan University, Guangzhou 510632 (China)

2011-12-15

Highlights: Black-Right-Pointing-Pointer Photocatalytic degradation kinetics of antivirus drug lamivudine. Black-Right-Pointing-Pointer The degradation kinetics was optimized by the single-variable-at-a-time. Black-Right-Pointing-Pointer The degradation kinetics was optimized by central composite design. Black-Right-Pointing-Pointer The contribution of reactive species was investigated with addition of scavengers. Black-Right-Pointing-Pointer Six intermediates were identified and a degradation mechanism was proposed. - Abstract: Photocatalytic degradation kinetics of antivirus drug-lamivudine in aqueous TiO{sub 2} dispersions was systematically optimized by both single-variable-at-a-time and central composite design based on the response surface methodology. Three variables, TiO{sub 2} content, initial pH and lamivudine concentration, were selected to determine the dependence of degradation efficiencies of lamivudine on independent variables. Response surface methodology modeling results indicated that degradation efficiencies of lamivudine were highly affected by TiO{sub 2} content and initial lamivudine concentration. The highest degradation efficiency was achieved at suitable amount of TiO{sub 2} and with maintaining initial lamivudine concentration to a minimum. In addition, the contribution experiments of various primary reactive species produced during the photocatalysis were investigated with the addition of different scavengers and found that hydroxyl radicals was the major reactive species involved in lamivudine degradation in aqueous TiO{sub 2}. Six degradation intermediates were identified using HPLC/MS/MS, and photocatalytic degradation mechanism of lamivudine was proposed by utilizing collective information from both experimental results of HPLC/MS/MS, ion chromatography as well as total organic carbon and theoretical data of frontier electron densities and point charges.

Sleep loss and acute drug abuse can induce DNA damage in multiple organs of mice.

Science.gov (United States)

Alvarenga, T A; Ribeiro, D A; Araujo, P; Hirotsu, C; Mazaro-Costa, R; Costa, J L; Battisti, M C; Tufik, S; Andersen, M L

2011-09-01

The purpose of the present study was to characterize the genetic damage induced by paradoxical sleep deprivation (PSD) in combination with cocaine or ecstasy (3,4-methylenedioxymethamphetamine; MDMA) in multiple organs of male mice using the single cell gel (comet) assay. C57BL/6J mice were submitted to PSD by the platform technique for 72 hours, followed by drug administration and evaluation of DNA damage in peripheral blood, liver and brain tissues. Cocaine was able to induce genetic damage in the blood, brain and liver cells of sleep-deprived mice at the majority of the doses evaluated. Ecstasy also induced increased DNA migration in peripheral blood cells for all concentrations tested. Analysis of damaged cells by the tail moment data suggests that ecstasy is a genotoxic chemical at the highest concentrations tested, inducing damage in liver or brain cells after sleep deprivation in mice. Taken together, our results suggest that cocaine and ecstasy/MDMA act as potent genotoxins in multiple organs of mice when associated with sleep loss.

A Highest Order Hypothesis Compatibility Test for Monocular SLAM

OpenAIRE

Edmundo Guerra; Rodrigo Munguia; Yolanda Bolea; Antoni Grau

2013-01-01

Simultaneous Location and Mapping (SLAM) is a key problem to solve in order to build truly autonomous mobile robots. SLAM with a unique camera, or monocular SLAM, is probably one of the most complex SLAM variants, based entirely on a bearing-only sensor working over six DOF. The monocular SLAM method developed in this work is based on the Delayed Inverse-Depth (DI-D) Feature Initialization, with the contribution of a new data association batch validation technique, the Highest Order Hyp...

21 CFR 146.148 - Reduced acid frozen concentrated orange juice.

Science.gov (United States)

2010-04-01

... 21 Food and Drugs 2 2010-04-01 2010-04-01 false Reduced acid frozen concentrated orange juice. 146... Canned Fruit Juices and Beverages § 146.148 Reduced acid frozen concentrated orange juice. (a) Reduced acid frozen concentrated orange juice is the food that complies with the requirements for composition...

Kinetic Degradation and Controlled Drug Delivery System Studies for Sensitive Hydrogels Prepared by Gamma Irradiation

International Nuclear Information System (INIS)

Eid, M.; El-Arnaouty, M.B.

2008-01-01

Ternary mixtures of N-vinyle-2-pyrrolidone(NVP ), itaconic acid (IA) and gelatin (G) were gamma irradiated to prepared poly(NVP/IA/G) hydrogels. The equilibrium kinetic swelling, drug release behavior, Scan Electron Microscope (SEM) and the swelling-degradation kinetics were studied. Both the diffusion exponent and the diffusion coefficient increase with increasing content of (IA). Also, the swelling behavior of copolymer hydrogels in response to ph value of the external media was studied, it is noted that the highest swelling values at ph 4. The in vitro drug release behavior of these hydrogels was examined by quantification analysis with a UV/VIS spectrophotometers. Chlorpromazine hydrochloride was loaded into dried hydrogels to investigate the stimuli-sensitive property at the specific ph. The release studies show that the highest value of release was at ph 4 which can be used for drug delivery system

A facile drug delivery system preparation through the interaction between drug and iron ion of transferrin

International Nuclear Information System (INIS)

Zhou, Lin; Liu, Jihua; Wei, Shaohua; Ge, Xuefeng; Zhou, Jiahong; Yu, Boyang; Shen, Jian

2013-01-01

Many anticancer drugs have the capability to form stable complex with metal ions. Based on such property, a simple method to combine these drugs with transferrin, through the interaction between drug and Fe ion of transferrin, to improve their anticancer activity, is proposed. To demonstrate this technique, the complex of photosensitive anticancer drug hypocrellin A and transferrin was prepared by such facile method. The results indicated that the complex of hypocrellin A and transferrin can stabilize in aqueous solution. In vitro studies have demonstrated the superior cancer cell uptake ability of hypocrellin A–transferrin complex to the free hypocrellin A. Significant damage to such drug-impregnated tumor cells was observed upon irradiation and the cancer cells killing ability of hypocrellin A–transferrin was stronger than the free hypocrellin A within a certain range of concentrations. The above results demonstrated the validity and potential of our proposed strategy to prepare the drug delivery system of this type of anti-cancer drugs and transferrin

A facile drug delivery system preparation through the interaction between drug and iron ion of transferrin

Energy Technology Data Exchange (ETDEWEB)

Zhou, Lin [Nanjing Normal University, Jiangsu Key Laboratory Biofunctional Materials, Key Laboratory of Applied Photochemistry, Analysis and Testing Center, College of Chemistry and Materials Science (China); Liu, Jihua [China Pharmaceutical University, Department of Complex Prescription of TCM (China); Wei, Shaohua; Ge, Xuefeng; Zhou, Jiahong, E-mail: zhoujiahong@njnu.edu.cn [Nanjing Normal University, Jiangsu Key Laboratory Biofunctional Materials, Key Laboratory of Applied Photochemistry, Analysis and Testing Center, College of Chemistry and Materials Science (China); Yu, Boyang, E-mail: boyangyu59@163.com [China Pharmaceutical University, Department of Complex Prescription of TCM (China); Shen, Jian [Nanjing Normal University, Jiangsu Key Laboratory Biofunctional Materials, Key Laboratory of Applied Photochemistry, Analysis and Testing Center, College of Chemistry and Materials Science (China)

2013-09-15

Many anticancer drugs have the capability to form stable complex with metal ions. Based on such property, a simple method to combine these drugs with transferrin, through the interaction between drug and Fe ion of transferrin, to improve their anticancer activity, is proposed. To demonstrate this technique, the complex of photosensitive anticancer drug hypocrellin A and transferrin was prepared by such facile method. The results indicated that the complex of hypocrellin A and transferrin can stabilize in aqueous solution. In vitro studies have demonstrated the superior cancer cell uptake ability of hypocrellin A-transferrin complex to the free hypocrellin A. Significant damage to such drug-impregnated tumor cells was observed upon irradiation and the cancer cells killing ability of hypocrellin A-transferrin was stronger than the free hypocrellin A within a certain range of concentrations. The above results demonstrated the validity and potential of our proposed strategy to prepare the drug delivery system of this type of anti-cancer drugs and transferrin.

Pharmacokinetics of antiretroviral drugs in infancy | McIlleron ...

African Journals Online (AJOL)

Dosing in infancy is complicated by inadequate characterisation of pharmacokinetics, unpredictable drug concentrations and a lack of suitable dosage forms. Additional challenges are presented by the concomitant administration of interacting drugs (e.g. rifampicin in antituberculosis treatment) and disease conditions that ...

Stability of drugs of abuse in urine samples stored at -20 degrees C.

Science.gov (United States)

Dugan, S; Bogema, S; Schwartz, R W; Lappas, N T

1994-01-01

Isolated studies of the stability of individual drugs of abuse have been reported. However, few have evaluated stability in frozen urine samples stored for 12 months. We have determined the stability of 11-nor-9-carboxy-delta 9-tetrahydrocannabinol (9-COOH-THC), amphetamine, methamphetamine, morphine, codeine, cocaine, benzoylecgonine, and phencyclidine in 236 physiological urine samples. Following the initial quantitative analysis, the samples were stored at -20 degrees C for 12 months and then reanalyzed. All drug concentrations were determined by gas chromatographic-mass spectrometric methods with cutoff concentrations of 5 ng/mL for 9-COOH-THC and phencyclidine and 100 ng/mL for each of the other drugs. The average change in the concentrations of these drugs following this long-term storage was not extensive except for an average change of -37% in cocaine concentrations.

Pharmacokinetic equivalence study of nonsteroidal anti-inflammatory drug etoricoxib

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Tjandrawinata RR

2018-04-01

Full Text Available Raymond R Tjandrawinata,1 Arini Setiawati,2 Dwi Nofiarny,1 Liana W Susanto,1 Effi Setiawati3 1Dexa Laboratories of Biomolecular Sciences Unit, Dexa Medica Group, Cikarang, West Java, Indonesia; 2Department of Pharmacology and Therapeutics, Medical Faculty, University of Indonesia, Jakarta, Indonesia; 3Bioavailability and Bioequivalence Laboratory Unit, PT Equilab International, Jakarta, Indonesia Purpose: The current study aimed to evaluate whether a generic product of etoricoxib 120 mg film-coated tablet (the test drug was bioequivalent to the reference product (Arcoxia® film-coated tablet 120 mg.Methods: This was a randomized, open-label, two-sequence, crossover study under fasting condition, with a 14-day washout period, involving 26 healthy adult male and female subjects. Blood samples were taken and analyzed for plasma concentrations of etoricoxib (Chemical Abstracts Service [CAS] 202409-33-4 using a high-pressure liquid chromatography–ultraviolet detector (HPLC-UV system capable of measuring etoricoxib concentrations ranging from 5.00 to 5002.90 ng/mL, with the lowest limit of quantitation of 5.00 ng/mL. A noncompartmental method was used to determine the pharmacokinetic parameters of a single-dose administration of the drug, including the area under plasma concentration–time curve from time zero to the time of last observed concentration (AUC0-t, the area under plasma concentration–time curve from time zero to infinity (AUC0-∞, the maximum plasma concentration (Cmax, the time to reach the maximum plasma concentration (tmax, and the terminal half-life (t½.Results: After a single-dose administration of etoricoxib 120 mg film-coated tablet, the mean (SD values for the AUC0-72h and Cmax of the test drug were 45913.42 (13142.19 ng·h/mL and 3155.93 (752.81 ng/mL, respectively; the values for the reference drug were 44577.20 (13541.85 ng⋅h/mL and 2915.13 (772.81 ng/mL, respectively. The geometric mean ratios (90% CIs of the test

Drugs and drug delivery systems targeting amyloid-β in Alzheimer's disease

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Morgan Robinson

2015-07-01

Full Text Available Alzheimer's disease (AD is a devastating neurodegenerative disorder with no cure and limited treatment solutions that are unable to target any of the suspected causes. Increasing evidence suggests that one of the causes of neurodegeneration is the overproduction of amyloid beta (Aβ and the inability of Aβ peptides to be cleared from the brain, resulting in self-aggregation to form toxic oligomers, fibrils and plaques. One of the potential treatment options is to target Aβ and prevent self-aggregation to allow for a natural clearing of the brain. In this paper, we review the drugs and drug delivery systems that target Aβ in relation to Alzheimer's disease. Many attempts have been made to use anti-Aβ targeting molecules capable of targeting Aβ (with much success in vitro and in vivo animal models, but the major obstacle to this technique is the challenge posed by the blood brain barrier (BBB. This highly selective barrier protects the brain from toxic molecules and pathogens and prevents the delivery of most drugs. Therefore novel Aβ aggregation inhibitor drugs will require well thought-out drug delivery systems to deliver sufficient concentrations to the brain.

Applications of linking PBPK and PD models to predict the impact of genotypic variability, formulation differences, differences in target binding capacity and target site drug concentrations on drug responses and variability.

Science.gov (United States)

Chetty, Manoranjenni; Rose, Rachel H; Abduljalil, Khaled; Patel, Nikunjkumar; Lu, Gaohua; Cain, Theresa; Jamei, Masoud; Rostami-Hodjegan, Amin

2014-01-01

This study aimed to demonstrate the added value of integrating prior in vitro data and knowledge-rich physiologically based pharmacokinetic (PBPK) models with pharmacodynamics (PDs) models. Four distinct applications that were developed and tested are presented here. PBPK models were developed for metoprolol using different CYP2D6 genotypes based on in vitro data. Application of the models for prediction of phenotypic differences in the pharmacokinetics (PKs) and PD compared favorably with clinical data, demonstrating that these differences can be predicted prior to the availability of such data from clinical trials. In the second case, PK and PD data for an immediate release formulation of nifedipine together with in vitro dissolution data for a controlled release (CR) formulation were used to predict the PK and PD of the CR. This approach can be useful to pharmaceutical scientists during formulation development. The operational model of agonism was used in the third application to describe the hypnotic effects of triazolam, and this was successfully extrapolated to zolpidem by changing only the drug related parameters from in vitro experiments. This PBPK modeling approach can be useful to developmental scientists who which to compare several drug candidates in the same therapeutic class. Finally, differences in QTc prolongation due to quinidine in Caucasian and Korean females were successfully predicted by the model using free heart concentrations as an input to the PD models. This PBPK linked PD model was used to demonstrate a higher sensitivity to free heart concentrations of quinidine in Caucasian females, thereby providing a mechanistic understanding of a clinical observation. In general, permutations of certain conditions which potentially change PK and hence PD may not be amenable to the conduct of clinical studies but linking PBPK with PD provides an alternative method of investigating the potential impact of PK changes on PD.

Applications of linking PBPK and PD models to predict the impact of genotypic variability, formulation differences, differences in target binding capacity and target site drug concentrations on drug responses and variability.

Directory of Open Access Journals (Sweden)

Manoranjenni eChetty

2014-11-01

Full Text Available This study aimed to demonstrate the added value of integrating prior in vitro data and knowledge-rich physiologically based pharmacokinetic (PBPK models with pharmacodynamics (PD models. Four distinct applications that were developed and tested are presented here. PBPK models were developed for metoprolol using different CYP2D6 genotypes based on in vitro data. Application of the models for prediction of phenotypic differences in the pharmacokinetics (PK and PD compared favourably with clinical data, demonstrating that these differences can be predicted prior to the availability of such data from clinical trials. In the second case, PK and PD data for an immediate release formulation of nifedipine together with in vitro dissolution data for a controlled release formulation (CR were used to predict the PK and PD of the CR. This approach can be useful to pharmaceutical scientists during formulation development. The operational model of agonism was used in the third application to describe the hypnotic effects of triazolam, and this was successfully extrapolated to zolpidem by changing only the drug related parameters from in vitro experiments. This PBPK modelling approach can be useful to developmental scientists who which to compare several drug candidates in the same therapeutic class. Finally, differences in QTc prolongation due to quinidine in Caucasian and Korean females were successfully predicted by the model using free heart concentrations as an input to the PD models. This PBPK linked PD model was used to demonstrate a higher sensitivity to free heart concentrations of quinidine in Caucasian females, thereby providing a mechanistic understanding of a clinical observation. In general, permutations of certain conditions which potentially change PK and hence PD may not be amenable to the conduct of clinical studies but linking PBPK with PD provides an alternative method of investigating the potential impact of PK changes on PD.

Study of antimicrobial property of some hypoglycemic drugs

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Arun Kumar Dash

2011-01-01

Full Text Available In the present work, a comparative antimicrobial study of different hypoglycemic drugs (Metformin, Phenformin, and Rosiglitazone was carried out. The main objective was to ascertain the antimicrobial activity by using "non-antibiotics" as the test substances. The antimicrobial activity was carried out against different bacteria and fungi namely Bacillus liceniformis, Escherichia coli, Proteus vulgaris, Pseudomonas aeruginosa, Shigella flexneri, Bacillus subtilis, Staphylococcus aureus subspp., and Staphylococcus epidermidis by using disc diffusion method and agar dilution method. Ciprofloxacin was taken as the standard antibiotic. The entire procedure was carried out in an aseptic area under the laminar flow by inoculating the bacterial strain to the agar media in which the drug solution was added. Different concentrations (300 and 400 μg/ml of the standard antibiotic and selected drugs were subjected for minimum inhibitory concentration, and zone of inhibition tests and the antimicrobial activity of the selected drugs were determined.

ß-endorphins as Possible Markers for Therapeutic Drug Monitoring

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Radivoj Jadrić

2007-02-01

Full Text Available This study was performed in order to investigate possible role of brain beta-endorphins as markers of antidepressive drugs therapy monitoring. Experiment was done using amitriptyline and trazodone as antidepressants. For quantification of brain beta-endorphins we used RIA technique. Our results showed significant decrease of brain beta-endorphins concentration in drug-pretreated animals, vs. those in of control group treated with 0,95% NaCl. The lower values were obtained in trazodone pre-treated animals. This study shows that use of psychoactive drugs have influence on brain beta-endorphins concentration. beta-endorphins could be of great importance, used as markers for evaluation of patient treatment.

A comparative study of vitamin E TPGS/HPMC supersaturated system and other solubilizer/polymer combinations to enhance the permeability of a poorly soluble drug through the skin.

Science.gov (United States)

Ghosh, Indrajit; Michniak-Kohn, Bozena

2012-11-01

In transdermal drug delivery systems (TDDS), it is a challenge to achieve stable and prolonged high permeation rates across skin, because the concentration of the drug dissolved in the matrix has to be high in order to maintain zero order release kinetics of the drug. In case of poorly soluble drugs, due to thermodynamic challenges, there is a high tendency for the drug to nucleate immediately after formulating or even during storage. The present study focuses on the efficiency of vitamin E TPGS/HPMC supersaturated solution and other solubilizer/polymer systems to improve the solubility of the drug and inhibit crystal growth in the transdermal formulation. Effect of several solubilizers, for example, Pluronic F-127, vitamin E TPGS and co-solvent, for example, propylene glycol (PG) were studied on the supersaturated systems of ibuprofen as model drug. Various stabilizers such as hydroxylpropyl methylcellulose (HPMC 3 cps) and polyvinylpyrrolidone (PVP K-30) were examined to evaluate their crystal inhibitory effects. Different analytical tools were used in this study to detect the growth of crystals in the systems. Vitamin E TPGS and HPMC 3 cps formulation produced the highest permeation rate of the drug as compared to other systems. In addition, the onset of crystallization time was shown to be longer with this formulation as compared to other solubilizer/polymer combinations.

Effect of cell culture medium components on color of formulated monoclonal antibody drug substance.

Science.gov (United States)

Vijayasankaran, Natarajan; Varma, Sharat; Yang, Yi; Mun, Melissa; Arevalo, Silvana; Gawlitzek, Martin; Swartz, Trevor; Lim, Amy; Li, Feng; Zhang, Boyan; Meier, Steve; Kiss, Robert

2013-01-01

As the industry moves toward subcutaneous delivery as a preferred route of drug administration, high drug substance concentrations are becoming the norm for monoclonal antibodies. At such high concentrations, the drug substance may display a more intense color than at the historically lower concentrations. The effect of process conditions and/or changes on color is more readily observed in the higher color, high concentration formulations. Since color is a product quality attribute that needs to be controlled, it is useful to study the impact of process conditions and/or modifications on color. This manuscript summarizes cell culture experiments and reports on findings regarding the effect of various media components that contribute to drug substance color for a specific monoclonal antibody. In this work, lower drug substance color was achieved via optimization of the cell culture medium. Specifically, lowering the concentrations of B-vitamins in the cell culture medium has the effect of reducing color intensity by as much as 25%. In addition, decreasing concentration of iron was also directly correlated color intensity decrease of as much as 37%. It was also shown that the color of the drug substance directly correlates with increased acidic variants, especially when increased iron levels cause increased color. Potential mechanisms that could lead to antibody coloration are briefly discussed. © 2013 American Institute of Chemical Engineers.

Clinically relevant potential drug-drug interactions among outpatients: A nationwide database study.

Science.gov (United States)

Jazbar, Janja; Locatelli, Igor; Horvat, Nejc; Kos, Mitja

2018-06-01

Adverse drug events due to drug-drug interactions (DDIs) represent a considerable public health burden, also in Slovenia. A better understanding of the most frequently occurring potential DDIs may enable safer pharmacotherapy and minimize drug-related problems. The aim of this study was to evaluate the prevalence and predictors of potential DDIs among outpatients in Slovenia. An analysis of potential DDIs was performed using health claims data on prescription drugs from a nationwide database. The Lexi-Interact Module was used as the reference source of interactions. The influence of patient-specific predictors on the risk of potential clinically relevant DDIs was evaluated using logistic regression model. The study population included 1,179,803 outpatients who received 15,811,979 prescriptions. The total number of potential DDI cases identified was 3,974,994, of which 15.6% were potentially clinically relevant. Altogether, 9.3% (N = 191,213) of the total population in Slovenia is exposed to clinically relevant potential DDIs, and the proportion is higher among women and the elderly. After adjustment for cofactors, higher number of medications and older age are associated with higher odds of clinically relevant potential DDIs. The burden of DDIs is highest with drug combinations that increase risk of bleeding, enhance CNS depression or anticholinergic effects or cause cardiovascular complications. The current study revealed that 1 in 10 individuals in the total Slovenian population is exposed to clinically relevant potential DDIs yearly. Taking into account the literature based conservative estimate that approximately 1% of potential DDIs result in negative health outcomes, roughly 1800 individuals in Slovenia experience an adverse health outcome each year as a result of clinically relevant potential interactions alone. Copyright © 2017 Elsevier Inc. All rights reserved.

Therapeutic drug management of linezolid: a missed opportunity for clinicians?

Science.gov (United States)

Cattaneo, Dario; Gervasoni, Cristina; Cozzi, Valeria; Castoldi, Simone; Baldelli, Sara; Clementi, Emilio

2016-12-01

Some studies have shown that adjustments to the linezolid dose guided by therapeutic drug monitoring (TDM) can reduce interindividual variability in drug exposure and improve linezolid tolerability. In this study, 6 years of linezolid TDM, a diagnostic service for our hospital and others in the Milan (Italy) area, is described. Samples were collected immediately before the morning dose intake (trough concentrations) in steady-state conditions. Linezolid concentrations were quantified by a validated high-performance liquid chromatography (HPLC) method. Four hundred linezolid trough concentrations from 220 patients were collected. A 20-fold variability in linezolid levels was observed. Positive and significant correlations between linezolid trough concentrations and patient age (r = 0.325, P linezolid concentrations with time was observed in a subgroup of patients with more than one TDM assessment. Elderly patients, especially those aged >80 years and with impaired renal function, are at a higher risk of overexposure to linezolid. Despite the observed progressive increase in linezolid concentrations over time, most physicians did not change the drug dose according to the TDM results, even in the presence of frank overexposure to linezolid. Copyright © 2016 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.

Metal concentrations in selected organs and tissues of five Red ...

African Journals Online (AJOL)

The absence of metalprocessing industries in the catchments of the Florida Lake and the Steynsrus farm dams reflects the low liver and kidney concentrations of Cd, Ni and Cu, respectively. The blood of the Natalspruit wetland coots contained the highest dry weight concentrations of Ni (11.4 mg/g), Cd (1.8 mg/g) and Cu ...

Pharmaceutical penetration of new drug and pharmaceutical market structure in Taiwan: hospital-level prescription of thiazolidinediones for diabetes.

Science.gov (United States)

Tsai, Yi-Wen; Wen, Yu-Wen; Huang, Weng-Foung; Kuo, Ken N; Chen, Pei-Fen; Shih, Hsin-Wei; Lee, Yue-Chune

2010-06-01

This study used Taiwan's National Health Insurance claim database (years 2000-2005) to examine how thiazolidinediones (TZD), a new class of drugs for diabetes, penetrated into Taiwan's hospitals, and its association with the concentration of all diabetes drugs at the hospital level. We collected 72 monthly summaries of diabetes prescriptions from all hospitals in Taiwan. Hospital-level pharmaceutical concentration was measured by penetration of TZD, defined as monthly market share of TZD in each hospital. Concentration of diabetes drugs was measured by Herfindahl-Hirschman indices. We found a negative association (coefficient = -0.3610) between TZD penetration and concentration of diabetes drug but a positive association between penetration of TZD and the volume of prescribed diabetes drugs (coefficient = 0.4088). In conclusion, hospital characteristics and volume of services determined the concentration of pharmaceuticals at the institution level, reflecting the heterogeneous competition between pharmaceutical companies within each hospital. Institution-level pharmaceutical concentration influences the adoption and penetration of new drugs.

Increase in tiagabine serum concentration with coadministration of gemfibrozil.

Science.gov (United States)

Burstein, Aaron H; Boudreau, Eilis A; Theodore, William H

2009-02-01

To report a case of possible acute tiagabine toxicity secondary to administration of gemfibrozil. A 39-year-old male was taking tiagabine 16 mg orally 3 times per day and carbamazepine 500 mg orally twice per day for complex partial seizures secondary to mesial temporal sclerosis. He was found to have type IV hypertriglyceridemia and was prescribed gemfibrozil. Because he reported severe confusion and altered consciousness shortly after a single 600-mg dose of gemfibrozil, he was admitted for controlled challenge with that drug. A single 300-mg dose of gemfibrozil resulted in lightheadedness and led to a 59% and 75% increase in total tiagabine serum concentrations at 2 and 5 hours, respectively, without significant change in baseline carbamazepine concentrations. This is the first report of an interaction between the widely used antihyperlipidemic drug gemfibrozil and tiagabine. Since tiagabine, which was originally developed as an antiepileptic medication, is now being used widely for a variety of other indications such as anxiety and depression, there is an increased risk for clinically significant interactions with gemfibrozil. Increased total and unbound tiagabine concentrations following a single 300-mg dose of gemfibrozil and reproduction of clinical symptoms with gemfibrozil rechallenge suggests the toxicity our patient experienced was due to a pharmacokinetic drug interaction. Use of the Horn Drug Interaction Probability Scale showed a probable interaction between gemfibrozil and tiagabine.

[Interactions of cytostatic agents with other drugs].

Science.gov (United States)

Sauter, C

1991-08-31

With the degree of polypharmacy currently practiced in the field of oncology, there are undoubtedly many drug interactions. In the present study the influence of "non-cytotoxic" drugs on anticancer drugs is discussed, but not the reverse. Not only is the augmentation (reversal of multidrug resistance) or the reduction of antitumor properties of cytotoxic drugs observed, but also cytostatic activities of "non-cytotoxic" drugs themselves. Examples are calmodulin inhibitors such as phenothiazines and tricyclic antidepressants. Interactions may also increase side effects of cytostatic drugs or even neutralize the antitumoral activity. To ensure that interactions are not overlooked, all medicaments being administered should be listed. It is, however, not feasible yet to determine serum concentrations of all the drugs given to the patient. The antitumor activity of supportive care could be evaluated in randomized studies (e.g. cytostatic drugs +/- antidepressants).

The Effect of Muscle Dysmorphia and Social Physique Anxiety on the Use of Supplements and Drugs

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Yadollah Khorramabady

2017-09-01

Full Text Available Background The use of dietary supplements and drugs to improve performance and physical appearance has recently increased among professional and recreational ‎athletes. Literature shows that bodybuilders, more than other athletes use supplements and drugs. Objectives This study aims to predict the use of supplements and drugs by muscle dysmorphia and social physique anxiety variables among Hamedan bodybuilders. Methods This cross-sectional investigation was conducted with 438 bodybuilders in Hamedan province. For collecting data, we used a demographic questionnaire, muscle dysmorphia scale, and social ‎physique anxiety scale. Results The results showed that 79.2% of the subjects used supplements, and vitamins (22.1% and protein powders (21.9% had the highest rates of use among supplements. Moreover, 145 subjects (33.1% used drugs, and steroid derivatives (16.2% and peptide hormones and growth factors (12.6% had the highest rates of use among drugs. The results of t-test showed that muscle dysmorphia and social physique anxiety were significantly higher in the subjects who used supplements and drugs than those who did not. Additionally, the results of logistic regression indicated that muscle dysmorphia and social physique anxiety can predict the likelihood of drug abuse. Conclusions The present study provides novel findings of the effect of social physique anxiety and muscle ‎dysmorphia on nutritional supplement and drugs use among bodybuilders. ‎

Infection control, genetic assessment of drug resistance and drug susceptibility testing in the current management of multidrug/extensively-resistant tuberculosis (M/XDR-TB) in Europe

DEFF Research Database (Denmark)

Bothamley, Graham H.; Lange, Christoph; Albrecht, Dirk

2017-01-01

AIM: Europe has the highest documented caseload and greatest increase in multidrug and extensively drug-resistant tuberculosis (M/XDR-TB) of all World Health Organization (WHO) regions. This survey examines how recommendations for M/XDR-TB management are being implemented. METHODS: TBNET is a pan...

Unintentional drowning: Role of medicinal drugs and alcohol.

Science.gov (United States)

Pajunen, Tuulia; Vuori, Erkki; Vincenzi, Frank F; Lillsunde, Pirjo; Smith, Gordon; Lunetta, Philippe

2017-05-19

Alcohol is a well-known risk factor in unintentional drownings. Whereas psychotropic drugs, like alcohol, may cause psychomotor impairment and affect cognition, no detailed studies have focused on their association with drowning. Finland provides extensive post-mortem toxicological data for studies on drowning because of its high medico-legal autopsy rates. Drowning cases, 2000 through 2009, for which post-mortem toxicological analysis was performed, came from the database of the Toxicological Laboratory, Department of Forensic Medicine, University of Helsinki, using the ICD-10 nature-of-injury code T75.1. The data were narrowed to unintentional drowning, using the ICD-10 external-injury codes V90, V92, and W65-74. Each drowning case had its blood alcohol concentration (BAC) and concentrations of other drugs recorded. Evaluation of the contribution of psychotropic drugs to drowning was based on their blood concentration by means of a 6-grade scale. Among victims ≥15 years old, unintentional drownings numbered 1697, of which, 303 (17.9%) were boating-related and 1394 (82.1%) non-boating-related. Among these, 65.0% of boating-related and 61.8% of non-boating-related victims were alcohol-positive (=BAC ≥ 50 mg/dL). The male-to-female ratio in alcohol-positive drownings was 7.3. At least one psychotropic drug appeared in 453 (26.7%) drowning cases, with some victims' bodies showing up to 7 different drugs. Overall 70 different psychotropic drugs were detectable, with 134 (7.9%) cases both alcohol-negative and psychotropic-drug-positive, of these, 59 (3.5%) were graded 4 to 6, indicating a possible to very probable contribution to drowning. Our findings suggest that psychotropic drugs may play a significant role in drowning, in up to 14.5% of cases, independently or in association with alcohol. Psychotropic drugs alone or in association with alcohol may be an overlooked risk factor in drowning, due to their effects on psychomotor function and cognition. Future

Fixed drug eruption: topical provocation and subsequent phenomena

Energy Technology Data Exchange (ETDEWEB)

Mahboob, A; Haroon, T S [Shaikh Zayed FPGMI, Lahore (Pakistan). Dept. of Dermatology; Haroon, T S [King Edward Medical Univ., Lahore (Pakistan). Dept. of Dematology; Iqbal, Z; Iqbal, F [Shaikh Zayed FPGMI, Lahore (Pakistan). Dept. of Medicine

2006-12-15

To determine the usefulness of topical provocation in detecting the incriminated drug causing fixed eruption. Three hundred and five, clinically diagnosed cases of Fixed Drug Eruption (FDE) of either gender and of any age were subjected to topical provocation with different drugs by using concentration of 1% (n=203), 2% (n=210) and 5% (n=235) in white soft paraffin. Drug ointment of one strength was applied one at a time on normal skin of flexor surface of right or left forearm. The effects of tests on involved and uninvolved skin were observed for 48 hours. The changes in lesions like erythema, hyperpigmentation, itching, burning or appearance of new lesion were considered a positive response. In case of no change, the patients (n=5) were subjected to oral provocation test, by giving half to full therapeutic dose of the suspected drug depending upon the severity of the initial attack. A patient who exhibited see-sawing phenomenon with 5% metamizole TPT was given oral challenge with same drug. Control topical tests were repeated in equal number of normal persons with various drug ointments and in patients of FDE with white soft paraffin on normal and affected skin. One hundred and thirty-seven patients were males and one hundred and sixty-eight patients were females. Maximum number of patients belonged to third decade. With 1% drug preparations 12 out of 316, with 2% drug preparations 28 out of 422 and with 5% drug preparations, 312 out of 523 TPTs were positive. The comparison revealed a highly significant association (Chi-square 448.1 and p<0.000) among various strengths of preparations and positive response. Sulphamethoxazole was found to be the most commonly incriminated cause of FDE applied in 5% concentration yielded sensitivity rate of 91% compared to 4% with lower concentrations. Positive patch test was also observed with oxytetracycline. Five patients who were given oral provocation with different drugs were found to be positive to tinidazole, dapsone

Fixed drug eruption: topical provocation and subsequent phenomena

International Nuclear Information System (INIS)

Mahboob, A.; Haroon, T.S.; Haroon, T.S.; Iqbal, Z.; Iqbal, F.

2006-01-01

To determine the usefulness of topical provocation in detecting the incriminated drug causing fixed eruption. Three hundred and five, clinically diagnosed cases of Fixed Drug Eruption (FDE) of either gender and of any age were subjected to topical provocation with different drugs by using concentration of 1% (n=203), 2% (n=210) and 5% (n=235) in white soft paraffin. Drug ointment of one strength was applied one at a time on normal skin of flexor surface of right or left forearm. The effects of tests on involved and uninvolved skin were observed for 48 hours. The changes in lesions like erythema, hyperpigmentation, itching, burning or appearance of new lesion were considered a positive response. In case of no change, the patients (n=5) were subjected to oral provocation test, by giving half to full therapeutic dose of the suspected drug depending upon the severity of the initial attack. A patient who exhibited see-sawing phenomenon with 5% metamizole TPT was given oral challenge with same drug. Control topical tests were repeated in equal number of normal persons with various drug ointments and in patients of FDE with white soft paraffin on normal and affected skin. One hundred and thirty-seven patients were males and one hundred and sixty-eight patients were females. Maximum number of patients belonged to third decade. With 1% drug preparations 12 out of 316, with 2% drug preparations 28 out of 422 and with 5% drug preparations, 312 out of 523 TPTs were positive. The comparison revealed a highly significant association (Chi-square 448.1 and p<0.000) among various strengths of preparations and positive response. Sulphamethoxazole was found to be the most commonly incriminated cause of FDE applied in 5% concentration yielded sensitivity rate of 91% compared to 4% with lower concentrations. Positive patch test was also observed with oxytetracycline. Five patients who were given oral provocation with different drugs were found to be positive to tinidazole, dapsone

Prolonged Drug-Drug Interaction between Terbinafine and Perphenazine.

Science.gov (United States)

Park, Young-Min

2012-12-01

I report here an elderly woman receiving perphenazine together with terbinafine. After 1 week of terbinafine treatment she experienced extrapyramidal symptoms and, in particular, akathisia. Her symptoms did not disappear for 6 weeks, and so at 2 weeks prior to this most recent admission she had stopped taking terbinafine. However, these symptoms persisted for 3 weeks after discontinuing terbinafine. It is well known that terbinafine inhibits CYP2D6 and that perphenazine is metabolized mainly by CYP2D6. Thus, when terbinafine and perphenazine are coadministrated, the subsequent increase in the concentration of perphenazine may induce extrapyramidal symptoms. Thus, terbinafine therapy may be associated with the induction and persistence of extrapyramidal symptoms, including akathisia. This case report emphasizes the importance of monitoring drug-drug interactions in patients undergoing terbinafine and perphenazine therapy.

Two Dimensional Drug Diffusion Between Nanoparticles and Fractal Tumors

Science.gov (United States)

Samioti, S. E.; Karamanos, K.; Tsiantis, A.; Papathanasiou, A.; Sarris, I.

2017-11-01

Drug delivery methods based on nanoparticles are some of the most promising medical applications in nanotechnology to treat cancer. It is observed that drug released by nanoparticles to the cancer tumors may be driven by diffusion. A fractal tumor boundary of triangular Von Koch shape is considered here and the diffusion mechanism is studied for different drug concentrations and increased fractality. A high order Finite Elements method based on the Fenics library is incorporated in fine meshes to fully resolve these irregular boundaries. Drug concentration, its transfer rates and entropy production are calculated in an up to forth order fractal iteration boundaries. We observed that diffusion rate diminishes for successive prefractal generations. Also, the entropy production around the system changes greatly as the order of the fractal curve increases. Results indicate with precision where the active sites are, in which most of the diffusion takes place and thus drug arrives to the tumor.

Intraoperative radiotherapy in combination with misonidazole. In special reference to the drug concentration in tumors and normal tissues and to the initial effect of the treatment

Energy Technology Data Exchange (ETDEWEB)

Takahashi, Masaji; Ono, Kouji; Hamanaka, Daizaburo; Dodo, Yoshihiro; Hiraoka, Masahiro [Kyoto Univ. (Japan). Faculty of Medicine

1983-03-01

A hypoxic cell radiosensitizer, misonidazole, was applied to 28 patients with carcinoma who received intraoperative radiotherapy. A single dose of 2-3g/m/sup 2/ of the drug was given orally to each patient three hours prior to the start of general anesthesia. The levels of misonidazole and its metabolite, desmethylmisonidazole, in blood, tumors and normal tissues taken from excised materials were measured by a high performance liquid chromatography. The results showed that the concentration levels of misonidazole and desmethylmisonidazole in blood correlated neither to oral doses of 2-3g/m/sup 2/ nor to the function of time after drug ingestion until eight hours. The mean value of blood levels was 77.1 +- 10.9..mu..g/ml. A wide range of 10-96% of the blood level was found in tumors. High levels were observed in gastric cancer and brain tumor (glioblastoma) but not in colorectal cancer and osteosarcoma. It was, however, likely that the concentrations in tumors depended on tumor sizes and/or necrotic areas rather than histologic types and/or sites of tumors. It was also noted that the concentration in normal tissues ranged widely from 11 to 87% of the blood level. Higher concentrations showing more than 75% were found in the ulnar nerve, the stomach and the skin. However, 3 of 4 materials for the stomach and 2 of 3 materials for the skin showed low levels of less than 30% and less than 22% respectively. In 27 of 28 cases different doses of 28-50 Gy with different energies of electrons were delivered intraoperatively. It is impossible so far to derive conclusive results of this study, really because of the short period of observation following the treatment.

Population PK modelling and simulation based on fluoxetine and norfluoxetine concentrations in milk: a milk concentration-based prediction model.

Science.gov (United States)

Tanoshima, Reo; Bournissen, Facundo Garcia; Tanigawara, Yusuke; Kristensen, Judith H; Taddio, Anna; Ilett, Kenneth F; Begg, Evan J; Wallach, Izhar; Ito, Shinya

2014-10-01

Population pharmacokinetic (pop PK) modelling can be used for PK assessment of drugs in breast milk. However, complex mechanistic modelling of a parent and an active metabolite using both blood and milk samples is challenging. We aimed to develop a simple predictive pop PK model for milk concentration-time profiles of a parent and a metabolite, using data on fluoxetine (FX) and its active metabolite, norfluoxetine (NFX), in milk. Using a previously published data set of drug concentrations in milk from 25 women treated with FX, a pop PK model predictive of milk concentration-time profiles of FX and NFX was developed. Simulation was performed with the model to generate FX and NFX concentration-time profiles in milk of 1000 mothers. This milk concentration-based pop PK model was compared with the previously validated plasma/milk concentration-based pop PK model of FX. Milk FX and NFX concentration-time profiles were described reasonably well by a one compartment model with a FX-to-NFX conversion coefficient. Median values of the simulated relative infant dose on a weight basis (sRID: weight-adjusted daily doses of FX and NFX through breastmilk to the infant, expressed as a fraction of therapeutic FX daily dose per body weight) were 0.028 for FX and 0.029 for NFX. The FX sRID estimates were consistent with those of the plasma/milk-based pop PK model. A predictive pop PK model based on only milk concentrations can be developed for simultaneous estimation of milk concentration-time profiles of a parent (FX) and an active metabolite (NFX). © 2014 The British Pharmacological Society.

[Drugs and occupational accident].

Science.gov (United States)

Bratzke, H; Albers, C

1996-02-01

In a case of a fatal occupational accident (construction worker, fall from roof, urine test positive for cocaine and THC, e.g. cannabis) the question arised to what extent those drug-related occupational accidents occur. In the literature only few cases, mainly dealing with cannabis influence, have been reported, however, a higher number is suspected. Cocaine and other stimulating drugs (amphetamine) are more often used to increase physical fitness. By direct or indirect interference with vigilance these compounds may provoke accidents. Due to the lack of a legal basis proving of the influence of drugs at the working place is still very limited, although highly sensitive chemical-toxicological assay procedures are available to detect even the chronic abuse (in hair). In the general conditions of accident insurances a compensation is excluded when alcohol is involved, but drugs are not mentioned. It is indeed difficult to establish a concentration limit for drugs like that existing for alcohol (1.1%). In each case the assay of the drug involved and exact knowledge of its specific effects is in an essential prerequisite to prove the causal relationship.

Factor concentrates for the treatment of factor XIII deficiency.

Science.gov (United States)

Gootenberg, J E

1998-11-01

Factor XIII deficiency is a severe autosomal recessive bleeding disorder associated with a characteristic pattern of neonatal hemorrhage and a lifelong bleeding diathesis. Even relatively minor trauma can be followed by prolonged and recurrent bleeding. Intracranial hemorrhage is a frequent complication. With the development of safe and effective factor XIII concentrates, reliable prophylactic treatment is possible. Two plasma-derived, virus-inactivated factor XIII concentrates are currently in production. The first, Fibrogammin P, (Centeon LLC, King of Prussia, PA, USA; and Centeon Pharma GmbH, Marburg, Germany) is marketed in Europe, South America, South Africa, and Japan. It is distributed in the United States under a Food and Drug Administration Investigational New Drug Application. A second factor XIII concentrate (Bio Products Laboratory, Elstree, UK) is available for use only on a "named patient" compassionate basis in the United Kingdom. Patients with factor XIII deficiency who receive appropriately timed periodic infusions of such factor XIII concentrates are able to live normal lives, free from catastrophic bleeding episodes.

The impact of calcium carbonate as pore forming agent and drug entrapment method towards drug dissolution mechanism of amoxicillin trihydrate encapsulated by chitosan-methyl cellulose semi-IPN hydrogel for floating drug delivery system

Science.gov (United States)

Dewantara, Fauzi; Budianto, Emil

2018-04-01

Chitosan-methyl cellulose semi-IPN hydrogel is used as floating drug delivery system, and calcium carbonate also added as pore forming agent. The hydrogel network arranged by not only using biopolymer chitosan and methyl cellulose, but also the crosslink agent that is glutaraldehyde. Amoxicillin trihydrate entrapped into the polymer network with two different method, in situ loading and post loading. Furthermore both method has been tested for drug entrapment efficiency along with drug dissolution test, and the result for drug entrapment efficiency is in situ loading method has highest value of 100%, compared to post loading method which has value only 71%. Moreover, at the final time of drug dissolution test shows in situ loading method has value of 96% for total accumulative of drug dissolution, meanwhile post loading method has 72%. The value of drug dissolution test from both method is used for analyzing drug dissolution mechanism of amoxicillin trihydrate from hydrogel network with four mathematical drug mechanism models as parameter. The polymer network encounter destructive degradation causes by acid solution which used as dissolution medium, and the level of degradation is observed with optical microscope. However the result shows that degradation of the polymer network doesn't affect drug dissolution mechanism directly. Although the pore forming agent causes the pore inside the hydrogel network create interconnection and it was quite influential to drug dissolution mechanism. Interconnected pore is observed with Scanning Electron Microscope (SEM) and shows that the amount and area of interconnected pore inside the hydrogel network is increasing as drug dissolution goes on.

Enhanced drug delivery capabilities from stents coated with absorbable polymer and crystalline drug.

Science.gov (United States)

Carlyle, Wenda C; McClain, James B; Tzafriri, Abraham R; Bailey, Lynn; Zani, Brett G; Markham, Peter M; Stanley, James R L; Edelman, Elazer R

2012-09-28

Current drug eluting stent (DES) technology is not optimized with regard to the pharmacokinetics of drug delivery. A novel, absorbable-coating sirolimus-eluting stent (AC-SES) was evaluated for its capacity to deliver drug more evenly within the intimal area rather than concentrating drug around the stent struts and for its ability to match coating erosion with drug release. The coating consisted of absorbable poly-lactide-co-glycolic acid (PLGA) and crystalline sirolimus deposited by a dry-powder electrostatic process. The AC-SES demonstrated enhanced drug stability under simulated use conditions and consistent drug delivery balanced with coating erosion in a porcine coronary implant model. The initial drug burst was eliminated and drug release was sustained after implantation. The coating was absorbed within 90 days. Following implantation into porcine coronary arteries the AC-SES coating is distributed in the surrounding intimal tissue over the course of several weeks. Computational modeling of drug delivery characteristics demonstrates how distributed coating optimizes the load of drug immediately around each stent strut and extends drug delivery between stent struts. The result was a highly efficient arterial uptake of drug with superior performance to a clinical bare metal stent (BMS). Neointimal thickness (0.17±0.07 mm vs. 0.28±0.11 mm) and area percent stenosis (22±9% vs. 35±12%) were significantly reduced (pstent implantation in an overlap configuration in porcine coronary arteries. Inflammation was significantly reduced in the AC-SES compared to the BMS at both 30 and 90 days after implantation. Biocompatible, rapidly absorbable stent coatings enable the matching of drug release with coating erosion and provide for the controlled migration of coating material into tissue to reduce vicissitudes in drug tissue levels, optimizing efficacy and reducing potential toxicity. Copyright © 2012 Elsevier B.V. All rights reserved.

Drug loading optimization and extended drug delivery of corticoids from pHEMA based soft contact lenses hydrogels via chemical and microstructural modifications.

Science.gov (United States)

García-Millán, Eva; Koprivnik, Sandra; Otero-Espinar, Francisco Javier

2015-06-20

This paper proposes an approach to improve drug loading capacity and release properties of poly(2-hydroxyethyl methacrylate) (p(HEMA)) soft contact lenses based on the optimization of the hydrogel composition and microstructural modifications using water during the polymerization process. P(HEMA) based soft contact lenses were prepared by thermal or photopolymerization of 2-hydroxyethyl methacrylate (HEMA) solutions containing ethylene glycol di-methacrylate as crosslinker and different proportions of N-vinyl-2-pyrrolidone (NVP) or methacrylic acid (MA) as co-monomers. Transmittance, water uptake, swelling, microstructure, drug absorption isotherms and in vitro release were characterized using triamcinolone acetonide (TA) as model drug. Best drug loading ratios were obtained with lenses containing the highest amount (200 mM) of MA. Incorporation of 40% V/V of water during the polymerization increases the hydrogel porosity giving a better drug loading capacity. In vitro TA release kinetics shows that MA hydrogels released the drug significantly faster than NVP-hydrogels. Drug release was found to be diffusion controlled and kinetics was shown to be reproducible after consecutive drug loading/release processes. Results of p(HEMA) based soft contact lenses copolymerized with ethylene glycol dimethacrylate (EGDMA) and different co-monomers could be a good alternative to optimize the loading and ocular drug delivery of this corticosteroid drug. Copyright © 2015. Published by Elsevier B.V.

Effects of self-aggregation on the hydration of an amphiphilic antidepressant drug in different aqueous media

International Nuclear Information System (INIS)

Taboada, Pablo; Gutierrez-Pichel, Manuel; Mosquera, Victor

2004-01-01

Apparent molal volumes and adiabatic compressibilities of aqueous solutions of the amphiphilic antidepressant drug clomipramine hydrochloride have been determined from density and ultrasound velocity measurements in the temperature range 288.15-313.15 K in buffered aqueous solution of pH 3.0 and 5.5. Critical concentrations of aggregation of this drug were obtained from inflections on the plots of the sound velocity against drug concentration. Apparent molal adiabatic compressibilities of the aggregates formed by the drug, calculated by combining the ultrasound velocity and density data, were typical of those for a stacked aggregate. From the temperature dependence of the critical concentration and using the mass action model combined with the Phillips definition of the critical concentration the thermodynamic standard quantities: free Gibbs energy, enthalpy and entropy of aggregate formation were calculated. The critical concentration and energy involved in the aggregation process of this drug have been also evaluated experimentally using isothermal titration calorimetry at 298.15 K. The solvent-drug interactions have been discussed from compressibility and calorimetry data

Treatment of hypopituitarism in patients receiving antiepileptic drugs.

Science.gov (United States)

Paragliola, Rosa Maria; Prete, Alessandro; Kaplan, Peter W; Corsello, Salvatore Maria; Salvatori, Roberto

2015-02-01

Evidence suggests that there may be drug interactions between antiepileptic drugs and hormonal therapies, which can present a challenge to endocrinologists dealing with patients who have both hypopituitarism and neurological diseases. Data are scarce for this subgroup of patients; however, data for the interaction of antiepileptic drugs with the pituitary axis have shown that chronic use of many antiepileptic drugs, such as carbamazepine, oxcarbazepine, and topiramate, enhances hepatic cytochrome P450 3A4 (CYP3A4) activity, and can decrease serum concentrations of sex hormones. Other antiepileptic drugs increase sex hormone-binding globulin, which reduces the bioactivity of testosterone and estradiol. Additionally, the combined oestrogen-progestagen contraceptive pill might decrease lamotrigine concentrations, which could worsen seizure control. Moreover, sex hormones and their metabolites can directly act on neuronal excitability, acting as neurosteroids. Because carbamazepine and oxcarbazepine can enhance the sensitivity of renal tubules, a reduction in desmopressin dose might be necessary in patients with central diabetes insipidus. Although the effects of antiepileptic drugs in central hypothyroidism have not yet been studied, substantial evidence indicates that several antiepileptic drugs can increase thyroid hormone metabolism. However, although it is reasonable to expect a need for a thyroxine dose increase with some antiepileptic drugs, the effect of excessive thyroxine in lowering seizure threshold should also be considered. There are no reports of significant interactions between antiepileptic drugs and the efficacy of human growth hormone therapy, and few data are available for the effects of second-generation antiepileptic drugs on hypopituitarism treatment. Copyright © 2015 Elsevier Ltd. All rights reserved.

The Concentration of Nutrients in Tissues of Plantation-Grown Eastern Cottonwood (Populus deltoides Bart.)

Science.gov (United States)

M. G. Shelton; L. E. Nelson; G. L. Switzer; B. G. Blackmon

1981-01-01

Nutrient concentrations were determined for 10 tissues from each of 24 cottonwood trees that ranged in age from four to 16 years. Highest concentrations occurred in the most physiologically active tissues; i.e., stemtips, current branches and foliage. Tree age had little influence on the variation in nutrient concentration of tissues. Some differences in concentrations...

Concentrations of Heavy Metals in NPK Fertilizers Imported in Serbia

Directory of Open Access Journals (Sweden)

Jelena Milinović

2008-01-01

Full Text Available Concentrations of Pb, Cd, Cu and Mn in sixteen NPK fertilizers imported and widely used in Serbia were determined by flame atomic absorption spectrometry (AAS. The results show that contents of heavy metals varied significantly in different fertilizers dependingon N:P:K ratio and fertilizer origin. Pb and Cd contents in water solution of fertilizers occurred at low ranges: 2.0-3.1 and 0.03- 1.56 mg/kg, respectively. An NPK (15:15:15 fertilizer from Romania was found to contain the highest concentration of Pb and Cd as impurities. Cu content, ranging from 7.1 to 974.7 mg/kg, was the highest in coloured fertilizers from Hungary, the Netherlands and Greece. Mn value in a Hungarian NPK product (10:10:20 exceeds the average Mn value in soil. The data indicate variable contents of heavy metals in fertilizers, some of which are significantly higher than natural concentrations in soil, which suggests that they need to be continuously monitored.

Assay method for organic calcium antagonist drugs and a kit for such an assay

International Nuclear Information System (INIS)

Snyder, S. H.; Gould, R. J.

1985-01-01

A method for measuring the level of organic calcium antagonist drug in a body fluid comprises preparing a mixture of a radioactive calcium antagonist drug, a body fluid containing a calcium antagonist drug and a calcium antagonist receptor material, measuring the radioactivity of the radioactive calcium antagonist drug bound to said calcium antagonist receptor material and deriving the concentration of the calcium antagonist drug in the body fluid from a standard curve indicating the concentration of calcium antagonist drug versus inhibition of binding of said radioactive calcium antagonist drug to said receptor sites caused by the calcium antagonist drug in said body fluid. A kit for measuring the level of an organic calcium drug comprises a receptacle containing a radioactive calcium antagonist drug, a calcium antagonist receptor material and a standard amount of a nonradioactive calcium antagonist drug

Heavy metal concentrations in the razor clams (Solen spp.) from Muara Tebas, Sarawak

International Nuclear Information System (INIS)

Devagi Kanakaraju; Connie Jios; Shabdin Mohd Long

2008-01-01

The razor clams (Solen spp) or locally known as ambal in Sarawak collected from Muara Tebas were studied for their heavy metals contents in tissues and shells. Sediment samples were also tested for their metal contents. Concentrations of Pb, Fe, Zn, Cu, Cd and Mn were determined by using Flame Atomic Absorption Spectrophotometer (FAAS). Tissues of razor clams showed highest concentrations of Fe and Zn, while shells accumulated highest concentrations of Pb and Mn. The lowest metal concentrations found were Cu and Cd. In general, the levels of metals in ambal were within the permissible limit recommended by international standard, the Food and Agricultural Organization (FAO). However, the study revealed that the sediments at Muara Tebas fall under the category of slightly polluted (for Pb) when compared to the guidelines suggested by United States Environment Protection Agency (USEPA). (author)

Chemical dependency and drug testing in the workplace.

Science.gov (United States)

Osterloh, J D; Becker, C E

1990-05-01

Urine testing for drug use in the workplace is now widespread, with the prevalence of positive drug tests in the work force being 0% to 15%. The prevalence of marijuana use is highest, and this can be reliably tested. Though it is prudent to rid the workplace of drug use, there is little scientific study on the relationship of drug use and workplace outcomes, such as productivity and safety. Probable-cause testing and preemployment testing are the most common applications. Random testing has been less accepted owing to its higher costs, unresolved legal issues, and predictably poor test reliability. Legal issues have focused on the right to policy, discrimination, and the lack of due process. The legal cornerstone of a good program is a policy that is planned and agreed on by both labor and management, which serves both as a contract and as a procedure in which expectations and consequences are known. The National Institute on Drug Abuse is certifying laboratories doing employee drug testing. Testing methods when done correctly are less prone to error than in the past, but screening tests can be defeated by adulterants. Although the incidence of false-positive results is low, such tests are less reliable when the prevalence of drug abuse is also low.

Minimalism in fabrication of self-organized nanogels holding both anti-cancer drug and targeting moiety.

Science.gov (United States)

Kim, Sungwon; Park, Kyong Mi; Ko, Jin Young; Kwon, Ick Chan; Cho, Hyeon Geun; Kang, Dongmin; Yu, In Tag; Kim, Kwangmeyung; Na, Kun

2008-05-01

Recent researches to develop nano-carrier systems in anti-cancer drug delivery have focused on more complicated design to improve therapeutic efficacy and to reduce side effects. Although such efforts have great impact to biomedical science and engineering, the complexity has been a huddle because of clinical and economic problems. In order to overcome the problems, a simplest strategy to fabricate nano-carriers to deliver doxorubicin (DOX) was proposed in the present study. Two significant subjects (i) formation of nanoparticles loading and releasing DOX and (ii) binding specificity of them to cells, were examined. Folic acid (FA) was directly coupled with pullulan (Pul) backbone by ester linkage (FA/Pul conjugate) and the degree of substitution (DS) was varied, which were confirmed by 1H NMR and UV spectrophotometry. Light scattering results revealed that the nanogels possessed two major size distributions around 70 and 270 nm in an aqueous solution. Their critical aggregation concentrations (CACs) were less than 10 microg/mL, which are lower than general critical micelle concentrations (CMCs) of low-molecular-weight surfactants. Transmission electron microscopy (TEM) images showed well-dispersed nanogel morphology in a dried state. Depending on the DS, the nanogels showed different DOX-loading and releasing profiles. The DOX release rate from FA8/Pul (with the highest DS) for 24h was slower than that from FA4/or FA6/Pul, indicating that the FA worked as a hydrophobic moiety for drug holding. Cellular uptake of the nanogels (KB cells) was also monitored by confocal microscopy. All nanogels were internalized regardless of the DS of FA. Based on the results, the objectives of this study, to suggest a new method overcoming the complications in the drug carrier design, were successfully verified.

Isoflurane minimum alveolar concentration reduction by fentanyl.

Science.gov (United States)

McEwan, A I; Smith, C; Dyar, O; Goodman, D; Smith, L R; Glass, P S

1993-05-01

Isoflurane is commonly combined with fentanyl during anesthesia. Because of hysteresis between plasma and effect site, bolus administration of fentanyl does not accurately describe the interaction between these drugs. The purpose of this study was to determine the MAC reduction of isoflurane by fentanyl when both drugs had reached steady biophase concentrations. Seventy-seven patients were randomly allocated to receive either no fentanyl or fentanyl at several predetermined plasma concentrations. Fentanyl was administered using a computer-assisted continuous infusion device. Patients were also randomly allocated to receive a predetermined steady state end-tidal concentration of isoflurane. Blood samples for fentanyl concentration were taken at 10 min after initiation of the infusion and before and immediately after skin incision. A minimum of 20 min was allowed between the start of the fentanyl infusion and skin incision. The reduction in the MAC of isoflurane by the measured fentanyl concentration was calculated using a maximum likelihood solution to a logistic regression model. There was an initial steep reduction in the MAC of isoflurane by fentanyl, with 3 ng/ml resulting in a 63% MAC reduction. A ceiling effect was observed with 10 ng/ml providing only a further 19% reduction in MAC. A 50% decrease in MAC was produced by a fentanyl concentration of 1.67 ng/ml. Defining the MAC reduction of isoflurane by all the opioids allows their more rational administration with inhalational anesthetics and provides a comparison of their relative anesthetic potencies.

Illicit Drug Use, Illicit Drug Use Disorders, and Drug Overdose Deaths in Metropolitan and Nonmetropolitan Areas - United States.

Science.gov (United States)

Mack, Karin A; Jones, Christopher M; Ballesteros, Michael F

2017-10-20

Drug overdoses are a leading cause of injury death in the United States, resulting in approximately 52,000 deaths in 2015. Understanding differences in illicit drug use, illicit drug use disorders, and overall drug overdose deaths in metropolitan and nonmetropolitan areas is important for informing public health programs, interventions, and policies. Illicit drug use and drug use disorders during 2003-2014, and drug overdose deaths during 1999-2015. The National Survey of Drug Use and Health (NSDUH) collects information through face-to-face household interviews about the use of illicit drugs, alcohol, and tobacco among the U.S. noninstitutionalized civilian population aged ≥12 years. Respondents include residents of households and noninstitutional group quarters (e.g., shelters, rooming houses, dormitories, migratory workers' camps, and halfway houses) and civilians living on military bases. NSDUH variables include sex, age, race/ethnicity, residence (metropolitan/nonmetropolitan), annual household income, self-reported drug use, and drug use disorders. National Vital Statistics System Mortality (NVSS-M) data for U.S. residents include information from death certificates filed in the 50 states and the District of Columbia. Cases were selected with an underlying cause of death based on the ICD-10 codes for drug overdoses (X40-X44, X60-X64, X85, and Y10-Y14). NVSS-M variables include decedent characteristics (sex, age, and race/ethnicity) and information on intent (unintentional, suicide, homicide, or undetermined), location of death (medical facility, in a home, or other [including nursing homes, hospices, unknown, and other locations]) and county of residence (metropolitan/nonmetropolitan). Metropolitan/nonmetropolitan status is assigned independently in each data system. NSDUH uses a three-category system: Core Based Statistical Area (CBSA) of ≥1 million persons; CBSA of illicit drugs, the prevalence was highest for the large metropolitan areas compared with

Tritium concentration analysis in atmospheric precipitation in Serbia.

Science.gov (United States)

Janković, Marija M; Janković, Bojan Ž; Todorović, Dragana J; Ignjatović, Ljubiša M

2012-01-01

Tritium activity concentration were monitored in monthly precipitation at five locations in Serbia (Meteorological Station of Belgrade at Zeleno Brdo, Vinča Institute of Nuclear Sciences, Smederevska Palanka, Kraljevo and Niš) over 2005, using electrolytic enrichment and liquid scintillation counting. The obtained concentrations ranged from 3.36 to 127.02 TU. The activity values obtained in samples collected at Zeleno Brdo were lower or close to the minimum detectable activity (MDA), which has a value of 3.36 TU. Significantly higher tritium levels were obtained in samples collected in Vinča Institute of Nuclear Sciences compared with samples from the other investigated locations. Amount of precipitation were also recorded. A good linear correlation (r = 0.75) for Zeleno Brdo and VINS between their tritium activity was obtained. It was found that the value of the symmetrical index n (which indicates the magnitude of tritium content changes with time (months) through its second derivative) is the highest for Vinča Institute of Nuclear Sciences compared to other locations, which is in accordance with the fact that the highest concentrations of tritium were obtained in the samples from the cited place.

Drug Abuse, HIV, and HCV in Asian Countries.

Science.gov (United States)

Hser, Yih-Ing; Liang, Di; Lan, Yu-Ching; Vicknasingam, Balasingam Kasinather; Chakrabarti, Amit

2016-09-01

Drug abuse and co-occurring infections are associated with significant morbidity and mortality. Asian countries are particularly vulnerable to the deleterious consequences of these risks/problems, as they have some of the highest rates of these diseases. This review describes drug abuse, HIV, and hepatitis C (HCV) in Asian countries. The most commonly used illicit drugs include opioids, amphetamine-type stimulants (ATS), cannabis, and ketamine. Among people who inject drugs, HIV rates range from 6.3 % in China to 19 % in Malaysia, and HCV ranges from 41 % in India and Taiwan to 74 % in Vietnam. In the face of the HIV epidemics, drug policies in these countries are slowly changing from the traditional punitive approach (e.g., incarcerating drug users or requiring registration as a drug user) to embrace public health approaches, including, for example, community-based treatment options as well as harm reduction approaches to reduce needle sharing and thus HIV transmission. HIV and HCV molecular epidemiology indicates limited geographic diffusion. While the HIV prevalence is declining in all five countries, use of new drugs (e.g., ATS, ketamine) continues to increase, as well as high-risk sexual behaviors associated with drug use-increasing the risk of sexual transmission of HIV, particularly among men who have sex with men. Screening, early intervention, and continued scaling up of therapeutic options (drug treatment and recovery support, ART, long-term HIV and HCV care for drug users) are critical for effective control or continued reduction of drug abuse and co-infections.

Drug membrane interaction and the importance for drug transport, distribution, accumulation, efficacy and resistance.

Science.gov (United States)

Seydel, J K; Coats, E A; Cordes, H P; Wiese, M

1994-10-01

Some aspects of drug membrane interaction and its influence on drug transport, accumulation, efficacy and resistance have been discussed. The interactions manifest themselves macroscopically in changes in the physical and thermodynamic properties of "pure membranes" or bilayers. As various amounts of foreign molecules enter the membrane, in particular the main gel to liquid crystalline phase transition can be dramatically changed. This may change permeability, cell-fusion, cell resistance and may also lead to changes in conformation of the embedded receptor proteins. Furthermore, specific interactions with lipids may lead to drug accumulation in membranes and thus to much larger concentrations at the active site than present in the surrounding water phase. The lipid environment may also lead to changes in the preferred conformation of drug molecules. These events are directly related to drug efficacy. The determination of essential molecular criteria for the interaction could be used to design new and more selective therapeutics. This excursion in some aspects of drug membrane interaction underlines the importance of lipids and their interaction with drug molecules for our understanding of drug action, but this is not really a new thought but has been formulated in 1884 by THUDICUM: "Phospholipids are the centre, life and chemical soul of all bioplasm whatsoever, that of plants as well as of animals".