Metabolic profiling using HPLC allows classification of drugs according to their mechanisms of action in HL-1 cardiomyocytes

International Nuclear Information System (INIS)

Strigun, Alexander; Wahrheit, Judith; Beckers, Simone; Heinzle, Elmar; Noor, Fozia

2011-01-01

Along with hepatotoxicity, cardiotoxic side effects remain one of the major reasons for drug withdrawals and boxed warnings. Prediction methods for cardiotoxicity are insufficient. High content screening comprising of not only electrophysiological characterization but also cellular molecular alterations are expected to improve the cardiotoxicity prediction potential. Metabolomic approaches recently have become an important focus of research in pharmacological testing and prediction. In this study, the culture medium supernatants from HL-1 cardiomyocytes after exposure to drugs from different classes (analgesics, antimetabolites, anthracyclines, antihistamines, channel blockers) were analyzed to determine specific metabolic footprints in response to the tested drugs. Since most drugs influence energy metabolism in cardiac cells, the metabolite 'sub-profile' consisting of glucose, lactate, pyruvate and amino acids was considered. These metabolites were quantified using HPLC in samples after exposure of cells to test compounds of the respective drug groups. The studied drug concentrations were selected from concentration response curves for each drug. The metabolite profiles were randomly split into training/validation and test set; and then analysed using multivariate statistics (principal component analysis and discriminant analysis). Discriminant analysis resulted in clustering of drugs according to their modes of action. After cross validation and cross model validation, the underlying training data were able to predict 50%-80% of conditions to the correct classification group. We show that HPLC based characterisation of known cell culture medium components is sufficient to predict a drug's potential classification according to its mode of action.

Profiles of drug addicts in relation to personality variables and disorders.

Science.gov (United States)

Carou, María; Romero, Estrella; Luengo, Mª Ángeles

2016-10-07

In recent decades, research has identified a set of impulsive/disinhibited personality variables closely associated with drug addiction. As well as this, disorders linked with these variables, such as ADHD and personality disorders, are being closely studied in the field of drug addiction. Although much knowledge has been accumulated about the relation of these variables and disorders taken separately, less is known about how these constructs allow identify-specific profiles within the drug dependent population to be identified. This work, on the basis of data collected on a sample of drug addicts in treatment, analyzes how impulsiveness, sensation seeking, self-control, ADHD and personality disorders contribute to identifying specific profiles of addicts. Cluster analysis allowed two profiles to be outlined according to these personality and psychopathology characteristics. Self-control, impulsiveness, impulsive and antisocial personality disorders, as well as scores in ADHD, emerge as the variables that contribute more to profile differentiation. One of these profiles (56.1% of participants) with a high disinhibition pattern, is associated with severe indicators of consumption and criminal career patterns. These results allow us to emphasize the role of personality and impulsiveness-related disorders in the identification of distinctive profiles within the addict population, and suggest the need to generate treatment strategies adapted to personal/psychopathology configurations of drug addicts.

Identification of drug targets by chemogenomic and metabolomic profiling in yeast

KAUST Repository

Wu, Manhong

2012-12-01

OBJECTIVE: To advance our understanding of disease biology, the characterization of the molecular target for clinically proven or new drugs is very important. Because of its simplicity and the availability of strains with individual deletions in all of its genes, chemogenomic profiling in yeast has been used to identify drug targets. As measurement of drug-induced changes in cellular metabolites can yield considerable information about the effects of a drug, we investigated whether combining chemogenomic and metabolomic profiling in yeast could improve the characterization of drug targets. BASIC METHODS: We used chemogenomic and metabolomic profiling in yeast to characterize the target for five drugs acting on two biologically important pathways. A novel computational method that uses a curated metabolic network was also developed, and it was used to identify the genes that are likely to be responsible for the metabolomic differences found. RESULTS AND CONCLUSION: The combination of metabolomic and chemogenomic profiling, along with data analyses carried out using a novel computational method, could robustly identify the enzymes targeted by five drugs. Moreover, this novel computational method has the potential to identify genes that are causative of metabolomic differences or drug targets. © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Time and spatial concentration profile inside a membrane by means of a memory formalism

Science.gov (United States)

Caputo, Michele; Cametti, Cesare; Ruggero, Vittorio

2008-03-01

In this note, the profile concentration of diffusing particles inside a membrane has been calculated on the basis of the Fick diffusion equation modified by introducing a memory formalism. In highly heterogeneous systems, such as biological membranes, the intrinsic structural complexity of the medium restricts the applicability of continuum diffusion models and suggests that diffusion parameters could depend at a certain time or position on what happens at preceding times (diffusion with memory). Here, we deal with two particular cases, the diffusion of glucose across an erythrocyte membrane, when the concentration at both sides of the membrane are assigned, and the permeation transport of small molecular weight solute through an artificial hydrogel polymeric membrane. However, the present procedure can be easily extended to more general conditions. The knowledge of the concentration profile within a membranous structure, which is usually not easily experimentally accessible, completes the description of the rather complex phenomenon of the transport across a highly structured confined medium and can also lead to an improvement in controlled drug-delivery systems.

Seasonal variation in diurnal atmospheric grass pollen concentration profiles

DEFF Research Database (Denmark)

Peel, Robert George; Ørby, Pia Viuf; Skjøth, Carsten Ambelas

2014-01-01

the time of day when peak concentrations are most likely to occur using seasonally averaged diurnal profiles. Atmospheric pollen loads are highly dependent upon emissions, and different species of grass are known to flower and emit pollen at different times of the day and during different periods......In this study, the diurnal atmospheric grass pollen concentration profile within the Danish city of Aarhus was shown to change in a systematic manner as the pollen season progressed. Although diurnal grass pollen profiles can differ greatly from day-to-day, it is common practice to establish...... of the pollen season. Pollen concentrations are also influenced by meteorological factors - directly through those parameters that govern pollen dispersion and transport, and indirectly through the weather-driven flowering process. We found that three different profiles dominated the grass pollen season...

Physician access to drug profiles to reduce adverse reactions

Science.gov (United States)

Yasnoff, William A.; Tomkins, Edward L.; Dunn, Louise M.

1995-10-01

Adverse drug reactions (ADRs) are a major source of preventable morbidity and mortality, especially among the elderly, who use more drugs and are more sensitive to them. The insurance industry has recently addressed this problem through the implementation of drug interaction alerts to pharmacists in conjunction with immediate online claims adjudication for almost 60% of prescriptions (expected to reach 90% within 5 years). These alerts are based on stored patient drug profiles maintained by pharmacy benefit managers (PBMs) which are updated whenever prescriptions are filled. While these alerts are very helpful, the pharmacist does not prescribe, resulting in time-consuming and costly delays to contact the physician and remedy potential interactions. We have developed and demonstrated the feasibility of the PINPOINT (Pharmaceutical Information Network for prevention of interactions) system for making the drug profile and interaction information easily available to the physician before the prescription is written. We plan to test the cost-effectiveness of the system in a prospective controlled clinical trial.

The toxicological significance of post-mortem drug concentrations in bile.

Science.gov (United States)

Ferner, Robin E; Aronson, Jeffrey K

2018-01-01

Some authors have proposed that post-mortem drug concentrations in bile are useful in estimating concentrations in blood. Both The International Association of Forensic Toxicologists (TIAFT) and the US Federal Aviation Administration recommend that samples of bile should be obtained in some circumstances. Furthermore, standard toxicological texts compare blood and bile concentrations, implying that concentrations in bile are of forensic value. To review the evidence on simultaneous measurements of blood and bile drug concentrations reported in the medical literature. We made a systematic search of EMBASE 1980-2016 using the search terms ("bile/" OR "exp drug bile level/concentration/") AND "drug blood level/concentration/", PubMed 1975-2017 for ("bile[tw]" OR "biliary[tw]") AND ("concentration[tw]" OR "concentrations[tw]" OR "level[tw]" OR "levels[tw]") AND "post-mortem[tw]" and also MEDLINE 1990-2016 for information on drugs whose biliary concentrations were mentioned in standard textbooks. The search was limited to human studies without language restrictions. We also examined recent reviews, indexes of relevant journals and citations in Web of Science and Google Scholar. We calculated the bile:blood concentration ratio. The searches together yielded 1031 titles with abstracts. We scanned titles and abstracts for relevance and retrieved 230, of which 161 were considered further. We excluded 49 papers because: the paper reported only one case (30 references); the data referred only to a metabolite (1); the work was published before 1980 (3); the information concerned only samples taken during life (10); or the paper referred to a toxin or unusual recreational drug (5). The remaining 112 papers provided data for analysis, with at least two observations for each of 58 drugs. Bile:blood concentration ratios: Median bile:blood concentration ratios varied from 0.18 (range 0.058-0.32) for dextromoramide to 520 (range 0.62-43,000) for buprenorphine. Median bile

Five-Factor Model personality profiles of drug users

Directory of Open Access Journals (Sweden)

Crum Rosa M

2008-04-01

Full Text Available Abstract Background Personality traits are considered risk factors for drug use, and, in turn, the psychoactive substances impact individuals' traits. Furthermore, there is increasing interest in developing treatment approaches that match an individual's personality profile. To advance our knowledge of the role of individual differences in drug use, the present study compares the personality profile of tobacco, marijuana, cocaine, and heroin users and non-users using the wide spectrum Five-Factor Model (FFM of personality in a diverse community sample. Method Participants (N = 1,102; mean age = 57 were part of the Epidemiologic Catchment Area (ECA program in Baltimore, MD, USA. The sample was drawn from a community with a wide range of socio-economic conditions. Personality traits were assessed with the Revised NEO Personality Inventory (NEO-PI-R, and psychoactive substance use was assessed with systematic interview. Results Compared to never smokers, current cigarette smokers score lower on Conscientiousness and higher on Neuroticism. Similar, but more extreme, is the profile of cocaine/heroin users, which score very high on Neuroticism, especially Vulnerability, and very low on Conscientiousness, particularly Competence, Achievement-Striving, and Deliberation. By contrast, marijuana users score high on Openness to Experience, average on Neuroticism, but low on Agreeableness and Conscientiousness. Conclusion In addition to confirming high levels of negative affect and impulsive traits, this study highlights the links between drug use and low Conscientiousness. These links provide insight into the etiology of drug use and have implications for public health interventions.

Case Studies: Profiles of Women Recovering from Drug Addiction.

Science.gov (United States)

Miller, Suzanne M.

1995-01-01

Profiles two women over an eight-month study who abused alcohol and other drugs while pregnant and describes their recovery from the addiction. Examines, from an ecological framework, the women's experiences with drug addiction, treatment, and recovery, and recounts their situation through each. (JPS)

Skin test concentrations for systemically administered drugs -- an ENDA/EAACI Drug Allergy Interest Group position paper

DEFF Research Database (Denmark)

Brockow, K; Garvey, L H; Aberer, W

2013-01-01

Skin tests are of paramount importance for the evaluation of drug hypersensitivity reactions. Drug skin tests are often not carried out because of lack of concise information on specific test concentrations. The diagnosis of drug allergy is often based on history alone, which is an unreliable...... indicator of true hypersensitivity.To promote and standardize reproducible skin testing with safe and nonirritant drug concentrations in the clinical practice, the European Network and European Academy of Allergy and Clinical Immunology (EAACI) Interest Group on Drug Allergy has performed a literature...... search on skin test drug concentration in MEDLINE and EMBASE, reviewed and evaluated the literature in five languages using the GRADE system for quality of evidence and strength of recommendation. Where the literature is poor, we have taken into consideration the collective experience of the group...

Derangement of lipid profile in antiepileptic drugs treated patients in local population

International Nuclear Information System (INIS)

Zuberi, N.A.; Perveen, T.

2012-01-01

Epilepsy is the third most common neurological disorder. It is not a single entity. The abnormal electrical activity may result in a variety of events, including loss of consciousness, abnormal movements, a typical or odd behavior or distorted perceptions falls seizers. Epilepsy is a chronic disorder and often requiring years of treatment. A large number of drugs are used for the treatment of epilepsy. The choice among the antiepileptic drugs depends on its effectiveness and side effects. Our retrospective study investigated the effect of anti epileptic drugs on lipid profile. Serum lipid profile was measured in 160 patients in which 40 patients were not started any antiepileptic drug .The remaining 120 patients were receiving antiepileptic drugs (AEDs). 40 control subjects were taken from general population for comparison. The height, weight and body mass index (BMI) and lipid profile of antiepileptic drugs treated patients were compared with control and untreated group. The weight and body mass index of antiepileptic drugs treated group was significantly increased when compared to the control group. Total Cholesterol (TC), Triglyceride (TO), High density lipoprotein (HDL-C), low density lipoprotein (LDL-C), ratio TC/HDL-C and ratio LDL-C/HDL-C were investigated for each group of drugs and controls. TC, TO, LDL-C, ratio TC/HDL-C and ratio LDL-C/HDL-C were significantly increased in patients who were on AEDs when compared with control but HDL-C of all drug treated groups showed significantly decreased when compared with control group. There was significant change in lipid profile was seen in AEDs treated group when compared with control group. Ratio TC/HDL-C and ratio LDUHDL-C alteration showed the risk of atherosclerosis and cardiovascular diseases. Anti-epileptic drugs also alter the BMI and so it could potentially facilitate the development of diabetes mellitus. Our results additionally suggest that there is a need for careful monitoring of lipid profile in

Brazilian Federal Police drug chemical profiling - the PeQui project.

Science.gov (United States)

Zacca, Jorge J; Botelho, Elvio Dias; Vieira, Maurício L; Almeida, Fernanda L A; Ferreira, Luciana S; Maldaner, Adriano O

2014-07-01

Over the past six years the Brazilian Federal Police has undertaken major efforts in order to implement and to develop its own drug chemical profiling program. This paper aims to provide a broad perspective regarding the managerial strategies and some examples of subsequent technical issues involved in the implementation of such a project. Close collaboration with local drug enforcement and investigation teams, establishment of proper worldwide partnerships with well recognized institutions in the field of drug analysis and the attainment of suitable funding and human resources are shown to be key success factors. Some preliminary results concerning the chemical profile of cocaine seizures in Brazil during this process are presented. Copyright © 2014 Forensic Science Society. Published by Elsevier Ireland Ltd. All rights reserved.

Urine Creatinine Concentrations in Drug Monitoring Participants and Hospitalized Patients.

Science.gov (United States)

Love, Sara A; Seegmiller, Jesse C; Kloss, Julie; Apple, Fred S

2016-10-01

Urine drug testing is commonly performed in both clinical and forensic arenas for screening, monitoring and compliance purposes. We sought to determine if urine creatinine concentrations in monitoring program participants were significantly different from hospital in-patients and out-patients undergoing urine drug testing. We retrospectively reviewed urine creatinine submitted in June through December 2015 for all specimens undergoing urine drug testing. The 20,479 creatinine results were categorized as hospitalized patients (H) and monitoring/compliance groups for pain management (P), legal (L) or recovery (R). Median creatinine concentrations (interquartile range, mg/dL) were significantly different (P creatinine concentrations were significantly lower in the R vs. L group (Pcreatinine concentration and may indicate participants' attempts to tamper with their drug test results through dilution means. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Integrative relational machine-learning for understanding drug side-effect profiles.

Science.gov (United States)

Bresso, Emmanuel; Grisoni, Renaud; Marchetti, Gino; Karaboga, Arnaud Sinan; Souchet, Michel; Devignes, Marie-Dominique; Smaïl-Tabbone, Malika

2013-06-26

Drug side effects represent a common reason for stopping drug development during clinical trials. Improving our ability to understand drug side effects is necessary to reduce attrition rates during drug development as well as the risk of discovering novel side effects in available drugs. Today, most investigations deal with isolated side effects and overlook possible redundancy and their frequent co-occurrence. In this work, drug annotations are collected from SIDER and DrugBank databases. Terms describing individual side effects reported in SIDER are clustered with a semantic similarity measure into term clusters (TCs). Maximal frequent itemsets are extracted from the resulting drug x TC binary table, leading to the identification of what we call side-effect profiles (SEPs). A SEP is defined as the longest combination of TCs which are shared by a significant number of drugs. Frequent SEPs are explored on the basis of integrated drug and target descriptors using two machine learning methods: decision-trees and inductive-logic programming. Although both methods yield explicit models, inductive-logic programming method performs relational learning and is able to exploit not only drug properties but also background knowledge. Learning efficiency is evaluated by cross-validation and direct testing with new molecules. Comparison of the two machine-learning methods shows that the inductive-logic-programming method displays a greater sensitivity than decision trees and successfully exploit background knowledge such as functional annotations and pathways of drug targets, thereby producing rich and expressive rules. All models and theories are available on a dedicated web site. Side effect profiles covering significant number of drugs have been extracted from a drug ×side-effect association table. Integration of background knowledge concerning both chemical and biological spaces has been combined with a relational learning method for discovering rules which explicitly

Zeolite-filled silicone rubber membranes. Experimental determination of concentration profiles

NARCIS (Netherlands)

te Hennepe, H.J.C.; Boswerger, W.B.F.; Bargeman, D.; Bargeman, D.; Mulder, M.H.V.; Smolders, C.A.; Smolders, C.A.

1994-01-01

Permeant concentrations in silicalite-filled silicone rubber membranes during pervaporation of propanol/water mixtures were measured using multi-layered membranes. Experimentally determined concentration profiles show that the propanol concentration in the silicalite-filled membrane increases with

Drug Release Profile from Calcium-Induced Alginate-Phosphate Composite Gel Beads

Directory of Open Access Journals (Sweden)

Yoshifumi Murata

2009-01-01

Full Text Available Calcium-induced alginate-phosphate composite gel beads were prepared, and model drug release profiles were investigated in vitro. The formation of calcium phosphate in the alginate gel matrix was observed and did not affect the rheological properties of the hydrogel beads. X-ray diffraction patterns showed that the calcium phosphate does not exist in crystalline form in the matrix. The initial release amount and release rate of a water-soluble drug, diclofenac, from the alginate gel beads could be controlled by modifying the composition of the matrix with calcium phosphate. In contrast, the release profile was not affected by the modification for hydrocortisone, a drug only slightly soluble in water.

Assessing one-dimensional diffusion in nanoporous materials from transient concentration profiles

International Nuclear Information System (INIS)

Heinke, Lars; Kaerger, Joerg

2008-01-01

The use of interference microscopy has enabled the direct observation of transient concentration profiles generated by intracrystalline transport diffusion in nanoporous materials. The thus accessible intracrystalline concentration profiles contain a wealth of information which cannot be deduced by any macroscopic method. In this paper, we illustrate five different ways for determining the concentration-dependent diffusivity in one-dimensional systems and two for the surface permeability. These methods are discussed by application to concentration profiles evolving during the uptake of methanol by the zeolite ferrierite and of methanol by the metal organic framework (MOF) manganese(II) formate. We show that the diffusivity can be calculated most precisely by means of Fick's 1st law. As the circumstances permit, Boltzmann's integration method also yields very precise results. Furthermore, we present a simple procedure that enables the estimation of the influence of the surface barrier on the overall uptake process by plotting the boundary concentration versus the overall uptake

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.

Tissue concentration-time profile of selenium after sodium selenite administration to rats

Energy Technology Data Exchange (ETDEWEB)

Kaneko, Megumi; Natsuhori, Masahiro; Ito, Nobuhiko [Department of Veterinary Radiology and Radiation Biology, Kitasato University School of Veterinary Medicine, Towada, Aomori (Japan); Sera, Koichiro [Cyclotron Research Center, Iwate Medical University, Takizuka, Iwate (Japan); Futatsugawa, Shoji [Nishina Memorial Cyclotron Center (NMCC), Takizuka, Iwate (Japan)

1999-07-01

Selenium (Se) concentration-time profiles in plasma and organs including liver, kidney, heart, lung, spleen and brain of rats (Jcl Wister, 9 wks old, n=32) were investigated after a single intravenous (iv) / oral (po) administration of sodium selenite (dose is equivalent to 2 mg/kg b.w. of Se). The Se concentration was determined by PIXE analysis. Among the investigated biological samples, Se concentration was the highest in the kidney or liver, followed by the heart, lung or spleen, then plasma, and the brain. Se concentrations in these organs were 0.5 to 5 times of plasma Se. The distribution profiles of Se in the organs were dependent on the route of administration. Furthermore, their profiles appeared almost parallel to the plasma Se-concentration in a logarithmic scale. Compared to the Se concentration-time profiles in plasma and organs by the route of administration, po group showed about 1/4-1/2 of the Se concentration in iv group except for kidney. Kidney kept relatively higher concentration of Se, which was similar in the both groups. This may explain our recently published data that urinary excretion was similar in the both groups. The relative oral bioavailability of plasma and each organ was calculated by the ratio of area under the concentration-time curve after oral administration (AUCpo) to AUCiv. Each organ appeared to have their own bioavailability (i.e., liver 39%, kidney 97%, heart 37%, lung 18%, spleen 10%, and brain 72%), where plasma was 46%. These results highly suggested that different Se distribution in organs by the different route of administration was due to the different metabolic profile. (author)

Tissue concentration-time profile of selenium after sodium selenite administration to rats

International Nuclear Information System (INIS)

Kaneko, Megumi; Natsuhori, Masahiro; Ito, Nobuhiko; Sera, Koichiro; Futatsugawa, Shoji

1999-01-01

Selenium (Se) concentration-time profiles in plasma and organs including liver, kidney, heart, lung, spleen and brain of rats (Jcl Wister, 9 wks old, n=32) were investigated after a single intravenous (iv) / oral (po) administration of sodium selenite (dose is equivalent to 2 mg/kg b.w. of Se). The Se concentration was determined by PIXE analysis. Among the investigated biological samples, Se concentration was the highest in the kidney or liver, followed by the heart, lung or spleen, then plasma, and the brain. Se concentrations in these organs were 0.5 to 5 times of plasma Se. The distribution profiles of Se in the organs were dependent on the route of administration. Furthermore, their profiles appeared almost parallel to the plasma Se-concentration in a logarithmic scale. Compared to the Se concentration-time profiles in plasma and organs by the route of administration, po group showed about 1/4-1/2 of the Se concentration in iv group except for kidney. Kidney kept relatively higher concentration of Se, which was similar in the both groups. This may explain our recently published data that urinary excretion was similar in the both groups. The relative oral bioavailability of plasma and each organ was calculated by the ratio of area under the concentration-time curve after oral administration (AUCpo) to AUCiv. Each organ appeared to have their own bioavailability (i.e., liver 39%, kidney 97%, heart 37%, lung 18%, spleen 10%, and brain 72%), where plasma was 46%. These results highly suggested that different Se distribution in organs by the different route of administration was due to the different metabolic profile. (author)

Factors that influence an elemental depth concentration profile

International Nuclear Information System (INIS)

McHugh, J.A.

1975-01-01

The use of secondary ion mass spectrometry in concentration profiling is discussed. Two classes of factors that influence an elemental concentration profile are instrumental effects and ion-matrix effects. Instrumental factors that must be considered are: (1) uniformity of the primary ion current density, (2) constancy of the primary ion current, (3) redeposition, (4) memory, (5) primary ion beam tailing and the nonfocused component, (6) chemical purity of the primary ion beam, and (7) residual gas impurities. Factors which can be classified as ion matrix effects are: (1) the mean escape depth of secondary ions, (2) recoil implantation, (3) molecular ion interferences, (4) primary ion beam induced diffusion of matrix species, (5) nonuniform sputter removal of matrix layers, and (6) implanted primary ion chemical and lattice damage effects

Choice of capillary electrophoresis systems for the impurity profiling of drugs

NARCIS (Netherlands)

Hilhorst, M.J; Somsen, G.W; de Jong, G.J.

In order to develop a strategy for the impurity profiling of drugs, the possibilities of some capillary electrophoresis systems were investigated. A mixture containing a drug and some of its possible impurities has been used as a model problem. The test compounds were investigated by capillary zone

Profiling online recreational/prescription drugs' customers and overview of drug vending virtual marketplaces.

Science.gov (United States)

Orsolini, Laura; Francesconi, Giulia; Papanti, Duccio; Giorgetti, Arianna; Schifano, Fabrizio

2015-07-01

Internet and social networking sites play a significant role in the marketing and distribution of recreational/prescription drugs without restrictions. We aimed here at reviewing data relating to the profile of the online drug customer and at describing drug vending websites. The PubMed, Google Scholar, and Scopus databases were searched here in order to elicit data on the socio-demographic characteristics of the recreational marketplaces/online pharmacies' customers and the determinants relating to online drug purchasing activities. Typical online recreational drugs' customers seem to be Caucasian, men, in their 20s, highly educated, and using the web to impact as minimally as possible on their existing work/professional status. Conversely, people without any health insurance seemed to look at the web as a source of more affordable prescription medicines. Drug vending websites are typically presented here with a "no prescription required" approach, together with aggressive marketing strategies. The online availability of recreational/prescriptions drugs remains a public health concern. A more precise understanding of online vending sites' customers may well facilitate the drafting and implementation of proper prevention campaigns aimed at counteracting the increasing levels of online drug acquisition and hence intake activities. Copyright © 2015 John Wiley & Sons, Ltd.

The deconvolution of sputter-etching surface concentration measurements to determine impurity depth profiles

International Nuclear Information System (INIS)

Carter, G.; Katardjiev, I.V.; Nobes, M.J.

1989-01-01

The quasi-linear partial differential continuity equations that describe the evolution of the depth profiles and surface concentrations of marker atoms in kinematically equivalent systems undergoing sputtering, ion collection and atomic mixing are solved using the method of characteristics. It is shown how atomic mixing probabilities can be deduced from measurements of ion collection depth profiles with increasing ion fluence, and how this information can be used to predict surface concentration evolution. Even with this information, however, it is shown that it is not possible to deconvolute directly the surface concentration measurements to provide initial depth profiles, except when only ion collection and sputtering from the surface layer alone occur. It is demonstrated further that optimal recovery of initial concentration depth profiles could be ensured if the concentration-measuring analytical probe preferentially sampled depths near and at the maximum depth of bombardment-induced perturbations. (author)

Enantiomeric profiling of chiral illicit drugs in a pan-European study

NARCIS (Netherlands)

Castrignanò, E.; Yang, Z.; Bade, R.; Baz-Lomba, J.A.; Castiglioni, S.; Causanilles, A.; Covaci, A.; Gracia-Lor, E.; Hernández, F.; Kinyua, J.; McCall, A.-K.; van Nuijs, A.L.N.; Ort, C.; Plósz, B.G.; Ramin, P.; Rousis, N.I.; Ryu, Y.; Thomas, K.V.; de Voogt, P.; Zuccato, E.; Kasprzyk-Hordern, B.

2018-01-01

The aim of this paper is to present the first study on spatial and temporal variation in the enantiomeric profile of chiral drugs in eight European cities. Wastewater-based epidemiology (WBE) and enantioselective analysis were combined to evaluate trends in illicit drug use in the context of their

Profiling of some amoxicillin drugs in Ghana using Nuclear Magnetic Resonance Spectroscopy

International Nuclear Information System (INIS)

Aboagye, Mary Esi

2016-07-01

The prevalence of counterfeit drugs is seen as a problem faced in both developed and developing countries where Ghana is not an exception. Antibiotics are amongst the most counterfeit drugs in developing countries. What is less understood is that there are inadequate and ineffective quality control procedures in monitoring of drugs manufactured and imported into the country. This research work is aimed at contributing towards the development of routine analytical procedures that will facilitate distinguishing between fake and genuine amoxicillin drugs. This was accomplished by elaborating operating procedures for the analysis of specific antibiotic drug using nuclear magnetic resonance (NMR) spectroscopy and establishing the NMR profile of active principal ingredient (API) of amoxicillin drug and assessing the API in samples of amoxicillin drug purchased in Accra. Three brands of amoxicillin samples consisting of imported amoxicillin, National Health Insurance Scheme (NHIS) amoxicillin were purchased from a licensed pharmacy shop in Accra and amoxicillin purchased from Okaishie market were used for analysis. Standard amoxicillin known as amoxicillin trihydrate obtained from Ernest Chemist in Accra was also used analysed. The authenticity of the drugs was analysed using 1H and C-13 nuclear magnetic resonance spectroscopy. Upon analysis H-NMR and C-13 NMR profiles were obtained for the API (Amoxicillin Trihydrate) in amoxicillin. H NMR showed relatively higher sensitivities for the drug than C-13 NMR therefore analysis for the antibiotics was focused on H-NMR. After analysis amoxicillin trihydrate was identified as the API. A procedure suitable for NMR sample preparation of amoxicillin for NMR analysis was elaborated. Dimethyl sulfoxide was identified as a suitable solvent for the experiments. The samples were prepared by dissolving suitable quantities (10mg) of the drug in (1ml) of the chosen solvent. H-NMR technique was used to provide an NMR profile for the Active

TargetNet: a web service for predicting potential drug-target interaction profiling via multi-target SAR models

Science.gov (United States)

Yao, Zhi-Jiang; Dong, Jie; Che, Yu-Jing; Zhu, Min-Feng; Wen, Ming; Wang, Ning-Ning; Wang, Shan; Lu, Ai-Ping; Cao, Dong-Sheng

2016-05-01

Drug-target interactions (DTIs) are central to current drug discovery processes and public health fields. Analyzing the DTI profiling of the drugs helps to infer drug indications, adverse drug reactions, drug-drug interactions, and drug mode of actions. Therefore, it is of high importance to reliably and fast predict DTI profiling of the drugs on a genome-scale level. Here, we develop the TargetNet server, which can make real-time DTI predictions based only on molecular structures, following the spirit of multi-target SAR methodology. Naïve Bayes models together with various molecular fingerprints were employed to construct prediction models. Ensemble learning from these fingerprints was also provided to improve the prediction ability. When the user submits a molecule, the server will predict the activity of the user's molecule across 623 human proteins by the established high quality SAR model, thus generating a DTI profiling that can be used as a feature vector of chemicals for wide applications. The 623 SAR models related to 623 human proteins were strictly evaluated and validated by several model validation strategies, resulting in the AUC scores of 75-100 %. We applied the generated DTI profiling to successfully predict potential targets, toxicity classification, drug-drug interactions, and drug mode of action, which sufficiently demonstrated the wide application value of the potential DTI profiling. The TargetNet webserver is designed based on the Django framework in Python, and is freely accessible at http://targetnet.scbdd.com.

TargetNet: a web service for predicting potential drug-target interaction profiling via multi-target SAR models.

Science.gov (United States)

Yao, Zhi-Jiang; Dong, Jie; Che, Yu-Jing; Zhu, Min-Feng; Wen, Ming; Wang, Ning-Ning; Wang, Shan; Lu, Ai-Ping; Cao, Dong-Sheng

2016-05-01

Drug-target interactions (DTIs) are central to current drug discovery processes and public health fields. Analyzing the DTI profiling of the drugs helps to infer drug indications, adverse drug reactions, drug-drug interactions, and drug mode of actions. Therefore, it is of high importance to reliably and fast predict DTI profiling of the drugs on a genome-scale level. Here, we develop the TargetNet server, which can make real-time DTI predictions based only on molecular structures, following the spirit of multi-target SAR methodology. Naïve Bayes models together with various molecular fingerprints were employed to construct prediction models. Ensemble learning from these fingerprints was also provided to improve the prediction ability. When the user submits a molecule, the server will predict the activity of the user's molecule across 623 human proteins by the established high quality SAR model, thus generating a DTI profiling that can be used as a feature vector of chemicals for wide applications. The 623 SAR models related to 623 human proteins were strictly evaluated and validated by several model validation strategies, resulting in the AUC scores of 75-100 %. We applied the generated DTI profiling to successfully predict potential targets, toxicity classification, drug-drug interactions, and drug mode of action, which sufficiently demonstrated the wide application value of the potential DTI profiling. The TargetNet webserver is designed based on the Django framework in Python, and is freely accessible at http://targetnet.scbdd.com .

Serum magnesium concentration in drug-addicted patients.

Science.gov (United States)

Karakiewicz, Beata; Kozielec, Tadeusz; Brodowski, Jacek; Chlubek, Dariusz; Noceń, Iwona; Starczewski, Andrzej; Brodowska, Agnieszka; Laszczyńska, Maria

2007-03-01

Drug addiction is a complex problem which leads to many somatic, psychic and social diseases. It is accompanied by the disturbed metabolism of various macro and micronutrients. The aim of this study was to assess serum magnesium concentration in drug-addicted patients and analyze whether Human Immunodeficiency Virus (HIV) infection and methadone treatment affect the level of serum magnesium in these patients. The examination was conducted in a group of 83 people - patients of Szczecin-Zdroje Psychiatric Hospital (Poland). They were 21 to 49 years old, and the mean age was 32 +/- 7 years. The control group consisted of 81 healthy individuals. Flame atomic-absorption spectrometry method was used to determine the magnesium concentration. The total serum magnesium concentration was calculated for the whole patient group, subgroups of women and men, a subgroup of people infected with HIV, and a subgroup receiving methadone substitution treatment. How magnesium behaves depending on age and addiction period, was checked. The mean concentration of magnesium in blood serum of the patients examined was 0.57 mmol/L, which was significantly lower than in the control group. In the subgroup of men it was 0.57 mmol/L, and in the subgroup of women - 0.55 mmol/L; the differences were not statistically significant. In the patient group nobody had the appropriate magnesium concentration in blood serum. No significant correlation was found between the magnesium concentration, age of the patients and addiction period. In the subgroup of seropositive people the mean concentration of magnesium was 0.55 mmol/L, and in the subgroup of non-infected patients - 0.58 mmol/L; the difference was not statistically significant. The mean concentration of magnesium in the subgroup treated with methadone was 0.59 mmol/L, and in the subgroup not involved in this type of therapy - 0.55 mmol/L; it was not a statistically significant difference.

Skin test concentrations for systemically administered drugs -- an ENDA/EAACI Drug Allergy Interest Group position paper

NARCIS (Netherlands)

Brockow, K.; Garvey, L. H.; Aberer, W.; Atanaskovic-Markovic, M.; Barbaud, A.; Bilo, M. B.; Bircher, A.; Blanca, M.; Bonadonna, B.; Campi, P.; Castro, E.; Cernadas, J. R.; Chiriac, A. M.; Demoly, P.; Grosber, M.; Gooi, J.; Lombardo, C.; Mertes, P. M.; Mosbech, H.; Nasser, S.; Pagani, M.; Ring, J.; Romano, A.; Scherer, K.; Schnyder, B.; Testi, S.; Torres, M.; Trautmann, A.; Terreehorst, I.

2013-01-01

Skin tests are of paramount importance for the evaluation of drug hypersensitivity reactions. Drug skin tests are often not carried out because of lack of concise information on specific test concentrations. The diagnosis of drug allergy is often based on history alone, which is an unreliable

Drug profile: transdermal rivastigmine patch in the treatment of Alzheimer disease.

Science.gov (United States)

Emre, Murat; Bernabei, Roberto; Blesa, Rafael; Bullock, Roger; Cunha, Luis; Daniëls, Hugo; Dziadulewicz, Edward; Förstl, Hans; Frölich, Lutz; Gabryelewicz, Tomasz; Levin, Oleg; Lindesay, James; Martínez-Lage, Pablo; Monsch, Andreas; Tsolaki, Magda; van Laar, Teus

2010-08-01

Cholinesterase inhibitors constitute one of the mainstays of treatment of Alzheimer disease (AD). Gastrointestinal side effects, difficulty accessing therapeutic doses and poor patient compliance have been identified as barriers to effective treatment with these substances. The rivastigmine transdermal patch provides continuous delivery of drug through the skin into the bloodstream, avoiding the fluctuations in plasma concentration associated with oral administration. This pharmacokinetic profile is associated with reduced side effects, resulting in easier access to expected target doses. These benefits, along with other practical advantages of the transdermal patch, may contribute to enhanced patient compliance. Here, we present a review of the current literature on rivastigmine patch, and offer advice based on our own collective clinical experience. Rivastigmine patch provides an efficient option for managing patients with AD, to be considered among the first line therapies for the disease.

Drug Use Patterns and Socio-Demographic Profiles of Substance ...

African Journals Online (AJOL)

Substance abuse is a critical problem in Botswana, yet empirical evidence on substance users is limited. The current study sought to examine patterns of drug use and sociodemographic profiles of clients who sought treatment at a substance abuse treatment centre in Gaborone, Botswana. Findings showed clients' age ...

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.

Validation of predicted exponential concentration profiles of chemicals in soils

International Nuclear Information System (INIS)

Hollander, Anne; Baijens, Iris; Ragas, Ad; Huijbregts, Mark; Meent, Dik van de

2007-01-01

Multimedia mass balance models assume well-mixed homogeneous compartments. Particularly for soils, this does not correspond to reality, which results in potentially large uncertainties in estimates of transport fluxes from soils. A theoretically expected exponential decrease model of chemical concentrations with depth has been proposed, but hardly tested against empirical data. In this paper, we explored the correspondence between theoretically predicted soil concentration profiles and 84 field measured profiles. In most cases, chemical concentrations in soils appear to decline exponentially with depth, and values for the chemical specific soil penetration depth (d p ) are predicted within one order of magnitude. Over all, the reliability of multimedia models will improve when they account for depth-dependent soil concentrations, so we recommend to take into account the described theoretical exponential decrease model of chemical concentrations with depth in chemical fate studies. In this model the d p -values should estimated be either based on local conditions or on a fixed d p -value, which we recommend to be 10 cm for chemicals with a log K ow > 3. - Multimedia mass model predictions will improve when taking into account depth dependent soil concentrations

Profiling persistent tubercule bacilli from patient sputa during therapy predicts early drug efficacy.

Science.gov (United States)

Honeyborne, Isobella; McHugh, Timothy D; Kuittinen, Iitu; Cichonska, Anna; Evangelopoulos, Dimitrios; Ronacher, Katharina; van Helden, Paul D; Gillespie, Stephen H; Fernandez-Reyes, Delmiro; Walzl, Gerhard; Rousu, Juho; Butcher, Philip D; Waddell, Simon J

2016-04-07

New treatment options are needed to maintain and improve therapy for tuberculosis, which caused the death of 1.5 million people in 2013 despite potential for an 86 % treatment success rate. A greater understanding of Mycobacterium tuberculosis (M.tb) bacilli that persist through drug therapy will aid drug development programs. Predictive biomarkers for treatment efficacy are also a research priority. Genome-wide transcriptional profiling was used to map the mRNA signatures of M.tb from the sputa of 15 patients before and 3, 7 and 14 days after the start of standard regimen drug treatment. The mRNA profiles of bacilli through the first 2 weeks of therapy reflected drug activity at 3 days with transcriptional signatures at days 7 and 14 consistent with reduced M.tb metabolic activity similar to the profile of pre-chemotherapy bacilli. These results suggest that a pre-existing drug-tolerant M.tb population dominates sputum before and after early drug treatment, and that the mRNA signature at day 3 marks the killing of a drug-sensitive sub-population of bacilli. Modelling patient indices of disease severity with bacterial gene expression patterns demonstrated that both microbiological and clinical parameters were reflected in the divergent M.tb responses and provided evidence that factors such as bacterial load and disease pathology influence the host-pathogen interplay and the phenotypic state of bacilli. Transcriptional signatures were also defined that predicted measures of early treatment success (rate of decline in bacterial load over 3 days, TB test positivity at 2 months, and bacterial load at 2 months). This study defines the transcriptional signature of M.tb bacilli that have been expectorated in sputum after two weeks of drug therapy, characterizing the phenotypic state of bacilli that persist through treatment. We demonstrate that variability in clinical manifestations of disease are detectable in bacterial sputa signatures, and that the changing M.tb m

Using Potentiometric Free Drug Sensors to Determine the Free Concentration of Ionizable Drugs in Colloidal Systems

DEFF Research Database (Denmark)

Tran, Thuy; Chakraborty, Anjan; Xi, Xi

2018-01-01

The present study investigates the use of free drug sensors (FDS) to measure free ionized drug concentrations in colloidal systems, including micellar solutions, emulsions, and lipid formulations during in vitro lipolysis. Diphenhydramine hydrochloride (DPH) and loperamide hydrochloride (LOP) wer...

MicroRNA expression profiles of drug-resistance breast cancer cells and their exosomes.

Science.gov (United States)

Zhong, Shanliang; Chen, Xiu; Wang, Dandan; Zhang, Xiaohui; Shen, Hongyu; Yang, Sujin; Lv, Mengmeng; Tang, Jinhai; Zhao, Jianhua

2016-04-12

Exosomes have been shown to transmit drug resistance through delivering miRNAs. We aimed to explore their roles in breast cancer. Three resistant sublines were established by exposing parental MDA-MB-231 cell line to docetaxel, epirubicin and vinorelbine, respectively. Preneoadjuvant chemotherapy biopsies and paired surgically-resected specimens embedded in paraffin from 23 breast cancer patients were collected. MiRNA expression profiles of the cell lines and their exosomes were evaluated using microarray. The result showed that most miRNAs in exosomes had a lower expression level than that in cells, however, some miRNAs expressed higher in exosomes than in cells, suggesting a number of miRNAs is concentrated in exosomes. Among the dysregulated miRNAs, 22 miRNAs were consistently up-regulated in exosomes and their cells of origin. We further found that 12 of the 22 miRNAs were significantly up-regulated after preneoadjuvant chemotherapy. Further study of the role of these 12 miRNAs in acquisition of drug resistance is needed to clarify their contribution to chemoresistance.

Does the performance of wet granulation and tablet hardness affect the drug dissolution profile of carvedilol in matrix tablets?

Science.gov (United States)

Košir, Darjan; Ojsteršek, Tadej; Vrečer, Franc

2018-06-14

Wet granulation is mostly used process for manufacturing matrix tablets. Compared to the direct compression method, it allows for a better flow and compressibility properties of compression mixtures. Granulation, including process parameters and tableting, can influence critical quality attributes (CQAs) of hydrophilic matrix tablets. One of the most important CQAs is the drug release profile. We studied the influence of granulation process parameters (type of nozzle and water quantity used as granulation liquid) and tablet hardness on the drug release profile. Matrix tablets contained HPMC K4M hydrophilic matrix former and carvedilol as a model drug. The influence of selected HPMC characteristics on the drug release profile was also evaluated using two additional HPMC batches. For statistical evaluation, partial least square (PLS) models were generated for each time point of the drug release profile using the same number of latent factors. In this way, it was possible to evaluate how the importance of factors influencing drug dissolution changes in dependence on time throughout the drug release profile. The results of statistical evaluation show that the granulation process parameters (granulation liquid quantity and type of nozzle) and tablet hardness significantly influence the release profile. On the other hand, the influence of HPMC characteristics is negligible in comparison to the other factors studied. Using a higher granulation liquid quantity and the standard nozzle type results in larger granules with a higher density and lower porosity, which leads to a slower drug release profile. Lower tablet hardness also slows down the release profile.

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.

[Health and drug consumption profile in Cameroon].

Science.gov (United States)

Commeyras, Christophe; Ndo, Jean Rolin; Merabet, Omar; Kone, Hamidou; Rakotondrabe, Faraniaina Patricia

2006-01-01

To begin a renewal of national health policy in Cameroon, a steering committee from the Cameroon Ministry of Health and its partners sought to analyze health demand through a national population survey and supply capacity through a national survey of retail drug stores. A survey of healthcare consumers was also conducted. The present publication describes the results of the consumer survey. Their socioeconomic profile of these consumers was much higher than that of the general population. This indicates that the poorest do not use health facilities or even self-medication. Within the population of healthcare consumers, women and children used private for-profit (60 %) and nonprofit (65 %) private health facilities most often, while men used mainly private pharmacies (60 %) and street drug (medication) sellers (62 %). In all, 85 % of the users of formal drug retailers had had a consultation with a healthcare provider. The average consultation cost was 1,440 CFA Francs, but the 7 % who paid the provider directly had an average cost of 1,794 CFA Francs. In all, 22 % did not pay at all, because of free consultations in some health facilities (40 %), personal relationships with prescribers, or other reasons. Hospitalization costs averaged 4,800 CFA Francs, and medical examinations 4,534 CFA Francs. These two categories had the highest percentage of insured patients (12 % and 5 %). Drug costs were 5,067 CFA Francs from pharmacies and 1,308 CFA Francs in the street. Total healthcare costs per person averaged 14,990 CFA Francs. Weighted, drugs accounted for the largest share, followed by hospitalisation, medical examinations, consultations, and transportation. In the formal sector, less than 10 % reported paying fees directly to the healthcare providers rather than to the HF cashier. Except for consultation in the public sector, paying providers was associated with a lower bill. However, 24 % purchased drugs from the healthcare workers, which indicates that drug sales are

Rapid Identification of Potential Drugs for Diabetic Nephropathy Using Whole-Genome Expression Profiles of Glomeruli

Directory of Open Access Journals (Sweden)

Jingsong Shi

2016-01-01

Full Text Available Objective. To investigate potential drugs for diabetic nephropathy (DN using whole-genome expression profiles and the Connectivity Map (CMAP. Methodology. Eighteen Chinese Han DN patients and six normal controls were included in this study. Whole-genome expression profiles of microdissected glomeruli were measured using the Affymetrix human U133 plus 2.0 chip. Differentially expressed genes (DEGs between late stage and early stage DN samples and the CMAP database were used to identify potential drugs for DN using bioinformatics methods. Results. (1 A total of 1065 DEGs (FDR 1.5 were found in late stage DN patients compared with early stage DN patients. (2 Piperlongumine, 15d-PGJ2 (15-delta prostaglandin J2, vorinostat, and trichostatin A were predicted to be the most promising potential drugs for DN, acting as NF-κB inhibitors, histone deacetylase inhibitors (HDACIs, PI3K pathway inhibitors, or PPARγ agonists, respectively. Conclusion. Using whole-genome expression profiles and the CMAP database, we rapidly predicted potential DN drugs, and therapeutic potential was confirmed by previously published studies. Animal experiments and clinical trials are needed to confirm both the safety and efficacy of these drugs in the treatment of DN.

Nitrogen concentration profiles in oxy-nitrited high-speed steel

International Nuclear Information System (INIS)

Barcz, A.; Turos, A.; Wielunski, L.

1976-01-01

Nuclear microanalysis has been applied for the determination of in-depth concentration profiles of nitrogen in oxy-nitrided high-speed steel. The concentration profiles were deduced from measurements of the nitrogen content, determined by means of the 14 N(d,α) 12 C reaction for the set of initially identical samples after the removal of surface layers of sequentially increasing thicknesses. The 1.2 MeV deuterons were obtained from the Institute of Nuclear Research Van de Graaf accelerator LECH. The α-particles produced in the 14 N(d,α) 12 C reaction were detected by means of silicon surface barrier detector mounted at 150 deg C. Strong blocking of the nitrogen diffusion due to the presence of oxygen has been observed. The accuracy of nitrogen detection is of the order of 5% for nitrogen-rich regions and 10% for the matrix. However, the local non-uniformity of the steel may cause a spread of about 20% of the measured values. (T.G.)

Cure of tuberculosis despite serum concentrations of antituberculosis drugs below published reference ranges.

Science.gov (United States)

Meloni, Monica; Corti, Natascia; Müller, Daniel; Henning, Lars; Gutteck, Ursula; von Braun, Amrei; Weber, Rainer; Fehr, Jan

2015-01-01

Therapeutic target serum concentrations of first-line antituberculosis drugs have not been well defined in clinical studies in tuberculosis (TB) patients. We retrospectively investigated the estimated maximum serum concentrations (eC max) of antituberculosis drugs and clinical outcome of TB patients with therapeutic drug monitoring performed between 2010-2012 at our institution, and follow-up until March 2014. The eC max was defined as the highest serum concentration during a sampling period (2, 4 and 6 hours after drug ingestion). We compared the results with published eC max values, and categorised them as either "within reference range", "low eC max", or "very low eC max".Low/very low eC max-levels were defined as follows: isoniazid 2-3/max levels were classified as "low" or "very low". The eC max was below the relevant reference range in 80% of isoniazid, 95% of rifampicin, 30% of pyrazinamide, and 30% of ethambutol measurements. All but one patient were cured of tuberculosis. Although many antituberculosis drug serum concentrations were below the widely used reference ranges, 16 of 17 patients were cured of tuberculosis. These results challenge the use of the published reference ranges for therapeutic drug monitoring.

Influence of drugs of abuse and alcohol upon patients admitted to acute psychiatric wards: physician's assessment compared to blood drug concentrations.

Science.gov (United States)

Mordal, Jon; Medhus, Sigrid; Holm, Bjørn; Mørland, Jørg; Bramness, Jørgen G

2013-06-01

In acute psychiatric services, rapid and accurate detection of psychoactive substance intake may be required for appropriate diagnosis and intervention. The aim of this study was to investigate the relationship between (a) drug influence as assessed by physicians and (b) blood drug concentrations among patients admitted to acute psychiatric wards. We also explored the possible effects of age, sex, and psychotic symptoms on physician's assessment of drug influence. In a cross-sectional study, the sample comprised 271 consecutive admissions from 2 acute psychiatric wards. At admission, the physician on call performed an overall judgment of drug influence. Psychotic symptoms were assessed with the positive subscale of the Positive and Negative Syndrome Scale. Blood samples were screened for a wide range of psychoactive substances, and quantitative results were used to calculate blood drug concentration scores. Patients were judged as being under the influence of drugs and/or alcohol in 28% of the 271 admissions. Psychoactive substances were detected in 56% of the blood samples. Altogether, 15 different substances were found; up to 8 substances were found in samples from 1 patient. Markedly elevated blood drug concentration scores were estimated for 15% of the patients. Physician's assessment was positively related to the blood drug concentration scores (r = 0.52; P < 0.001), to symptoms of excitement, and to the detection of alcohol, cannabis, and amphetamines. The study demonstrates the major impact of alcohol and drugs in acute psychiatric settings and illustrates the challenging nature of the initial clinical assessment.

Lung Tissue Concentrations of Pyrazinamide among Patients with Drug-Resistant Pulmonary Tuberculosis

Science.gov (United States)

Heinrichs, M. Tobias; Nikolaishvili, Ketino; Sabulua, Irina; Bablishvili, Nino; Gogishvili, Shota; Avaliani, Zaza; Tukvadze, Nestani; Little, Brent; Bernheim, Adam; Read, Timothy D.; Guarner, Jeannette; Derendorf, Hartmut; Peloquin, Charles A.; Blumberg, Henry M.; Vashakidze, Sergo

2017-01-01

ABSTRACT Improved knowledge regarding the tissue penetration of antituberculosis drugs may help optimize drug management. Patients with drug-resistant pulmonary tuberculosis undergoing adjunctive surgery were enrolled. Serial serum samples were collected, and microdialysis was performed using ex vivo lung tissue to measure pyrazinamide concentrations. Among 10 patients, the median pyrazinamide dose was 24.7 mg/kg of body weight. Imaging revealed predominant lung lesions as cavitary (n = 6 patients), mass-like (n = 3 patients), or consolidative (n = 1 patient). On histopathology examination, all tissue samples had necrosis; eight had a pH of ≤5.5. Tissue samples from two patients were positive for Mycobacterium tuberculosis by culture (pH 5.5 and 7.2). All 10 patients had maximal serum pyrazinamide concentrations within the recommended range of 20 to 60 μg/ml. The median lung tissue free pyrazinamide concentration was 20.96 μg/ml. The median tissue-to-serum pyrazinamide concentration ratio was 0.77 (range, 0.54 to 0.93). There was a significant inverse correlation between tissue pyrazinamide concentrations and the amounts of necrosis (R = −0.66, P = 0.04) and acid-fast bacilli (R = −0.75, P = 0.01) identified by histopathology. We found good penetration of pyrazinamide into lung tissue among patients with pulmonary tuberculosis with a variety of radiological lesion types. Our tissue pH results revealed that most lesions had a pH conducive to pyrazinamide activity. The tissue penetration of pyrazinamide highlights its importance in both drug-susceptible and drug-resistant antituberculosis treatment regimens. PMID:28373198

Lung Tissue Concentrations of Pyrazinamide among Patients with Drug-Resistant Pulmonary Tuberculosis.

Science.gov (United States)

Kempker, Russell R; Heinrichs, M Tobias; Nikolaishvili, Ketino; Sabulua, Irina; Bablishvili, Nino; Gogishvili, Shota; Avaliani, Zaza; Tukvadze, Nestani; Little, Brent; Bernheim, Adam; Read, Timothy D; Guarner, Jeannette; Derendorf, Hartmut; Peloquin, Charles A; Blumberg, Henry M; Vashakidze, Sergo

2017-06-01

Improved knowledge regarding the tissue penetration of antituberculosis drugs may help optimize drug management. Patients with drug-resistant pulmonary tuberculosis undergoing adjunctive surgery were enrolled. Serial serum samples were collected, and microdialysis was performed using ex vivo lung tissue to measure pyrazinamide concentrations. Among 10 patients, the median pyrazinamide dose was 24.7 mg/kg of body weight. Imaging revealed predominant lung lesions as cavitary ( n = 6 patients), mass-like ( n = 3 patients), or consolidative ( n = 1 patient). On histopathology examination, all tissue samples had necrosis; eight had a pH of ≤5.5. Tissue samples from two patients were positive for Mycobacterium tuberculosis by culture (pH 5.5 and 7.2). All 10 patients had maximal serum pyrazinamide concentrations within the recommended range of 20 to 60 μg/ml. The median lung tissue free pyrazinamide concentration was 20.96 μg/ml. The median tissue-to-serum pyrazinamide concentration ratio was 0.77 (range, 0.54 to 0.93). There was a significant inverse correlation between tissue pyrazinamide concentrations and the amounts of necrosis ( R = -0.66, P = 0.04) and acid-fast bacilli ( R = -0.75, P = 0.01) identified by histopathology. We found good penetration of pyrazinamide into lung tissue among patients with pulmonary tuberculosis with a variety of radiological lesion types. Our tissue pH results revealed that most lesions had a pH conducive to pyrazinamide activity. The tissue penetration of pyrazinamide highlights its importance in both drug-susceptible and drug-resistant antituberculosis treatment regimens. Copyright © 2017 American Society for Microbiology.

Solubility-pH profiles of some acidic, basic and amphoteric drugs.

Science.gov (United States)

Shoghi, Elham; Fuguet, Elisabet; Bosch, Elisabeth; Ràfols, Clara

2013-01-23

The solubility vs. pH profiles of five ionizable drugs of different nature (a monoprotic acid, a monoprotic base, a diprotic base and two amphoteric compounds showing a zwitterionic species each one) have been determined through two different methodologies: the classical shake-flask (S-F) and the potentiometric Cheqsol methods using in both instances the appropriate Henderson-Hasselbalch (H-H) or derived relationships. The results obtained independently from both approaches are consistent. A critical revision about the influence of the electrolyte used as buffering agent in the S-F method on the obtained solubility values is also performed. Thus, some deviations of the experimental points with respect the H-H profiles can be attributed to specific interactions between the buffering electrolyte and the drug due to the hydrotrophic character of citric and lactic acids. In other cases, the observed deviations are independent of the buffers used since they are caused by the formation of new species such as drug aggregates (cefadroxil) or the precipitation of a salt from a cationic species of the analyzed compound (quetiapine). Copyright © 2012 Elsevier B.V. All rights reserved.

Capillary electrokinetic separation techniques for profiling of drugs and related products

NARCIS (Netherlands)

Hilhorst, M.J; Somsen, G.W; de Jong, G.J.

Capillary electrokinetic separation techniques offer high efficiency and peak capacity, and can be very useful for the analysis of samples containing a large variety of (unknown) compounds. Such samples are frequently met in impurity profiling of drugs (detection of potential impurities in a

Plasma vs heart tissue concentration in humans - literature data analysis of drugs distribution.

Science.gov (United States)

Tylutki, Zofia; Polak, Sebastian

2015-03-12

Little is known about the uptake of drugs into the human heart, although it is of great importance nowadays, when science desires to predict tissue level behavior rather than to measure it. Although the drug concentration in cardiac tissue seems a better predictor for physiological and electrophysiological changes than its level in plasma, knowledge of this value is very limited. Tissue to plasma partition coefficients (Kp) come to rescue since they characterize the distribution of a drug among tissues as being one of the input parameters in physiologically based pharmacokinetic (PBPK) models. The article reviews cardiac surgery and forensic medical studies to provide a reference for drug concentrations in human cardiac tissue. Firstly, the focus is on whether a drug penetrates into heart tissue at a therapeutic level; the provided values refer to antibiotics, antifungals and anticancer drugs. Drugs that directly affect cardiomyocyte electrophysiology are another group of interest. Measured levels of amiodarone, digoxin, perhexiline and verapamil in different sites in human cardiac tissue where the compounds might meet ion channels, gives an insight into how these more lipophilic drugs penetrate the heart. Much data are derived from postmortem studies and they provide insight to the cardiac distribution of more than 200 drugs. The analysis depicts potential problems in defining the active concentration location, what may indirectly suggest multiple mechanisms involved in the drug distribution within the heart. Copyright © 2015 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd.

Can fluconazole concentrations in saliva be used for therapeutic drug monitoring?

NARCIS (Netherlands)

Koks, C. H.; Crommentuyn, K. M.; Hoetelmans, R. M.; Mathôt, R. A.; Beijnen, J. H.

2001-01-01

The saliva/plasma concentration ratio of fluconazole was investigated in 22 HIV-1-infected individuals with an oropharyngeal Candida infection to determine whether saliva fluconazole concentrations could provide useful information for therapeutic drug monitoring in this population. Steady-state

Hypnosis control based on the minimum concentration of anesthetic drug for maintaining appropriate hypnosis.

Science.gov (United States)

Furutani, Eiko; Nishigaki, Yuki; Kanda, Chiaki; Takeda, Toshihiro; Shirakami, Gotaro

2013-01-01

This paper proposes a novel hypnosis control method using Auditory Evoked Potential Index (aepEX) as a hypnosis index. In order to avoid side effects of an anesthetic drug, it is desirable to reduce the amount of an anesthetic drug during surgery. For this purpose many studies of hypnosis control systems have been done. Most of them use Bispectral Index (BIS), another hypnosis index, but it has problems of dependence on anesthetic drugs and nonsmooth change near some particular values. On the other hand, aepEX has an ability of clear distinction between patient consciousness and unconsciousness and independence of anesthetic drugs. The control method proposed in this paper consists of two elements: estimating the minimum effect-site concentration for maintaining appropriate hypnosis and adjusting infusion rate of an anesthetic drug, propofol, using model predictive control. The minimum effect-site concentration is estimated utilizing the property of aepEX pharmacodynamics. The infusion rate of propofol is adjusted so that effect-site concentration of propofol may be kept near and always above the minimum effect-site concentration. Simulation results of hypnosis control using the proposed method show that the minimum concentration can be estimated appropriately and that the proposed control method can maintain hypnosis adequately and reduce the total infusion amount of propofol.

Binding kinetics of five drugs to beta2-adrenoceptor using peak profiling method and nonlinear chromatography.

Science.gov (United States)

Liang, Yuan; Wang, Jing; Fei, Fuhuan; Sun, Huanmei; Liu, Ting; Li, Qian; Zhao, Xinfeng; Zheng, Xiaohui

2018-02-23

Investigations of drug-protein interactions have advanced our knowledge of ways to design more rational drugs. In addition to extensive thermodynamic studies, ongoing works are needed to enhance the exploration of drug-protein binding kinetics. In this work, the beta2-adrenoceptor (β 2 -AR) was immobilized on N, N'-carbonyldiimidazole activated amino polystyrene microspheres to prepare an affinity column (4.6 mm × 5.0 cm, 8 μm). The β 2 -AR column was utilized to determine the binding kinetics of five drugs to the receptor. Introducing peak profiling method into this receptor chromatographic analysis, we determined the dissociation rate constants (k d ) of salbutamol, terbutaline, methoxyphenamine, isoprenaline hydrochloride and ephedrine hydrochloride to β 2 -AR to be 15 (±1), 22 (±1), 3.3 (±0.2), 2.3 (±0.2) and 2.1 (±0.1) s -1 , respectively. The employment of nonlinear chromatography (NLC) in this case exhibited the same rank order of k d values for the five drugs bound to β 2 -AR. We confirmed that both the peak profiling method and NLC were capable of routine measurement of receptor-drug binding kinetics. Compared with the peak profiling method, NLC was advantageous in the simultaneous assessment of the kinetic and apparent thermodynamic parameters. It will become a powerful method for high throughput drug-receptor interaction analysis. Copyright © 2018 Elsevier B.V. All rights reserved.

Contamination profiles and mass loadings of macrolide antibiotics and illicit drugs from a small urban wastewater treatment plant.

Science.gov (United States)

Loganathan, Bommanna; Phillips, Malia; Mowery, Holly; Jones-Lepp, Tammy L

2009-03-01

Information is limited regarding sources, distribution, environmental behavior, and fate of prescribed and illicit drugs. Wastewater treatment plant (WWTP) effluents can be one of the sources of pharmaceutical and personal care products (PPCP) into streams, rivers and lakes. The objective of this study was to determine the contamination profiles and mass loadings of urobilin (a chemical marker of human waste), macrolide antibiotics (azithromycin, clarithromycin, roxithromycin), and two drugs of abuse (methamphetamine and ecstasy), from a small (antibiotics analyzed, azithromycin was consistently detected in influent and effluent samples. In general, influent samples contained relatively higher concentrations of the analytes than the effluents. Based on the daily flow rates and an average concentration of 17.5 ng L(-1) in the effluent, the estimated discharge of azithromycin was 200 mg day(-1) (range 63-400 mg day(-1)). Removal efficiency of the detected analytes from this WWTP were in the following order: urobilin>methamphetamine>azithromycin with percentages of removal of 99.9%, 54.5% and 47%, respectively, indicating that the azithromycin and methamphetamine are relatively more recalcitrant than others and have potential for entering receiving waters.

Inhibition of crystal nucleation and growth by water-soluble polymers and its impact on the supersaturation profiles of amorphous drugs.

Science.gov (United States)

Ozaki, Shunsuke; Kushida, Ikuo; Yamashita, Taro; Hasebe, Takashi; Shirai, Osamu; Kano, Kenji

2013-07-01

The impact of water-soluble polymers on drug supersaturation behavior was investigated to elucidate the role of water-soluble polymers in enhancing the supersaturation levels of amorphous pharmaceuticals. Hydroxypropyl methylcellulose (HPMC), polyvinylpyrrolidone (PVP), and Eudragit L-100 (Eudragit) were used as representative polymers, and griseofulvin and danazol were used as model drugs. Supersaturation profiles of amorphous drugs were measured in biorelevant dissolution tests. Crystal growth rate was measured from the decrease in dissolved drug concentration in the presence of seed crystals. Nucleation kinetics was evaluated by measuring the induction time for nucleation. All experiments were performed in the presence and absence of polymers. The degree of supersaturation of the amorphous model drugs increased with an increase in the inhibitory efficiency of polymers against crystal nucleation and growth (HPMC > PVP > Eudragit). In the presence of HPMC, the addition of seed crystals diminished the supersaturation ratio dramatically for griseofulvin and moderately for danazol. The results demonstrated that the polymers contributed to drug supersaturation by inhibiting both nucleation and growth. The effect of the polymers was drug dependent. The detailed characterization of polymers would allow selection of appropriate crystallization inhibitors and a planned quality control strategy for the development of supersaturable formulations. Copyright © 2013 Wiley Periodicals, Inc.

Ionization rates and profiles of electron concentration in Martian atmosphere

International Nuclear Information System (INIS)

Komitov, B.; Spasov, S.; Gogoshev, M.

1981-01-01

The ionization and vertical profiles of electron concentration in the Martian atmosphere are calculated as functions of the solar zenith angles varying from O deg to 90 deg. A neutral atmospheric model based on direct mass-spectometric measurements from the Viking-1 landing modul is employed in the calculation. The Earth data of the ionization solar flux at the same level of the solar activity and for the month of the Viking-1 measurements reduced for the Mars orbit are used. The numerical result for the photoionization rates and quasi-equilibrium electron-concentration profiles in the upper Martian atmosphere at different solar zenith angles from 0 deg to 100 deg are presented. It is shown that the maxima of both quantities decrease and move towards the upper atmosphere regions. The calculated electron density at the zenith solar angle of 40 deg are compared to Viking-1 experimental data and a good agreement is achieved

Suspended particle and drug ingredient concentrations in hospital dispensaries and implications for pharmacists' working environments.

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Inaba, Ryoichi; Hioki, Atsushi; Kondo, Yoshihiro; Nakamura, Hiroki; Nakamura, Mitsuhiro

2016-03-01

The aim of this study was to assess the present status of working environments for pharmacists, including the concentrations of suspended particles and suspended drug ingredients in dispensaries. We conducted a survey on the work processes and working environment in 15 hospital dispensaries, and measured the concentrations of suspended particles and suspended drug ingredients using digital dust counter and high-performance liquid chromatography tandem mass spectrometry (LC-MS/MS), respectively. Of 25 types of powdered drugs that were frequently handled in the 15 dispensaries surveyed, 11 could be quantitatively determined. The amounts of suspended particles were relatively high, but below the reference value, in three dispensaries without dust collectors. The sedative-hypnotic drug zopiclone was detected in the suspended particles at one dispensary that was not equipped with dust collectors, and the antipyretic and analgesic drug acetaminophen was detected in two dispensaries equipped with dust collectors. There was no correlation between the daily number of prescriptions containing powdered drugs and the concentration of suspended particles in dispensaries. On the basis of the suspended particle concentrations measured, we concluded that dust collectors were effective in these dispensaries. However, suspended drug ingredients were detected also in dispensaries with dust collectors. These results suggest that the drug dust control systems of individual dispensaries should be properly installed and managed.

Determining concentration depth profiles in fluorinated networks by means of electric force microscopy

International Nuclear Information System (INIS)

Miccio, Luis A.; Kummali, Mohammed M.; Alegria, Angel; Montemartini, Pablo E.; Oyanguren, Patricia A.; Schwartz, Gustavo A.; Colmenero, Juan

2011-01-01

By means of electric force microscopy, composition depth profiles were measured with nanometric resolution for a series of fluorinated networks. By mapping the dielectric permittivity along a line going from the surface to the bulk, we were able to experimentally access to the fluorine concentration profile. Obtained data show composition gradient lengths ranging from 30 nm to 80 nm in the near surface area for samples containing from 0.5 to 5 wt. % F, respectively. In contrast, no gradients of concentration were detected in bulk. This method has several advantages over other techniques because it allows profiling directly on a sectional cut of the sample. By combining the obtained results with x-ray photoelectron spectroscopy measurements, we were also able to quantify F/C ratio as a function of depth with nanoscale resolution.

Clinical significance of 2 h plasma concentrations of first-line anti-tuberculosis drugs

DEFF Research Database (Denmark)

Prahl, Julie B; Johansen, Isik S; Cohen, Arieh S

2014-01-01

OBJECTIVES: To study 2 h plasma concentrations of the first-line tuberculosis drugs isoniazid, rifampicin, ethambutol and pyrazinamide in a cohort of patients with tuberculosis in Denmark and to determine the relationship between the concentrations and the clinical outcome. METHODS: After 6......-207 days of treatment (median 34 days) 2 h blood samples were collected from 32 patients with active tuberculosis and from three patients receiving prophylactic treatment. Plasma concentrations were determined using LC-MS/MS. Normal ranges were obtained from the literature. Clinical charts were reviewed...... failure occurred more frequently when the concentrations of isoniazid and rifampicin were both below the normal ranges (P = 0.013) and even more frequently when they were below the median 2 h drug concentrations obtained in the study (P = 0.005). CONCLUSIONS: At 2 h, plasma concentrations of isoniazid...

Influence of drug concentration on the diffusion parameters of caffeine

Science.gov (United States)

Mustapha, R.Ben; Lafforgue, C.; Fenina, N.; Marty, J.P.

2011-01-01

Background and Objectives: In the fields of the pharmaceutical and cosmetic industries and in toxicology, the study of the skin penetration of molecules is very interesting. Various studies have considered the impact of different physicochemical drug characteristics, skin thickness, and formulations, on the transition from the surface of the skin to the underlying tissues or to the systemic circulation; however, the influence of drug concentration on the permeation flux of molecules has rarely been raised. Our study aims to discover the influence of caffeine concentration in a formulation on the percutaneous penetration from gels, as a result of different dose applications to polysulfate membrane and human skin. Materials and Methods: For this purpose, three identical base gels were used at 1, 3, and 5% of caffeine, to evaluate the effect of the concentration of caffeine on in vitro release through the synthetic membrane and ex vivo permeation through the human skin, using diffusion FranzTM cells. Results: The diffusion through the epidermal tissue was significantly slower than through the synthetic membrane, which recorded an increase of flux with an increase in the concentration of caffeine. The skin permeation study showed that diffusion depended not only on the concentration, but also on the deposited amount of gel. Nevertheless, for the same amount of caffeine applied, the flux was more significant from the less concentrated gel. Conclusion: Among all the different concentrations of caffeine examined, 1% gel of caffeine applied at 5 mg / cm2 showed the highest absorption characteristics across human skin. PMID:21572649

Sodium lauryl sulfate impedes drug release from zinc-crosslinked alginate beads: switching from enteric coating release into biphasic profiles.

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Taha, Mutasem O; Nasser, Wissam; Ardakani, Adel; Alkhatib, Hatim S

2008-02-28

The aim of this research is to investigate the effects of sodium lauryl sulfate (SLS) on ionotropically cross-linked alginate beads. Different levels of SLS were mixed with sodium alginate and chlorpheniramine maleate (as loaded model drug). The resulting viscous solutions were dropped onto aqueous solutions of zinc or calcium ions for ionotropic curing. The generated beads were assessed by their drug releasing profiles, infrared and differential scanning colorimetery (DSC) traits. SLS was found to exert profound concentration-dependent impacts on the characteristics of zinc-crosslinked alginate beads such that moderate modifications in the levels of SLS switched drug release from enteric coating-like behavior to a biphasic release modifiable to sustained-release by the addition of minute amounts of xanthan gum. Calcium cross-linking failed to reproduce the same behavior, probably due to the mainly ionic nature of calcium-carboxylate bonds compared to the coordinate character of their zinc-carboxylate counterparts. Apparently, moderate levels of SLS repel water penetration into the beads, and therefore minimize chlorpheniramine release. However, higher SLS levels seem to discourage polymeric cross-linking and therefore allow biphasic drug release.

How good are publicly available web services that predict bioactivity profiles for drug repurposing?

Science.gov (United States)

Murtazalieva, K A; Druzhilovskiy, D S; Goel, R K; Sastry, G N; Poroikov, V V

2017-10-01

Drug repurposing provides a non-laborious and less expensive way for finding new human medicines. Computational assessment of bioactivity profiles shed light on the hidden pharmacological potential of the launched drugs. Currently, several freely available computational tools are available via the Internet, which predict multitarget profiles of drug-like compounds. They are based on chemical similarity assessment (ChemProt, SuperPred, SEA, SwissTargetPrediction and TargetHunter) or machine learning methods (ChemProt and PASS). To compare their performance, this study has created two evaluation sets, consisting of (1) 50 well-known repositioned drugs and (2) 12 drugs recently patented for new indications. In the first set, sensitivity values varied from 0.64 (TarPred) to 1.00 (PASS Online) for the initial indications and from 0.64 (TarPred) to 0.98 (PASS Online) for the repurposed indications. In the second set, sensitivity values varied from 0.08 (SuperPred) to 1.00 (PASS Online) for the initial indications and from 0.00 (SuperPred) to 1.00 (PASS Online) for the repurposed indications. Thus, this analysis demonstrated that the performance of machine learning methods surpassed those of chemical similarity assessments, particularly in the case of novel repurposed indications.

Effect of cyclodextrin concentration on the oral bioavailability of danazol and cinnarizine in rats

DEFF Research Database (Denmark)

Holm, Rene; Olesen, Niels Erik; Andersen Hartvig, Rune

2016-01-01

Cyclodextrins (CDs) are frequently used as an excipient to enhance the intestinal drug absorption of compounds with a low aqueous solubility. However, there exists an intricate interplay between opposing effects that determine the optimal dosing criterion. These opposing effects are the benefits...... of circumventing the dissolution time required to dissolve the non-absorbable drug particles in the intestine versus the disadvantage of decreasing the concentration of the drug available to permeate the intestinal membrane if excessive CD concentrations are used. This study investigated whether...... that surplus CD concentrations can have a major effect on the pharmacokinetic profile of one compound and a minor effect on the pharmacokinetic profile of another. This suggests that there are some compounds where the CD excipient should be used with care and others where it can be used without major concerns....

Stability and in vitro release profile of enalapril maleate from different commercially available tablets: possible therapeutic implications.

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Lima, Dione Marçal; dos Santos, Leandro Dias; Lima, Eliana Martins

2008-08-05

Stability of enalapril maleate formulations can be affected when the product is exposed to higher temperature and humidity, with the formation of two main degradation products: enalaprilat and a diketopiperazine derivative. In this work, stability and drug release profiles of 20 mg enalapril maleate tablets (reference, generic and similar products) were evaluated. After 180 days of the accelerated stability testing, most products did not exhibit the specified amount of drug. Additionally, drug release profiles were markedly different from that of the reference product, mainly due to drug degradation. Changes in drug concentration and drug release profile of enalapril formulations are strong indicators of a compromised bioavailability, with possible interferences on the therapeutic response for this drug.

Study on characteristics of fluorine concentration profiles in fluorosis sheep teeth and bones

International Nuclear Information System (INIS)

Song Shizhan; Shui Yongqing; Wang Lianbin; Yang Huazhong; Zhai Xujiu; Wang Yuwen; Lei Guilin

1990-01-01

The deep-ward fluorine concentration profiles in fluorosis sheep teeth and bones were determined through 19 F(p, αγ) 16 O reaction with proton energy 3.2 MeV. The profiles show a diffusion characteristic, indicating that the fluorine ion diffusion may be one of the important factors that brought forth pathological changes of livestock teeth and bones

The Impact of Herbal Drug Use on Adverse Drug Reaction Profiles of Patients on Antiretroviral Therapy in Zimbabwe

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Tinashe Mudzviti

2012-01-01

Full Text Available Background. The main objective was to determine the impact of herbal drug use on adverse drug reactions in patients on antiretroviral therapy (ART. Methodology. Patients receiving first-line ART from the national roll-out program participated in this cross-sectional study. Participants were interviewed and a data collection sheet was used to collect information from the corresponding medical record. Results. The majority (98.2% of participants were using at least one herbal drug together with ART. The most common herbal remedies used were Allium Sativum (72.7%, Bidens pilosa (66.0%, Eucalyptus globulus (52.3%, Moringa oleifera (44.1%, Lippia javanica (36.3%, and Peltoforum africanum (34.3%. Two indigenous herbs, Musakavakadzi (OR=0.25; 95% CI 0.076–0.828 and Peltoforum africanum (OR=0.495; 95% CI 0.292–0.839 reduced the occurrence of adverse drug events. Conclusions. The use of herbal drugs is high in the HIV-infected population and there is need for pharmacovigilance programs to recognize the role they play in altering ADR profiles.

Enantiomeric profiling of chiral illicit drugs in a pan-European study

DEFF Research Database (Denmark)

Castrignanò, Erika; Yang, Zhugen; Bade, Richard

2018-01-01

The aim of this paper is to present the first study on spatial and temporal variation in the enantiomeric profile of chiral drugs in eight European cities. Wastewater-based epidemiology (WBE) and enantioselective analysis were combined to evaluate trends in illicit drug use in the context....... High loads of racemic methamphetamine were detected in Oslo (EF = 0.49 ± 0.02). This is in contrast to other European cities where S-(+)-methamphetamine was the predominant enantiomer. This indicates different methods of methamphetamine synthesis and/or trafficking routes in Oslo, compared...... with the other cities tested. An enrichment of MDMA with the R-(−)-enantiomer was observed in European wastewaters indicating MDMA consumption rather than disposal of unused drug. MDA's chiral signature indicated its enrichment with the S-(+)-enantiomer, which confirms its origin from MDMA metabolism in humans...

Measure of hydrogen concentration profile in materials by resonant nuclear reactions

International Nuclear Information System (INIS)

Livi, R.P.; Zawislak, F.C.; Acquadro, J.C.

1986-01-01

The technique for determining the profile of hydrogen concentration in proximities of the surface of materials, is presented. The preliminary measurements were done, using the Pelletron accelerator at Sao Paulo University (USP), in Brazil, for the resonant-nuclear reaction 1 H( 19 F, α γ) 16 O. By using this reaction the technique is sensitive for concentrations above 500 ppm, which could be reduced to 100 ppm through special shieldings and other techniques to reduce the background radiation. (M.C.K.) [pt

Design and Characterization of a Silk-Fibroin-Based Drug Delivery Platform Using Naproxen as a Model Drug

Directory of Open Access Journals (Sweden)

Tatyana Dyakonov

2012-01-01

Full Text Available The objective of this proof-of-concept study was to develop a platform for controlled drug delivery based on silk fibroin (SF and to explore the feasibility of using SF in oral drug delivery. The SF-containing matrixes were prepared via spray-drying and film casting, and the release profile of the model drug naproxen sodium was evaluated. Attenuated total reflectance Fourier transform infrared spectroscopy (FTIR has been used to observe conformational changes in SF- and drug-containing compositions. SF-based films, spray-dried microparticles, and matrixes loaded with naproxen were prepared. Both FTIR spectra and in vitro dissolution data demonstrated that SF β-sheet conformation regulates the release profile of naproxen. The controlled release characteristics of the SF-containing compositions were evaluated as a function of SF concentration, temperature, and exposure to dehydrating solvents. The results suggest that SF may be an attractive polymer for use in controlled drug delivery systems.

Hydrogen concentration profiles and chemical bonding in silicon nitride

International Nuclear Information System (INIS)

Peercy, P.S.; Stein, H.J.; Doyle, B.L.; Picraux, S.T.

1978-01-01

The complementary technique of nuclear reaction analysis and infrared absorption were used to study the concentration profile and chemical bonding of hydrogen in silicon nitride for different preparation and annealing conditions. Silicon nitride prepared by chemical vapor deposition from ammonia-silane mixtures is shown to have hydrogen concentrations of 8.1 and 6.5 at.% for deposition temperatures of 750 and 900 0 C, respectively. Plasma deposition at 300 0 C from these gases results in hydrogen concentrations of approximately 22 at.%. Comparison of nuclear reaction analysis and infrared absorption measurements after isothermal annealing shows that all of the hydrogen retained in the films remains bonded to either silicon or nitrogen and that hydrogen release from the material on annealing is governed by various trap energies involving at least two N-H and one Si-H trap. Reasonable estimates of the hydrogen release rates can be made from the effective diffusion coefficient obtained from measurements of hydrogen migration in hydrogen implanted and annealed films

Behavioural profile of drug users attending public drug-treatment centres in Sicily: the role of social context

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Francesco Vitale

2007-12-01

Full Text Available

Objective: Investigations of injecting drug users (IDUs have suggested that the social context may influence high-risk behaviours in this population. The aim of this study was to describe knowledge, attitudes and behaviours of IDUs attending public drug-treatment centres in our area.

Study design and methods: A cross-sectional survey was conducted between July 2002 and February 2004, enrolling 607 drug users attending four public drug-treatment centres in the Palermo area. Two of them were located inside the urban area, whereas the other two were in rural districts near the city. All participants answered an anonymous questionnaire concerning social and demographic characteristic and potential high-risk behaviours.

Results: IDUs living in urban context have a higher educational level, higher number of sexual partners, as well as a lower prevalence of exchanging sex for drugs. Conversely, IDUs living in suburban/rural context are less likely to share syringes and more likely to have used light drugs in the past. Suburban/rural IDUs drink more alcohol but smoke less cigarettes/day, although both groups are strong smokers.

Conclusions: The results suggest that public drug-treatment centres should take in consideration the adoption of specific programs targeting specific groups, in line with the profile and needs of the subjects in each context in order to promote approaches leading to risk reduction.

Safety profiles of anti-VEGF drugs: bevacizumab, ranibizumab, aflibercept and ziv-aflibercept on human retinal pigment epithelium cells in culture

Science.gov (United States)

Malik, Deepika; Tarek, Mohamed; Caceres del Carpio, Javier; Ramirez, Claudio; Boyer, David; Kenney, M Cristina; Kuppermann, Baruch D

2014-01-01

Purpose To compare the safety profiles of antivascular endothelial growth factor (VEGF) drugs ranibizumab, bevacizumab, aflibercept and ziv-aflibercept on retinal pigment epithelium cells in culture. Methods Human retinal pigment epithelium cells (ARPE-19) were exposed for 24 h to four anti-VEGF drugs at 1/2×, 1×, 2× and 10× clinical concentrations. Cell viability and mitochondrial membrane potential assay were performed to evaluate early apoptotic changes and rate of overall cell death. Results Cell viability decreased at 10× concentrations in bevacizumab (82.38%, p=0.0001), aflibercept (82.68%, p=0.0002) and ziv-aflibercept (77.25%, p<0.0001), but not at lower concentrations. However, no changes were seen in cell viability in ranibizumab-treated cells at all concentrations including 10×. Mitochondrial membrane potential was slightly decreased in 10× ranibizumab-treated cells (89.61%, p=0.0006) and 2× and 10× aflibercept-treated cells (88.76%, 81.46%; p<0.01, respectively). A larger reduction in mitochondrial membrane potential was seen at 1×, 2× and 10× concentrations of bevacizumab (86.53%, 74.38%, 66.67%; p<0.01) and ziv-aflibercept (73.50%, 64.83% and 49.65% p<0.01) suggestive of early apoptosis at lower doses, including the clinical doses. Conclusions At clinical doses, neither ranibizumab nor aflibercept produced evidence of mitochondrial toxicity or cell death. However, bevacizumab and ziv-aflibercept showed mild mitochondrial toxicity at clinically relevant doses. PMID:24836865

Concentrations and congener profiles of chlorinated paraffins in domestic polymeric products in China.

Science.gov (United States)

Wang, Chu; Gao, Wei; Liang, Yong; Wang, Yawei; Jiang, Guibin

2018-03-21

Chlorinated paraffins (CPs) are widely used in domestic polymeric products as plasticizers and fire retardants. In this study, concentrations and congener profiles of short-chain and medium-chain chlorinated paraffins (SCCPs and MCCPs) were investigated in domestic polymeric products, including plastics, rubber and food packaging in China. The average concentrations of SCCPs in polyethylene terephthalate (PET), polypropylene (PP), polyethylene (PE) and food packaging were 234, 3968, 150 and 188 ng/g, respectively and the corresponding average concentrations of MCCPs in these samples were 37.4, 2537, 208 and 644 ng/g, respectively. The concentrations of CPs in rubber and polyvinylchloride (PVC) were significantly higher than in other matrices. The highest concentrations of SCCPs and MCCPs were found in a PVC cable sheath with 191 mg/g and 145 mg/g, respectively. Congener group profiles analysis indicated C 11 - and C 13 -congener groups were predominant in carbon homologues of SCCPs, and C 14 -congener groups were predominant in MCCPs. High levels of SCCPs and MCCPs in domestic polymeric products implied that they might be a significant source to the environment and human exposure. Copyright © 2018. Published by Elsevier Ltd.

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

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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

Fabrication of Graded Porous and Skin-Core Structure RDX-Based Propellants via Supercritical CO2 Concentration Profile

Science.gov (United States)

Yang, Weitao; Li, Yuxiang; Ying, Sanjiu

2015-04-01

A fabrication process to produce graded porous and skin-core structure propellants via supercritical CO2 concentration profile is reported in this article. It utilizes a partial gas saturation technique to obtain nonequilibrium gas concentration profiles in propellants. Once foamed, the propellant obtains a graded porous or skin-pore structure. This fabrication method was studied with RDX(Hexogen)-based propellant under an SC-CO2 saturation condition. The principle was analyzed and the one-dimensional diffusion model was employed to estimate the gas diffusion coefficient and to predict the gas concentration profiles inside the propellant. Scanning electron microscopy images were used to analyze the effects of partial saturation on the inner structure. The results also suggested that the sorption time and desorption time played an important role in gas profile generation and controlled the inner structure of propellants.

The importance of Pharmacovigilance for the drug safety: Focus on cardiovascular profile of incretin-based therapy.

Science.gov (United States)

Sportiello, Liberata; Rafaniello, Concetta; Scavone, Cristina; Vitale, Cristiana; Rossi, Francesco; Capuano, Annalisa

2016-01-01

With the recent introduction of the new European Pharmacovigilance legislation, all new drugs must be carefully monitored after admission on the European market, in order to assess the long safety profile. Currently, special attention is given to several hypoglycemic agents with recent market approval (agonists of glucagon-like peptide-1 [GLP-1] receptor and dipeptidyl peptidase 4 inhibitors [DPP-4i]), which act through the potentiation of incretin hormone signaling. Their inclusion in European additional monitoring is also due to safety problems, which seem to characterize their pharmacological class. In fact, these drugs initially showed a good tolerability profile with mainly gastrointestinal adverse events, low risk of hypoglycemia and minor effects on body weight. But, new concerns such as infections, pancreatitis, pancreatic cancer and above all cardiovascular events (especially risk of heart failure requiring hospitalization) are now arising. In this review, we highlighted aspects of the new Pharmacovigilance European dispositions, and then we investigated the tolerability profile of incretin-based therapies, in particular DPP-4 inhibitors. Notably, we focused our attention on new safety concerns, which are emerging mostly in the post-marketing period, as the cardiovascular risk profile. Evidence in literature and opinions of regulatory agencies (e.g., European Medicines Agency and Food and Drug Administration) about risks of incretin-based therapies are yet controversial, and there are many open questions in particular on cancer and cardiovascular effects. Thus, it is important to continue to monitor closely the use of these drugs in clinical practice to improve the knowledge on their long-term safety and their place in diabetes therapy. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Profiles of risk: a qualitative study of injecting drug users in Tehran, Iran

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Green Traci

2006-03-01

Full Text Available Abstract Background In Iran, there are an estimated 200,000 injecting drug users (IDUs. Injecting drug use is a relatively new phenomenon for this country, where opium smoking was the predominant form of drug use for hundreds of years. As in many countries experiencing a rise in injecting drug use, HIV/AIDS in Iran is associated with the injection of drugs, accounting for transmission of more than two-thirds of HIV infections. This study aimed to: describe the range of characteristics of IDUs in Tehran, Iran's capital city; 2 examine the injecting-related HIV risk behaviors of IDUs, and 3 suggest necessary interventions to prevent HIV transmission among IDUs and their families and sex partners. Methods Using rapid assessment and response methods with a qualitative focus, six districts of Tehran were selected for study. A total of 81 key informants from different sectors and 154 IDUs were selected by purposeful, opportunistic and snowball sampling, then interviewed. Ethnographic observations were done for mapping and studying injecting-related HIV risk settings and behaviors. Modified content analysis methods were used to analyze the data and extract typologies of injecting drug users in Tehran. Results Evidence of injecting drug use and drug-related harm was found in 5 of 6 study districts. Several profiles of IDUs were identified: depending on their socioeconomic status and degree of stability, IDUs employed different injecting behaviors and syringe hygiene practices. The prevalence of sharing injection instruments ranged from 30–100%. Varied magnitudes of risk were evident among the identified IDU typologies in terms of syringe disinfection methods, level of HIV awareness, and personal hygiene exhibited. At the time of research, there were no active HIV prevention programs in existence in Tehran. Conclusion The recent rise of heroin injection in Iran is strongly associated with HIV risk. Sharing injection instruments is a common and complex

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.

Comparative study of the pharmacopeial quality and dissolution profiles of generic and other drug forms of sodium metamizole (dipyrone sold in Brazil

Directory of Open Access Journals (Sweden)

Morenna Alana Giordani

2012-08-01

Full Text Available In Brazil, in order for a pharmaceutical company to register a drug form as generic or ‘similar’ with the Brazilian food and drug agency (Anvisa, it must be proved bioequivalent to its innovatory branded form (reference drug. This requires comparative trials, carried out in conformity with official compendia (Brazilian Pharmacopeia or another officially recognized code. Additionally, according to the Anvisa resolution RDC 31/2010, the dissolution profile of the drug must be tested and compared with that of the branded reference, as a benchmark of quality. The aim of this study was to assess the quality of 500 mg sodium metamizole (dipyrone tablets produced by seven different laboratories in Brazil: three generic drugs (G1, G2, G3, three (branded similar drugs (S1, S2,S3 and their reference branded product (Novalgina®, Sanofi-Aventis, drug R. All tests were carried out by methods specified in the Brazilian Pharmacopeia 4th edition (Farmacopeia Brasileira IV. The following tests were performed: uniformity of mass, friability, disintegration time, hardness, assay, uniformity of dosage units, salicylic acid limit assay, dissolution and identification. The dissolution profile was also recorded, as recommended in RDC 31/2010. Whereas every sample was approved in all the Farmacopeia Brasileira IV tests, the results in the dissolution profile test showed that four of the test drugs (G1, G2, S1 and S2 were notpharmaceutically equivalent to drug R. Thus, only drugs G3 and S3 showed dissolution profiles similar to that of drug R and the other four drugs could not be considered equivalent to it and were not approved.

Exhaled methane concentration profiles during exercise on an ergometer

Science.gov (United States)

Szabó, A; Ruzsanyi, V; Unterkofler, K; Mohácsi, Á; Tuboly, E; Boros, M; Szabó, G; Hinterhuber, H; Amann, A

2016-01-01

Exhaled methane concentration measurements are extensively used in medical investigation of certain gastrointestinal conditions. However, the dynamics of endogenous methane release is largely unknown. Breath methane profiles during ergometer tests were measured by means of a photoacoustic spectroscopy based sensor. Five methane-producing volunteers (with exhaled methane level being at least 1 ppm higher than room air) were measured. The experimental protocol consisted of 5 min rest—15 min pedalling (at a workload of 75 W)—5 min rest. In addition, hemodynamic and respiratory parameters were determined and compared to the estimated alveolar methane concentration. The alveolar breath methane level decreased considerably, by a factor of 3–4 within 1.5 min, while the estimated ventilation-perfusion ratio increased by a factor of 2–3. Mean pre-exercise and exercise methane concentrations were 11.4 ppm (SD:7.3) and 2.8 ppm (SD:1.9), respectively. The changes can be described by the high sensitivity of exhaled methane to ventilationperfusion ratio and are in line with the Farhi equation. PMID:25749807

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.

In silico drug metabolism and pharmacokinetic profiles of natural products from medicinal plants in the Congo basin.

Science.gov (United States)

Ntie-Kang, Fidele; Lifongo, Lydia L; Mbah, James A; Owono Owono, Luc C; Megnassan, Eugene; Mbaze, Luc Meva'a; Judson, Philip N; Sippl, Wolfgang; Efange, Simon M N

2013-01-01

Drug metabolism and pharmacokinetics (DMPK) assessment has come to occupy a place of interest during the early stages of drug discovery today. The use of computer modelling to predict the DMPK and toxicity properties of a natural product library derived from medicinal plants from Central Africa (named ConMedNP). Material from some of the plant sources are currently employed in African Traditional Medicine. Computer-based methods are slowly gaining ground in this area and are often used as preliminary criteria for the elimination of compounds likely to present uninteresting pharmacokinetic profiles and unacceptable levels of toxicity from the list of potential drug candidates, hence cutting down the cost of discovery of a drug. In the present study, we present an in silico assessment of the DMPK and toxicity profile of a natural product library containing ~3,200 compounds, derived from 379 species of medicinal plants from 10 countries in the Congo Basin forests and savannas, which have been published in the literature. In this analysis, we have used 46 computed physico-chemical properties or molecular descriptors to predict the absorption, distribution, metabolism and elimination and toxicity (ADMET) of the compounds. This survey demonstrated that about 45% of the compounds within the ConMedNP compound library are compliant, having properties which fall within the range of ADME properties of 95% of currently known drugs, while about 69% of the compounds have ≤ 2 violations. Moreover, about 73% of the compounds within the corresponding "drug-like" subset showed compliance. In addition to the verified levels of "drug-likeness", diversity and the wide range of measured biological activities, the compounds from medicinal plants in Central Africa show interesting DMPK profiles and hence could represent an important starting point for hit/lead discovery.

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.

Dynamic changes in amino acid concentration profiles in patients with sepsis.

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Longxiang Su

Full Text Available The goal of this work was to explore the dynamic concentration profiles of 42 amino acids and the significance of these profiles in relation to sepsis, with the aim of providing guidance for clinical therapies.Thirty-five critically ill patients with sepsis were included. These patients were further divided into sepsis (12 cases and severe sepsis (23 cases groups or survivor (20 cases and non-survivor (15 cases groups. Serum samples from the patients were collected on days 1, 3, 5, 7, 10, and 14 following intensive care unit (ICU admission, and the serum concentrations of 42 amino acids were measured.The metabolic spectrum of the amino acids changed dramatically in patients with sepsis. As the disease progressed further or with poor prognosis, the levels of the different amino acids gradually increased, decreased, or fluctuated over time. The concentrations of sulfur-containing amino acids (SAAs, especially taurine, decreased significantly as the severity of sepsis worsened or with poor prognosis of the patient. The serum concentrations of SAAs, especially taurine, exhibited weak negative correlations with the Sequential Organ Failure Assessment (SOFA (r=-0.319 and Acute Physiology and Chronic Health Evaluation (APACHE II (r=-0.325 scores. The areas under the receiver operating characteristic curves of cystine, taurine, and SAA levels and the SOFA and APACHE II scores, which denoted disease prognosis, were 0.623, 0.674, 0.678, 0.86, and 0.857, respectively.Critically ill patients with disorders of amino acid metabolism, especially of SAAs such as cystine and taurine, may provide an indicator of the need for the nutritional support of sepsis in the clinic.ClinicalTrial.gov identifier NCT01818830.

3D printing of tablets containing multiple drugs with defined release profiles.

Science.gov (United States)

Khaled, Shaban A; Burley, Jonathan C; Alexander, Morgan R; Yang, Jing; Roberts, Clive J

2015-10-30

We have employed three-dimensional (3D) extrusion-based printing as a medicine manufacturing technique for the production of multi-active tablets with well-defined and separate controlled release profiles for three different drugs. This 'polypill' made by a 3D additive manufacture technique demonstrates that complex medication regimes can be combined in a single tablet and that it is viable to formulate and 'dial up' this single tablet for the particular needs of an individual. The tablets used to illustrate this concept incorporate an osmotic pump with the drug captopril and sustained release compartments with the drugs nifedipine and glipizide. This combination of medicines could potentially be used to treat diabetics suffering from hypertension. The room temperature extrusion process used to print the formulations used excipients commonly employed in the pharmaceutical industry. Attenuated Total Reflectance Fourier Transform Infrared Spectroscopy (ATR-FTIR) and X-ray powder diffraction (XRPD) were used to assess drug-excipient interaction. The printed formulations were evaluated for drug release using USP dissolution testing. We found that the captopril portion showed the intended zero order drug release of an osmotic pump and noted that the nifedipine and glipizide portions showed either first order release or Korsmeyer-Peppas release kinetics dependent upon the active/excipient ratio used. Copyright © 2015. Published by Elsevier B.V.

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.

Retrieval of vertical concentration profiles from OSIRIS UV-visible limb spectra

International Nuclear Information System (INIS)

Strong, K.; Joseph, B.M.; Dosanjh, R.; McDade, I.C.; McLinden, C.A.; McConnell, J.C.; Stegman, J.; Murtagh, D.P.; Llewellyn, E.J.

2002-01-01

The OSIRIS instrument, launched on the Odin satellite in February 2001, includes an optical spectrograph that will record UV-visible spectra of sunlight scattered from the limb over a range of tangent heights. These spectra will be used to retrieve vertical profiles of ozone, NO 2 , OC1O, BrO, NO 3 , O 2 , and aerosols, for the investigation of both stratospheric and mesospheric processes, particularly those related to ozone chemistry. In this work, the retrieval of vertical profiles of trace-gas concentrations from OSIRIS limb-radiance spectra is described. A forward model has been developed to simulate these spectra, and it consists of a single-scattering radiative-transfer model with partial spherical geometry, trace-gas absorption, Mic scattering by stratospheric aerosols, a Lambertian surface contribution, and OSIRIS instrument response and noise. Number-density profiles have been retrieved by using optimal estimation (OE) to combine an a priori profile with the information from sets of synthetic 'measurements'. For ozone, OE has been applied both to limb radiances at one or more discrete wavelengths and to effective-column abundances retrieved over a broad spectral range using differential optical absorption spectroscopy (DOAS). The results suggest that, between 15 and 35 km, ozone number densities can be retrieved to 10% accuracy or better on 1 and 2 km grids and to 5% on a 5 km grid. The combined DOAS-OE approach has also been used to retrieve NO 2 number densities, yielding 13% accuracy or better for altitudes from 18 to 36 km (in a 2 km grid. Differential optical absorption spectroscopy - optimal estimation retrievals of BrO and OC1O reproduce the true profiles above 15 km in the noise-free case, but the quality of the retrievals is highly sensitive to noise on the simulated OSIRIS spectra because of the weak absorption of these two gases. The development of inversion methods for the retrieval of trace-gas concentrations from OSIRIS spectra is continuing

Molar concentration-depth profiles at the solution surface of a cationic surfactant reconstructed with angle resolved X-ray photoelectron spectroscopy

International Nuclear Information System (INIS)

Wang Chuangye; Morgner, Harald

2011-01-01

In the current work, we first reconstructed the molar fraction-depth profiles of cation and anion near the surface of tetrabutylammonium iodide dissolved in formamide by a refined calculation procedure, based on angle resolved X-ray photoelectron spectroscopy experiments. In this calculation procedure, both the transmission functions of the core levels and the inelastic mean free paths of the photoelectrons have been taken into account. We have evaluated the partial molar volumes of surfactant and solvent by the densities of such solutions with different bulk concentrations. With those partial molar volumes, the molar concentration-depth profiles of tetrabutylammonium ion and iodide ion were determined. The surface excesses of both surfactant ions were then achieved directly by integrating these depth profiles. The anionic molar concentration-depth profiles and surface excesses have been compared with their counterparts determined by neutral impact ion scattering spectroscopy. The comparisons exhibit good agreements. Being capable of determining molar concentration-depth profiles of surfactant ions by core levels with different kinetic energies may extend the applicable range of ARXPS in investigating solution surfaces.

Profile of male Brazilian injecting drug users who have sex with men

Directory of Open Access Journals (Sweden)

Ferreira Aline Dayrell

2006-01-01

Full Text Available This study aims to characterize the profile of male injecting drug users who have sex with other men (MSM IDUs recruited through a cross-sectional multi-city survey (AjUDE-Brasil II Project in six Brazilian cities, in 2000-2001. MSM IDUs were compared to other male IDUs using bivariate and multivariate procedures (logistic regression and answer tree analysis with the CHAID algorithm. Among the 709 male IDUs, 187 (26.4% reported ever having had sex with other men, while only 37 reported sex with other men in the previous six months. MSM IDUs were more likely to be unemployed (OR = 2.3, to have injected tranquilizers (OR = 3.6, and to be HIV-seropositive (OR = 2.1, compared to other male IDUs. Male same-sex relations in this subgroup appear to be associated with strategies to finance drug consuming habits, including sex for drugs with occasional female partners or obtaining injection paraphernalia from occasional sex partners. Further studies should focus on this especially vulnerable subgroup of IDUs, due to the bidirectional and complex interrelationships between their drug injecting habits and sexual risk behaviors.

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...

Artificial neural networks to evaluate the boron concentration decreasing profile in Blood-BPA samples of BNCT patients

Energy Technology Data Exchange (ETDEWEB)

Garcia-Reiriz, Alejandro, E-mail: garciareiriz@gmail.com [Department of Analytical Chemistry, Faculty of Biochemical and Pharmaceutical Sciences, National University of Rosario, Rosario Institute of Chemistry (IQUIR-CONICET), Suipacha 531, Rosario S2002LRK (Argentina); Magallanes, Jorge [Comision Nacional de Energia Atomica, Av. Gral. Paz 1499, San Martin, B1650KNA, Buenos Aires (Argentina); Zupan, Jure [National Institute of Chemistry, Hajdrihova 19, SLO-1000 Ljubljana, Eslovenia (Slovenia); Liberman, Sara [Comision Nacional de Energia Atomica, Av. Gral. Paz 1499, San Martin, B1650KNA, Buenos Aires (Argentina)

2011-12-15

For the prediction of decay concentration profiles of the p-boronophenylalanine (BPA) in blood during BNCT treatment, a method is suggested based on Kohonen neural networks. The results of a model trained with the concentration profiles from the literature are described. The prediction of the model was validated by the leave-one-out method. Its robustness shows that it is mostly independent on small variations. The ability to fit retrospective experimental data shows an uncertainty lower than the two compartment model used previously. - Highlights: Black-Right-Pointing-Pointer We predicted decaying concentration profiles of BPA in blood during BNCT therapy. Black-Right-Pointing-Pointer Is suggested a method based on Kohonen neural networks. Black-Right-Pointing-Pointer The results show that it is very robust and mostly independent of small variations. Black-Right-Pointing-Pointer It has a better ability to fit retrospective experimental data. Black-Right-Pointing-Pointer The model could be progressively improved by adding new data to the training matrix.

Artificial neural networks to evaluate the boron concentration decreasing profile in Blood-BPA samples of BNCT patients

International Nuclear Information System (INIS)

García-Reiriz, Alejandro; Magallanes, Jorge; Zupan, Jure; Líberman, Sara

2011-01-01

For the prediction of decay concentration profiles of the p-boronophenylalanine (BPA) in blood during BNCT treatment, a method is suggested based on Kohonen neural networks. The results of a model trained with the concentration profiles from the literature are described. The prediction of the model was validated by the leave-one-out method. Its robustness shows that it is mostly independent on small variations. The ability to fit retrospective experimental data shows an uncertainty lower than the two compartment model used previously. - Highlights: ► We predicted decaying concentration profiles of BPA in blood during BNCT therapy. ► Is suggested a method based on Kohonen neural networks. ► The results show that it is very robust and mostly independent of small variations. ► It has a better ability to fit retrospective experimental data. ► The model could be progressively improved by adding new data to the training matrix.

Simple strategy to assess linezolid exposure in patients with multi-drug-resistant and extensively-drug-resistant tuberculosis.

Science.gov (United States)

Kamp, Jasper; Bolhuis, Mathieu S; Tiberi, Simon; Akkerman, Onno W; Centis, Rosella; de Lange, Wiel C; Kosterink, Jos G; van der Werf, Tjip S; Migliori, Giovanni B; Alffenaar, Jan-Willem C

2017-06-01

Linezolid is used increasingly for the treatment of multi-drug-resistant (MDR) and extensively-drug-resistant (XDR) tuberculosis (TB). However, linezolid can cause severe adverse events, such as peripheral and optical neuropathy or thrombocytopenia related to higher drug exposure. This study aimed to develop a population pharmacokinetic model to predict the area under the concentration curve (AUC) for linezolid using a limited number of blood samples. Data from patients with MDR-/XDR-TB who received linezolid and therapeutic drug monitoring as part of their TB treatment were used. Mw\\Pharm 3.82 (Mediware, Zuidhorn, The Netherlands) was used to develop a population pharmacokinetic model and limited sampling strategy (LSS) for linezolid. LSS was evaluated over a time span of 6 h. Blood sampling directly before linezolid administration and 2 h after linezolid administration were considered to be the most clinically relevant sampling points. The model and LSS were evaluated by analysing the correlation between AUC 12h,observed and AUC 12h,estimated . In addition, LSS was validated with an external group of patients with MDR-/XDR-TB from Sondalo, Italy. Fifty-two pharmacokinetic profiles were used to develop the model. Thirty-three profiles with a 300 mg dosing regimen and 19 profiles with a 600 mg dosing regimen were obtained. Model validation showed prediction bias of 0.1% and r 2 of 0.99. Evaluation of the most clinically relevant LSS showed prediction bias of 4.8% and r 2 of 0.97. The root mean square error corresponding to the most relevant LSS was 6.07%. The developed LSS could be used to enable concentration-guided dosing of linezolid. Copyright © 2017 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.

[Drug registries: post-marketing evaluation of the benefit-risk profile and promotion of appropriateness. The regional point of view].

Science.gov (United States)

Martelli, Luisa; Venegoni, Mauro

2013-06-01

Italian Regions and the Italian regulatory agency share a common interest in promoting the appropriateness of drug use, containing drug expenditure and acquiring additional evidence on the effectiveness and safety of drugs. Drug registries can help attaining these objectives. Specifically, the registries implemented in Italy were able to cover the first two objectives, whereas some critical issues were raised on the third one. For instance, the data recorded in the registries are not available at regional level to conduct safety and effectiveness investigations. This is a paradox, when considering that drugs included in the registries have a risk-benefit profile that is only partially defined at the moment of marketing. Currently, researchers and regions can conduct epidemiological research (cohort and case control studies), on the basis of record-linkage procedures, on all drugs prescribed in general practice (which are older drugs with a better defined risk-benefit profile). The expected outcomes of registries should be more clearly defined: when the main aim is to promote appropriateness, the recording of only a very limited amount of data should be required (to avoid a bureaucratic burden on clinicians).The Italian centers of the ENCePP network might play an important role in planning and conducting drug registries: through the presence in the steering committees of the registries, and in conducting epidemiological studies that make the most of this powerful instrument.

The future of drug discovery: enabling technologies for enhancing lead characterization and profiling therapeutic potential.

Science.gov (United States)

Janero, David R

2014-08-01

Technology often serves as a handmaiden and catalyst of invention. The discovery of safe, effective medications depends critically upon experimental approaches capable of providing high-impact information on the biological effects of drug candidates early in the discovery pipeline. This information can enable reliable lead identification, pharmacological compound differentiation and successful translation of research output into clinically useful therapeutics. The shallow preclinical profiling of candidate compounds promulgates a minimalistic understanding of their biological effects and undermines the level of value creation necessary for finding quality leads worth moving forward within the development pipeline with efficiency and prognostic reliability sufficient to help remediate the current pharma-industry productivity drought. Three specific technologies discussed herein, in addition to experimental areas intimately associated with contemporary drug discovery, appear to hold particular promise for strengthening the preclinical valuation of drug candidates by deepening lead characterization. These are: i) hydrogen-deuterium exchange mass spectrometry for characterizing structural and ligand-interaction dynamics of disease-relevant proteins; ii) activity-based chemoproteomics for profiling the functional diversity of mammalian proteomes; and iii) nuclease-mediated precision gene editing for developing more translatable cellular and in vivo models of human diseases. When applied in an informed manner congruent with the clinical understanding of disease processes, technologies such as these that span levels of biological organization can serve as valuable enablers of drug discovery and potentially contribute to reducing the current, unacceptably high rates of compound clinical failure.

The Drug Release Profile from Calcium-induced Alginate Gel Beads Coated with an Alginate Hydrolysate

Directory of Open Access Journals (Sweden)

Susumu Kawashima

2007-11-01

Full Text Available Calcium-induced alginate gel bead (Alg-Ca coated with an alginate hydrolysate(Alg, e.g. the guluronic acid block (GB was prepared and the model drug, hydrocortisonerelease profiles were investigated under simulated gastrointestinal conditions. Theirmolecular weights were one sixth or one tenth that of Alg and the diffraction patterns of thehydrolysates resembled that of Alg. The drug release rate from Alg-Ca coated with GBapparently lowered than that of Alg-Ca (coating-free in the gastric juice (pH1.2. And thecoating did not resist the disintegration of Alg-Ca in the intestinal juice (pH 6.8 and thegel erosion accelerated the drug release. On the other hand, for the coated Alg-Cacontaining chitosan, the drug release showed zero-order kinetics without rapid erosion ofAlg-Ca. The drug release rate from Alg-Ca was able to be controlled by the coating andmodifying the composition of the gel matrix.

Global proteomics profiling improves drug sensitivity prediction: results from a multi-omics, pan-cancer modeling approach.

Science.gov (United States)

Ali, Mehreen; Khan, Suleiman A; Wennerberg, Krister; Aittokallio, Tero

2018-04-15

Proteomics profiling is increasingly being used for molecular stratification of cancer patients and cell-line panels. However, systematic assessment of the predictive power of large-scale proteomic technologies across various drug classes and cancer types is currently lacking. To that end, we carried out the first pan-cancer, multi-omics comparative analysis of the relative performance of two proteomic technologies, targeted reverse phase protein array (RPPA) and global mass spectrometry (MS), in terms of their accuracy for predicting the sensitivity of cancer cells to both cytotoxic chemotherapeutics and molecularly targeted anticancer compounds. Our results in two cell-line panels demonstrate how MS profiling improves drug response predictions beyond that of the RPPA or the other omics profiles when used alone. However, frequent missing MS data values complicate its use in predictive modeling and required additional filtering, such as focusing on completely measured or known oncoproteins, to obtain maximal predictive performance. Rather strikingly, the two proteomics profiles provided complementary predictive signal both for the cytotoxic and targeted compounds. Further, information about the cellular-abundance of primary target proteins was found critical for predicting the response of targeted compounds, although the non-target features also contributed significantly to the predictive power. The clinical relevance of the selected protein markers was confirmed in cancer patient data. These results provide novel insights into the relative performance and optimal use of the widely applied proteomic technologies, MS and RPPA, which should prove useful in translational applications, such as defining the best combination of omics technologies and marker panels for understanding and predicting drug sensitivities in cancer patients. Processed datasets, R as well as Matlab implementations of the methods are available at https://github.com/mehr-een/bemkl-rbps. mehreen

Computational Analysis of Epidermal Growth Factor Receptor Mutations Predicts Differential Drug Sensitivity Profiles toward Kinase Inhibitors.

Science.gov (United States)

Akula, Sravani; Kamasani, Swapna; Sivan, Sree Kanth; Manga, Vijjulatha; Vudem, Dashavantha Reddy; Kancha, Rama Krishna

2018-05-01

A significant proportion of patients with lung cancer carry mutations in the EGFR kinase domain. The presence of a deletion mutation in exon 19 or L858R point mutation in the EGFR kinase domain has been shown to cause enhanced efficacy of inhibitor treatment in patients with NSCLC. Several less frequent (uncommon) mutations in the EGFR kinase domain with potential implications in treatment response have also been reported. The role of a limited number of uncommon mutations in drug sensitivity was experimentally verified. However, a huge number of these mutations remain uncharacterized for inhibitor sensitivity or resistance. A large-scale computational analysis of clinically reported 298 point mutants of EGFR kinase domain has been performed, and drug sensitivity profiles for each mutant toward seven kinase inhibitors has been determined by molecular docking. In addition, the relative inhibitor binding affinity toward each drug as compared with that of adenosine triphosphate was calculated for each mutant. The inhibitor sensitivity profiles predicted in this study for a set of previously characterized mutants correlated well with the published clinical, experimental, and computational data. Both the single and compound mutations displayed differential inhibitor sensitivity toward first- and next-generation kinase inhibitors. The present study provides predicted drug sensitivity profiles for a large panel of uncommon EGFR mutations toward multiple inhibitors, which may help clinicians in deciding mutant-specific treatment strategies. Copyright © 2018 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

FUNCTIONAL SUBCLONE PROFILING FOR PREDICTION OF TREATMENT-INDUCED INTRA-TUMOR POPULATION SHIFTS AND DISCOVERY OF RATIONAL DRUG COMBINATIONS IN HUMAN GLIOBLASTOMA

Science.gov (United States)

Reinartz, Roman; Wang, Shanshan; Kebir, Sied; Silver, Daniel J.; Wieland, Anja; Zheng, Tong; Küpper, Marius; Rauschenbach, Laurèl; Fimmers, Rolf; Shepherd, Timothy M.; Trageser, Daniel; Till, Andreas; Schäfer, Niklas; Glas, Martin; Hillmer, Axel M.; Cichon, Sven; Smith, Amy A.; Pietsch, Torsten; Liu, Ying; Reynolds, Brent A.; Yachnis, Anthony; Pincus, David W.; Simon, Matthias; Brüstle, Oliver; Steindler, Dennis A.; Scheffler, Björn

2016-01-01

Purpose Investigation of clonal heterogeneity may be key to understanding mechanisms of therapeutic failure in human cancer. However, little is known on the consequences of therapeutic intervention on the clonal composition of solid tumors. Experimental Design Here, we used 33 single cell-derived subclones generated from five clinical glioblastoma specimens for exploring intra- and inter-individual spectra of drug resistance profiles in vitro. In a personalized setting, we explored whether differences in pharmacological sensitivity among subclones could be employed to predict drug-dependent changes to the clonal composition of tumors. Results Subclones from individual tumors exhibited a remarkable heterogeneity of drug resistance to a library of potential anti-glioblastoma compounds. A more comprehensive intra-tumoral analysis revealed that stable genetic and phenotypic characteristics of co-existing subclones could be correlated with distinct drug sensitivity profiles. The data obtained from differential drug response analysis could be employed to predict clonal population shifts within the naïve parental tumor in vitro and in orthotopic xenografts. Furthermore, the value of pharmacological profiles could be shown for establishing rational strategies for individualized secondary lines of treatment. Conclusions Our data provide a previously unrecognized strategy for revealing functional consequences of intra-tumor heterogeneity by enabling predictive modeling of treatment-related subclone dynamics in human glioblastoma. PMID:27521447

A Physiologically Based Pharmacokinetic Model to Predict the Pharmacokinetics of Highly Protein-Bound Drugs and Impact of Errors in Plasma Protein Binding

Science.gov (United States)

Ye, Min; Nagar, Swati; Korzekwa, Ken

2015-01-01

Predicting the pharmacokinetics of highly protein-bound drugs is difficult. Also, since historical plasma protein binding data was often collected using unbuffered plasma, the resulting inaccurate binding data could contribute to incorrect predictions. This study uses a generic physiologically based pharmacokinetic (PBPK) model to predict human plasma concentration-time profiles for 22 highly protein-bound drugs. Tissue distribution was estimated from in vitro drug lipophilicity data, plasma protein binding, and blood: plasma ratio. Clearance was predicted with a well-stirred liver model. Underestimated hepatic clearance for acidic and neutral compounds was corrected by an empirical scaling factor. Predicted values (pharmacokinetic parameters, plasma concentration-time profile) were compared with observed data to evaluate model accuracy. Of the 22 drugs, less than a 2-fold error was obtained for terminal elimination half-life (t1/2, 100% of drugs), peak plasma concentration (Cmax, 100%), area under the plasma concentration-time curve (AUC0–t, 95.4%), clearance (CLh, 95.4%), mean retention time (MRT, 95.4%), and steady state volume (Vss, 90.9%). The impact of fup errors on CLh and Vss prediction was evaluated. Errors in fup resulted in proportional errors in clearance prediction for low-clearance compounds, and in Vss prediction for high-volume neutral drugs. For high-volume basic drugs, errors in fup did not propagate to errors in Vss prediction. This is due to the cancellation of errors in the calculations for tissue partitioning of basic drugs. Overall, plasma profiles were well simulated with the present PBPK model. PMID:26531057

Determination of Inorganic Ion Profiles of Illicit Drugs by Capillary Electrophoresis.

Science.gov (United States)

Evans, Elizabeth; Costrino, Carolina; do Lago, Claudimir L; Garcia, Carlos D; Roux, Claude; Blanes, Lucas

2016-11-01

A portable capillary electrophoresis instrument with dual capacitively coupled contactless conductivity detection (C 4 D) was used to determine the inorganic ionic profiles of three pharmaceutical samples and precursors of two illicit drugs (contemporary samples of methylone and para-methoxymethamphetamine). The LODs ranged from 0.10 μmol/L to 1.25 μmol/L for the 10 selected cations, and from 0.13 μmol/L to 1.03 μmol/L for the eight selected anions. All separations were performed in less than 6 min with migration times and peak area RSD values ranging from 2 to 7%. The results demonstrate the potential of the analysis of inorganic ionic species to aid in the identification and/or differentiation of unknown tablets, and real samples found in illicit drug manufacture scenarios. From the resulting ionic fingerprint, the unknown tablets and samples can be further classified. © 2016 American Academy of Forensic Sciences.

Bradsim-prediction of solute concentration. Temperature and physical property profiles along pulsed plate columns

International Nuclear Information System (INIS)

Logsdail, D.H.; Evans, S.F.; Jenkins, J.A.; Smith, I.J.

1988-01-01

Dynamic model of the operation of the BRADSIM pulsed plate column is developed. Examples of simulation of the pures process extraction system are given. Profiles of dissolved substances concentrations and profiles of physical properties of liquid along the column are provided. Calculated values are compared with the experimental data, obtained in case of the column 50 mm in diameter, Harwell extractional facility and Sellafield pulsed column 300 mm in diameter for extraction systems uranyl nitrate-nitric acid-20% and 30% TBP in kerosene. 2 refs.; 6 figs

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

Science.gov (United States)

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

Height profile of particle concentration in an aeolian saltating cloud: A wind tunnel investigation by PIV MSD

Science.gov (United States)

Dong, Zhibao; Wang, Hongtao; Zhang, Xiaohang; Ayrault, Michael

2003-10-01

Attempt is made to define the particle concentration in an aeolian saltating cloud and its variation with height using artificial spherical quartz sand in a wind tunnel. The height profiles of the relative particle concentration in aeolian saltating cloud at three wind velocities were detected by the state of the art PIV (Particle Image Velocimetry) MSD (Mie Scattering Diffusion) technique, and converted to actual concentration based on sand transport rate and the variation with height of velocity of the saltating cloud. The particle concentration was found to decay exponentially with height and to increase with wind velocity. It decayed more rapidly when the wind velocity decreased. The volume/volume concentration in the near-surface layer was at the order of 10-4. The results obtained by PIV MSD technique were in good agreement with those derived from the sand flux and velocity profiles, the former being about 15% greater than the later.

Duality based direct resolution of unique profiles using zero concentration region information.

Science.gov (United States)

Tavakkoli, Elnaz; Rajkó, Róbert; Abdollahi, Hamid

2018-07-01

Self Modeling Curve Resolution (SMCR) is a class of techniques concerned with estimating pure profiles underlying a set of measurements on chemical systems. In general, the estimated profiles are ambiguous (non-unique) except if some special conditions fulfilled. Implementing the adequate information can reduce the so-called rotational ambiguity effectively, and in the most desirable cases lead to the unique solution. Therefore, studies on circumstances resulting in unique solution are of particular importance. The conditions of unique solution can particularly be studied based on duality principle. In bilinear chemical (e.g., spectroscopic) data matrix, there is a natural duality between its row and column vector spaces using minimal constraints (non-negativity of concentrations and absorbances). In this article, the conditions of the unique solution according to duality concept and using zero concentration region information is intended to show. A simulated dataset of three components and an experimental system with synthetic mixtures containing three amino acids tyrosine, phenylalanine and tryptophan are analyzed. It is shown that in the presence of sufficient information, the reliable unique solution is obtained that is valuable in analytical qualification and for quantitative verification analysis. Copyright © 2018 Elsevier B.V. All rights reserved.

Safety Profile of the Newest Antiepileptic Drugs: A Curated Literature Review.

Science.gov (United States)

Palleria, Caterina; Cozza, Giuseppe; Khengar, Rajeshree; Libri, Vincenzo; De Sarro, Giovambattista

2017-01-01

Despite the introduction of new antiepileptic drugs (AEDs), the quality of life and therapeutic response for patients with epilepsy remain unsatisfactory. In addition, whilst several antiepileptic drugs (AEDs) have been approved and consequently marketed in recent years, little is known about their long-term safety and tolerability. Availability of the newest AEDs, characterized by improved pharmacokinetic profiles, has positively impacted the treatment approach for patients with partial seizures in clinical practice. However, the main cause of treatment failure is still poor patient compliance due to the occurrence of adverse drug reactions (ADRs) that lead to treatment withdrawal in about 25% of cases before achieving maximal efficacy, and is associated with increasing health care costs. In this Review, we conducted an online database search using Medline, PubMed, Embase, and the Cochrane Online Library to review the available studies highlighting the clinical relevance of side effects, pharmacological interactions, safety and tolerability of the newest AEDs: Brivaracetam (BRV), Cannabidiol (CBD), Eslicarbazepine acetate (ESL), Lacosamide (LCM), and Perampanel (PER). The principal benefit of the newest AEDs, in addition to reduced frequency and seizure severity, is the low number and severity of ADRs reported compared to more historic drugs. Early detection of ADRs could lead to an improvement in patients' quality of life, therefore it is important to monitor ADRs and to adequately perform post marketing surveillance in the clinical practice setting. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

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

Application of xCELLigence RTCA Biosensor Technology for Revealing the Profile and Window of Drug Responsiveness in Real Time

Directory of Open Access Journals (Sweden)

Dan Kho

2015-04-01

Full Text Available The xCELLigence technology is a real-time cellular biosensor, which measures the net adhesion of cells to high-density gold electrode arrays printed on custom-designed E-plates. The strength of cellular adhesion is influenced by a myriad of factors that include cell type, cell viability, growth, migration, spreading and proliferation. We therefore hypothesised that xCELLigence biosensor technology would provide a valuable platform for the measurement of drug responses in a multitude of different experimental, clinical or pharmacological contexts. In this manuscript, we demonstrate how xCELLigence technology has been invaluable in the identification of (1 not only if cells respond to a particular drug, but (2 the window of drug responsiveness. The latter aspect is often left to educated guess work in classical end-point assays, whereas biosensor technology reveals the temporal profile of the response in real time, which enables both acute responses and longer term responses to be profiled within the same assay. In our experience, the xCELLigence biosensor technology is suitable for highly targeted drug assessment and also low to medium throughput drug screening, which produces high content temporal data in real time.

Effect of abnormal outflow from end stages on concentration profile in uranium-stripping bank of PUREX flowsheet

International Nuclear Information System (INIS)

Ueda, Yoshinori; Matsumoto, Shiro

2002-01-01

The effect of the abnormal outflow from the end stages on the concentration profile was studied for the uranium-stripping bank to consider the design and the operation of the solvent extraction process, which eases the undesirable effects due to such abnormal flow. The abnormal outflow affected the concentration profile in the same manner as the decrease in the rate of the corresponding liquid flow rate entering the bank. The results suggested that the solvent extractor at the aqueous inlet stage in stripping banks and the solvent extractor at the organic inlet stage in extraction banks should be carefully designed to restrict the respective abnormal aqueous and organic outflows within the normal operational liquid flow rate range. Combining the result and the inherent phase separation behavior of the extractor suggested the possibility of designing the process with the self-controlled function of throughput, which eases the change of the concentration profile due to the undesirable increase in the rate of liquid flow rate entering the bank. Basically the proposed approaches are probably applicable to other general extraction and stripping processes. (author)

Validation of an ultra-high-performance liquid chromatography-tandem mass spectrometry method to quantify illicit drug and pharmaceutical residues in wastewater using accuracy profile approach.

Science.gov (United States)

Hubert, Cécile; Roosen, Martin; Levi, Yves; Karolak, Sara

2017-06-02

The analysis of biomarkers in wastewater has become a common approach to assess community behavior. This method is an interesting way to estimate illicit drug consumption in a given population: by using a back calculation method, it is therefore possible to quantify the amount of a specific drug used in a community and to assess the consumption variation at different times and locations. Such a method needs reliable analytical data since the determination of a concentration in the ngL -1 range in a complex matrix is difficult and not easily reproducible. The best analytical method is liquid chromatography - mass spectrometry coupling after solid-phase extraction or on-line pre-concentration. Quality criteria are not specially defined for this kind of determination. In this context, it was decided to develop an UHPLC-MS/MS method to analyze 10 illicit drugs and pharmaceuticals in wastewater treatment plant influent or effluent using a pre-concentration on-line system. A validation process was then carried out using the accuracy profile concept as an innovative tool to estimate the probability of getting prospective results within specified acceptance limits. Influent and effluent samples were spiked with known amounts of the 10 compounds and analyzed three times a day for three days in order to estimate intra-day and inter-day variations. The matrix effect was estimated for each compound. The developed method can provide at least 80% of results within ±25% limits except for compounds that are degraded in influent. Copyright © 2017 Elsevier B.V. All rights reserved.

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

Vertical profiles of black carbon concentration and particle number size distribution in the North China Plain

Science.gov (United States)

Ran, L.; Deng, Z.

2013-12-01

The vertical distribution of aerosols is of great importance to our understanding in the impacts of aerosols on radiation balance and climate, as well as air quality and public health. To better understand and estimate the effects of atmospheric components including trace gases and aerosols on atmospheric environment and climate, an intensive field campaign, Vertical Observations of trace Gases and Aerosols in the North China Plain (VOGA-NCP), was carried out from late July to early August 2013 over a rural site in the polluted NCP. During the campaign, vertical profiles of black carbon (BC) concentration and particle number size distribution were measured respectively by a micro-Aethalometer and an optical particle counter attached to a tethered balloon within 1000 m height. Meteorological parameters, including temperature, relative humidity, wind speed and wind direction, were measured simultaneously by a radiosonde also attached to the tethered balloon. Preliminary results showed distinct diurnal variations of the vertical distribution of aerosol total number concentration and BC concentration, following the development of the mixing layer. Generally, there was a well mixing of aerosols within the mixing layer and a sharp decrease above the mixing layer. Particularly, a small peak of BC concentrations was observed around 400-500 m height for several profiles. Further analysis would be needed to explain such phenomenon. It was also found that measured vertical profiles of BC using the filter-based method might be affected by the vertical distribution of relative humidity.

Promoter Methylation and BDNF and DAT1 Gene Expression Profiles in Patients with Drug Addiction.

Science.gov (United States)

Kordi-Tamandani, Dor Mohammad; Tajoddini, Shahrad; Salimi, Farzaneh

2015-01-01

Drug addiction is a brain disorder that has negative consequences for individuals and society. Addictions are chronic relapsing diseases of the brain that are caused by direct drug-induced effects and persevering neuroadaptations at the epigenetic, neuropeptide and neurotransmitter levels. Because the dopaminergic system has a significant role in drug abuse, the purpose of this study was to analyze the methylation and expression profile of brain-derived neurotrophic factor (BDNF) and dopamine transporter (DAT1) genes in individuals with drug addiction. BDNF and DAT1 promoter methylation were investigated with a methylation-specific polymerase chain reaction (PCR) technique in blood samples from 75 individuals with drug addiction and 65 healthy controls. The expression levels of BDNF and DAT1 were assessed in 12 mRNA samples from the blood of patients and compared to the samples of healthy controls (n = 12) with real-time quantitative reverse transcription PCR. No significant differences were found in the methylation of BDNF and DAT1 between patients and controls, but the relative levels of expression of BDNF and DAT1 mRNA differed significantly in the patients compared to controls (p drug addiction.

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.

Studying the relationship between the styles of attachment, drug addiction and psychological profile of addicts in comparison with non-addicts (in self-introduced centers of Bushehr Province

Directory of Open Access Journals (Sweden)

2004-05-01

Full Text Available Emphasizing on effective factors in drug dependency and multiple drug relapse, is probably related to formation of personality models. These models are heavily affected by development orientation personality. Various researches show that attachment as a development factor has a decisive role in forming personality models. Hence, in one hand, the present research evaluates the relationship between attachment styles and drug dependency and ,in the other hand, it addresses the relationship between attachment /drug addiction and psychological profile. The statistical community of this research consists of all male referrals to self-introduced centers in Bushehr province in summer 1381. The sample group consists 100 individuals of this community and comparison group cnosists another 100 individuals who had no history of drug abuse. They were controlled by counterpart variables. The tools of this research are MCMI-II and adults’ attachment questionnaire. The satisfaction of validity and reliabilty of research literature are reported. Apllied statistical methods include χ² statistical test and profile analysis. To compare the individual distribution based on attachment style, χ² test is obtained meaningfully in P<0/05 level. Also, the results of profile analysis for evaluating the effect of drug addiction and attachment style on psychological profile is meaningful in P<0/01 level. In summary, the research shows that there is a relationship between attachment style and drug addiction as well as between attachment/addiction and psychological profile.

STUDIES OF ADVERSE DRUG REACTION PROFILE OF ANTISNAKE VENOM AT DISTRICT GENERAL HOSPITAL

OpenAIRE

Mulchand Shende *, Sneha Gawali , Kanchan Bhongade , Vivek Bhuskade , Abhijit Nandgaonkar

2017-01-01

Snake bite is a common predominant problem of the rural and periurban areas, neglected and frequently devastating environmental and occupational disease, especially in rural areas of tropical developing countries. This study aimed to investigate of the adverse drug reaction profile of anti-snake venom (ASV) in a district general hospital. An observational study was conducted in hospital for six months. A total number of 142 indoor case papers of snake bite from October 2016 to April 2017 were...

A physiologically based pharmacokinetic model to predict the pharmacokinetics of highly protein-bound drugs and the impact of errors in plasma protein binding.

Science.gov (United States)

Ye, Min; Nagar, Swati; Korzekwa, Ken

2016-04-01

Predicting the pharmacokinetics of highly protein-bound drugs is difficult. Also, since historical plasma protein binding data were often collected using unbuffered plasma, the resulting inaccurate binding data could contribute to incorrect predictions. This study uses a generic physiologically based pharmacokinetic (PBPK) model to predict human plasma concentration-time profiles for 22 highly protein-bound drugs. Tissue distribution was estimated from in vitro drug lipophilicity data, plasma protein binding and the blood: plasma ratio. Clearance was predicted with a well-stirred liver model. Underestimated hepatic clearance for acidic and neutral compounds was corrected by an empirical scaling factor. Predicted values (pharmacokinetic parameters, plasma concentration-time profile) were compared with observed data to evaluate the model accuracy. Of the 22 drugs, less than a 2-fold error was obtained for the terminal elimination half-life (t1/2 , 100% of drugs), peak plasma concentration (Cmax , 100%), area under the plasma concentration-time curve (AUC0-t , 95.4%), clearance (CLh , 95.4%), mean residence time (MRT, 95.4%) and steady state volume (Vss , 90.9%). The impact of fup errors on CLh and Vss prediction was evaluated. Errors in fup resulted in proportional errors in clearance prediction for low-clearance compounds, and in Vss prediction for high-volume neutral drugs. For high-volume basic drugs, errors in fup did not propagate to errors in Vss prediction. This is due to the cancellation of errors in the calculations for tissue partitioning of basic drugs. Overall, plasma profiles were well simulated with the present PBPK model. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Characterizing contaminant concentrations with depth by using the USGS well profiler in Oklahoma, 2003-9

Science.gov (United States)

Smith, S. Jerrod; Becker, Carol J.

2011-01-01

Since 2003, the U.S. Geological Survey (USGS) Oklahoma Water Science Center has been using the USGS well profiler to characterize changes in water contribution and contaminant concentrations with depth in pumping public-supply wells in selected aquifers. The tools and methods associated with the well profiler, which were first developed by the USGS California Water Science Center, have been used to investigate common problems such as saline water intrusion in high-yield irrigation wells and metals contamination in high-yield public-supply wells.

Proteomic profiling in incubation medium of mouse, rat and human precision-cut liver slices for biomarker detection regarding acute drug-induced liver injury

NARCIS (Netherlands)

van Swelm, Rachel P L; Hadi, Mackenzie; Laarakkers, Coby M M; Masereeuw, R.|info:eu-repo/dai/nl/155644033; Groothuis, Geny M M; Russel, Frans G M

Drug-induced liver injury is one of the leading causes of drug withdrawal from the market. In this study, we investigated the applicability of protein profiling of the incubation medium of human, mouse and rat precision-cut liver slices (PCLS) exposed to liver injury-inducing drugs for biomarker

Effect of Entrainment and Overflow Occurrences on Concentration Profile in PUREX Flow Sheet

International Nuclear Information System (INIS)

Ueda, Yoshinori; Ishii, Junichi; Matsumoto, Shiro

2003-01-01

A deviation in the operational condition of a mixer settler and a centrifugal contactor causes an entrainment or an overflow, which affects the concentration profile. Although there has been no quantitative study about the effect of such abnormal flows on the concentration profile, the occurrence of such abnormal flows has been severely restricted for a PUREX flow sheet. However, the restriction of abnormal flows can be relaxed when the effect of such flows is limited within the allowable range such that the concentration of the product does not deviate from its specification. This relaxation could serve to benefit a continuous operation under a certain degree of deviation from the operational condition and a smaller design load of a solvent extractor. From this viewpoint, the relationship between the magnitude of abnormal flows and the effect of them on the process was studied quantitatively using a specially developed code in a wide range of PUREX flow sheet conditions, and the possibility of this relaxation was investigated. The results showed that the effect of the abnormal flow on the concentration in the organic outflow or aqueous raffinate was dominated by the leakage fraction under normal conditions regardless of each specific flow sheet condition. The common correlations were found between the leakage fraction of uranium and plutonium under the occurrence of abnormal flows and that under no abnormal flow for the stripping and extracting conditions, respectively. Comparing the given correlations and the usual specification of the leakage fraction of uranium and plutonium suggested that the restriction of the abnormal flows could be relaxed for a usual PUREX flow sheet

Profile of users intoxicated by drugs of abuse and association with death

Directory of Open Access Journals (Sweden)

Lúcia Margarete dos Reis

2016-01-01

Full Text Available Objective: to characterize the profile of users intoxicated by drugs of abuse reported to a center of information and toxicological assistance and related this to the occurrence of deaths. Methods: study of case series reported in the 2010-2011 biennium after active case finding. Data were obtained from epidemiological records filed in the center and submitted to univariate analysis, with chi-squared test and Fischer test. Results: three hundred and thirty nine cases were found, most were men (87.3%, with basic education (61.0% and elderly (37.2%. Alcohol use (83.8% and chronic intoxications (89.9% were predominant. Clinical complications were present in most medical diagnoses (63.4%. However, mortality was higher in the event deferral by cold and fire weapons. Conclusion: the consumption of drugs of abuse influences morbidity and mortality, particularly in men aged at 60 years or above and with low level of education.

Profile of users intoxicated by drugs of abuse and association with death

Directory of Open Access Journals (Sweden)

Lúcia Margarete dos Reis

2016-05-01

Full Text Available Objective: to characterize the profile of users intoxicated by drugs of abuse reported to a center of information and toxicological assistance and related this to the occurrence of deaths. Methods: study of case series reported in the 2010-2011 biennium after active case finding. Data were obtained from epidemiological records filed in the center and submitted to univariate analysis, with chi-squared test and Fischer test. Results: three hundred and thirty nine cases were found, most were men (87.3%, with basic education (61.0% and elderly (37.2%. Alcohol use (83.8% and chronic intoxications (89.9% were predominant. Clinical complications were present in most medical diagnoses (63.4%. However, mortality was higher in the event deferral by cold and fire weapons. Conclusion: the consumption of drugs of abuse influences morbidity and mortality, particularly in men aged at 60 years or above and with low level of education.

Expression Profile of Drug and Nutrient Absorption Related Genes in Madin-Darby Canine Kidney (MDCK Cells Grown under Differentiation Conditions

Directory of Open Access Journals (Sweden)

Balvinder S. Vig

2012-06-01

Full Text Available The expression levels of genes involved in drug and nutrient absorption were evaluated in the Madin-Darby Canine Kidney (MDCK in vitro drug absorption model. MDCK cells were grown on plastic surfaces (for 3 days or on Transwell^® membranes (for 3, 5, 7, and 9 days. The expression profile of genes including ABC transporters, SLC transporters, and cytochrome P450 (CYP enzymes was determined using the Affymetrix^® Canine GeneChip^®. Expression of genes whose probe sets passed a stringent confirmation process was examined. Expression of a few transporter (MDR1, PEPT1 and PEPT2 genes in MDCK cells was confirmed by RT-PCR. The overall gene expression profile was strongly influenced by the type of support the cells were grown on. After 3 days of growth, expression of 28% of the genes was statistically different (1.5-fold cutoff, p < 0.05 between the cells grown on plastic and Transwell^® membranes. When cells were differentiated on Transwell^® membranes, large changes in gene expression profile were observed during the early stages, which then stabilized after 5–7 days. Only a small number of genes encoding drug absorption related SLC, ABC, and CYP were detected in MDCK cells, and most of them exhibited low hybridization signals. Results from this study provide valuable reference information on endogenous gene expression in MDCK cells that could assist in design of drug-transporter and/or drug-enzyme interaction studies, and help interpret the contributions of various transporters and metabolic enzymes in studies with MDCK cells.

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.

Radon concentrations profiles over the brazilian Amazon basin during wet season

International Nuclear Information System (INIS)

Pereira, E.B.; Dias, P.L.S.; Nordemann, D.J.R.

1991-01-01

Atmospheric radon measurements were performed airborne in the Brazilian Amazon Basin during the wet season ABLE-2B experiment. The vertical profiles of radon showed a small decrease of concentration with increasing altitude at a rate varying from 6.5 to 11 x 10 - 2 Bq m - 3 km - 1. The calculation of the flux balance of radon in the troposphere above the Amazon Basin indicated a residual flux at the upper boundary of the measurement domain (6 km) of 0.14 atom cm - 2 s - 1. This residue may be associated with the turbulent transport of radon due to cloud activity. (author)

Determination of the concentration profile of chemical elements in superheater pipes

International Nuclear Information System (INIS)

Aldape U, F.; Aspiazu F, J.

1986-05-01

This work has for object to determine the profile of concentration of chemical elements at trace level in a superheater pipe of Thermoelectric Plants using the X-ray emission spectroscopy technique induced by protons coming from the Accelerator of the Nuclear Center. In the X-ray detection, a Si Li detector was used. The technique was chosen because it allows a multielemental analysis, of high sensitivity and precision. The results can help to understand the problems that are had in the change of flexibility or of corrosion. This will be from utility to the Federal Electricity Commission (CFE). (Author)

Organohalogen pollutants in herring from the northern Baltic Sea: Concentrations, congener profiles and explanatory factors

International Nuclear Information System (INIS)

Koistinen, Jaana; Kiviranta, Hannu; Ruokojaervi, Paeivi; Parmanne, Raimo; Verta, Matti; Hallikainen, Anja; Vartiainen, Terttu

2008-01-01

Organohalogen contaminants were investigated in Baltic herring caught from three catchment areas in the Baltic Sea, off the coasts of Finland. Pools of both small and large herring were analysed for polychlorinated biphenyls (PCB), dibenzo-p-dioxins, dibenzofurans, naphthalenes, camphenes (toxaphene), polybrominated diphenyl ethers and the pesticide DDT and its metabolites. PCB concentrations per fresh weight in small herring were at the same level in all catchment areas, i.e. the Bothnian Bay, the Bothnian Sea and the Gulf of Finland, revealing no hot spots and reflecting most likely long term emissions and atmospheric deposition. Differences in the levels and/or congener profiles of other contaminants between catchment areas may be explained by point sources. Similar concentrations in small and large herring in the Gulf of Finland were possibly due to their common nutrition. In the other areas, differences between small and large herring most likely reflected their different food sources. - Sources of pollutants are reflected in levels and congener profiles of pollutants in Baltic herring

An improved procedure for determining grain boundary diffusion coefficients from averaged concentration profiles

Science.gov (United States)

Gryaznov, D.; Fleig, J.; Maier, J.

2008-03-01

Whipple's solution of the problem of grain boundary diffusion and Le Claire's relation, which is often used to determine grain boundary diffusion coefficients, are examined for a broad range of ratios of grain boundary to bulk diffusivities Δ and diffusion times t. Different reasons leading to errors in determining the grain boundary diffusivity (DGB) when using Le Claire's relation are discussed. It is shown that nonlinearities of the diffusion profiles in lnCav-y6/5 plots and deviations from "Le Claire's constant" (-0.78) are the major error sources (Cav=averaged concentration, y =coordinate in diffusion direction). An improved relation (replacing Le Claire's constant) is suggested for analyzing diffusion profiles particularly suited for small diffusion lengths (short times) as often required in diffusion experiments on nanocrystalline materials.

Intermixing in heteroepitaxial islands: fast, self-consistent calculation of the concentration profile minimizing the elastic energy

International Nuclear Information System (INIS)

Gatti, R; UhlIk, F; Montalenti, F

2008-01-01

We present a novel computational method for finding the concentration profile which minimizes the elastic energy stored in heteroepitaxial islands. Based on a suitable combination of continuum elasticity theory and configurational Monte Carlo, we show that such profiles can be readily found by a simple, yet fully self-consistent, iterative procedure. We apply the method to SiGe/Si islands, considering realistic three-dimensional shapes (pyramids, domes and barns), finding strongly non-uniform distributions of Si and Ge atoms, in qualitative agreement with several experiments. Moreover, our simulated selective-etching profiles display, in some cases, a remarkable resemblance to the experimental ones, opening intriguing questions on the interplay between kinetic, entropic and elastic effects

Proteomic profiling of the antifungal drug response of Aspergillus fumigatus to voriconazole.

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Amarsaikhan, Nansalmaa; Albrecht-Eckardt, Daniela; Sasse, Christoph; Braus, Gerhard H; Ogel, Zumrut B; Kniemeyer, Olaf

2017-10-01

Antifungal resistance is an emerging problem and one of the reasons for treatment failure of invasive aspergillosis (IA). Voriconazole has become a standard therapeutic for the treatment of this often fatal infection. We studied the differentially expressed proteins as a response of Aspergillus fumigatus to voriconazole by employing the two-dimensional difference gel electrophoresis (DIGE) technique. Due to addition of drug, a total of 135 differentially synthesized proteins were identified by MALDI-TOF/TOF-mass spectrometry. In particular, the level of proteins involved in the general stress response and cell detoxification increased prominently. In contrast, cell metabolism and energy proteins were down-regulated, which suggests the cellular effort to maintain balance in energy utilization while trying to combat the cellular stress exerted by the drug. We detected several so-far uncharacterized proteins which may play a role in stress response and drug metabolism and which could be future targets for antifungal treatment. A mutant strain, which is deleted in the cross-pathway control gene cpcA, was treated with voriconazole to investigate the contribution of the general control of amino acid biosynthesis to drug resistance. We compared the mutant strain's protein expression profile with the wild-type strain. The absence of CpcA led to an increased resistance to voriconazole and a reduced activation of some general stress response proteins, while the transcript level of the triazole target gene erg11A (cyp51A) remained unchanged. In contrast, the sensitivity of strain ΔcpcA to terbinafine and amphotericin B was slightly increased. These findings imply a role of CpcA in the cellular stress response to azole drugs at the post transcriptional level. Copyright © 2017 Elsevier GmbH. All rights reserved.

Functional profiling of microtumors to identify cancer associated fibroblast-derived drug targets.

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Horman, Shane R; To, Jeremy; Lamb, John; Zoll, Jocelyn H; Leonetti, Nicole; Tu, Buu; Moran, Rita; Newlin, Robbin; Walker, John R; Orth, Anthony P

2017-11-21

Recent advances in chemotherapeutics highlight the importance of molecularly-targeted perturbagens. Although these therapies typically address dysregulated cancer cell proteins, there are increasing therapeutic modalities that take into consideration cancer cell-extrinsic factors. Targeting components of tumor stroma such as vascular or immune cells has been shown to represent an efficacious approach in cancer treatment. Cancer-associated fibroblasts (CAFs) exemplify an important stromal component that can be exploited in targeted therapeutics, though their employment in drug discovery campaigns has been relatively minimal due to technical logistics in assaying for CAF-tumor interactions. Here we report a 3-dimensional multi-culture tumor:CAF spheroid phenotypic screening platform that can be applied to high-content drug discovery initiatives. Using a functional genomics approach we systematically profiled 1,024 candidate genes for CAF-intrinsic anti-spheroid activity; identifying several CAF genes important for development and maintenance of tumor:CAF co-culture spheroids. Along with previously reported genes such as WNT, we identify CAF-derived targets such as ARAF and COL3A1 upon which the tumor compartment depends for spheroid development. Specifically, we highlight the G-protein-coupled receptor OGR1 as a unique CAF-specific protein that may represent an attractive drug target for treating colorectal cancer. In vivo , murine colon tumor implants in OGR1 knockout mice displayed delayed tumor growth compared to tumors implanted in wild type littermate controls. These findings demonstrate a robust microphysiological screening approach for identifying new CAF targets that may be applied to drug discovery efforts.

Real-time investigation of human topoisomerase I reaction kinetics using an optical sensor: a fast method for drug screening and determination of active enzyme concentrations

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Kristoffersen, Emil L.; Jørgensen, Line A.; Franch, Oskar; Etzerodt, Michael; Frøhlich, Rikke; Bjergbæk, Lotte; Stougaard, Magnus; Ho, Yi-Ping; Knudsen, Birgitta R.

2015-05-01

Human DNA topoisomerase I (hTopI) is a nuclear enzyme that catalyzes relaxation of super helical tension that arises in the genome during essential DNA metabolic processes. This is accomplished through a common reaction mechanism shared among the type IB topoisomerase enzymes, including eukaryotic and poxvirus topoisomerase I. The mechanism of hTopI is specifically targeted in cancer treatment using camptothecin derivatives. These drugs convert the hTopI activity into a cellular poison, and hence the cytotoxic effects of camptothecin derivatives correlate with the hTopI activity. Therefore, fast and reliable techniques for high throughput measurements of hTopI activity are of high clinical interest. Here we demonstrate potential applications of a fluorophore-quencher based DNA sensor designed for measurement of hTopI cleavage-ligation activities, which are the catalytic steps affected by camptothecin. The kinetic analysis of the hTopI reaction with the DNA sensor exhibits a characteristic burst profile. This is the result of a two-step ping-pong reaction mechanism, where a fast first reaction, the one creating the signal, is followed by a slower second reaction necessary for completion of the catalytic cycle. Hence, the burst profile holds information about two reactions in the enzymatic mechanism. Moreover, it allows the amount of active enzyme in the reaction to be determined. The presented results pave the way for future high throughput drug screening and the potential of measuring active hTopI concentrations in clinical samples for individualized treatment.Human DNA topoisomerase I (hTopI) is a nuclear enzyme that catalyzes relaxation of super helical tension that arises in the genome during essential DNA metabolic processes. This is accomplished through a common reaction mechanism shared among the type IB topoisomerase enzymes, including eukaryotic and poxvirus topoisomerase I. The mechanism of hTopI is specifically targeted in cancer treatment using

Drug-drug interaction and doping, part 1: an in vitro study on the effect of non-prohibited drugs on the phase I metabolic profile of toremifene.

Science.gov (United States)

Mazzarino, Monica; de la Torre, Xavier; Fiacco, Ilaria; Palermo, Amelia; Botrè, Francesco

2014-05-01

The present study was designed to provide preliminary information on the potential impact of metabolic drug-drug interaction on the effectiveness of doping control strategies currently followed by the anti-doping laboratories to detect the intake of banned agents. In vitro assays based on the use of human liver microsomes and recombinant CYP isoforms were designed and performed to characterize the phase I metabolic profile of the prohibited agent toremifene, selected as a prototype drug of the class of selective oestrogen receptor modulators, both in the absence and in the presence of medicaments (fluconazole, ketoconazole, itraconazole, miconazole, cimetidine, ranitidine, fluoxetine, paroxetine, nefazodone) not included in the World Anti-Doping Agency list of prohibited substances and methods and frequently administered to athletes. The results show that the in vitro model developed in this study was adequate to simulate the in vivo metabolism of toremifene, confirming the results obtained in previous studies. Furthermore, our data also show that ketoconazole, itraconazole, miconazole and nefazodone cause a marked modification in the production of the metabolic products (i.e. hydroxylated and carboxylated metabolites) normally selected by the anti-doping laboratories as target analytes to detect toremifene intake; moderate variations were registered in the presence of fluconazole, paroxetine and fluoxetine; while no significant modifications were measured in the presence of ranitidine and cimetidine. This evidence imposes that the potential effect of drug-drug interactions is duly taken into account in anti-doping analysis, also for a broader significance of the analytical results. Copyright © 2014 John Wiley & Sons, Ltd.

Culture and Drug Profiling of Patient Derived Malignant Pleural Effusions for Personalized Cancer Medicine.

Science.gov (United States)

Ruiz, Christian; Kustermann, Stefan; Pietilae, Elina; Vlajnic, Tatjana; Baschiera, Betty; Arabi, Leila; Lorber, Thomas; Oeggerli, Martin; Savic, Spasenija; Obermann, Ellen; Singer, Thomas; Rothschild, Sacha I; Zippelius, Alfred; Roth, Adrian B; Bubendorf, Lukas

2016-01-01

The use of patients' own cancer cells for in vitro selection of the most promising treatment is an attractive concept in personalized medicine. Human carcinoma cells from malignant pleural effusions (MPEs) are suited for this purpose since they have already adapted to the liquid environment in the patient and do not depend on a stromal cell compartment. Aim of this study was to develop a systematic approach for the in-vitro culture of MPEs to analyze the effect of chemotherapeutic as well as targeted drugs. MPEs from patients with solid tumors were selected for this study. After morphological and molecular characterization, they were cultured in medium supplemented with patient-derived sterile-filtered effusion supernatant. Growth characteristics were monitored in real-time using the xCELLigence system. MPEs were treated with a targeted therapeutic (erlotinib) according to the mutational status or chemotherapeutics based on the recommendation of the oncologists. We have established a robust system for the ex-vivo culture of MPEs and the application of drug tests in-vitro. The use of an antibody based magnetic cell separation system for epithelial cells before culture allowed treatment of effusions with only moderate tumor cell proportion. Experiments using drugs and drug-combinations revealed dose-dependent and specific growth inhibitory effects of targeted drugs. We developed a new approach for the ex-vivo culture of MPEs and the application of drug tests in-vitro using real-time measuring of cell growth, which precisely reproduced the effect of clinically established treatments by standard chemotherapy and targeted drugs. This sets the stage for future studies testing agents against specific targets from genomic profiling of metastatic tumor cells and multiple drug-combinations in a personalized manner.

Culture and Drug Profiling of Patient Derived Malignant Pleural Effusions for Personalized Cancer Medicine.

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Christian Ruiz

Full Text Available The use of patients' own cancer cells for in vitro selection of the most promising treatment is an attractive concept in personalized medicine. Human carcinoma cells from malignant pleural effusions (MPEs are suited for this purpose since they have already adapted to the liquid environment in the patient and do not depend on a stromal cell compartment. Aim of this study was to develop a systematic approach for the in-vitro culture of MPEs to analyze the effect of chemotherapeutic as well as targeted drugs.MPEs from patients with solid tumors were selected for this study. After morphological and molecular characterization, they were cultured in medium supplemented with patient-derived sterile-filtered effusion supernatant. Growth characteristics were monitored in real-time using the xCELLigence system. MPEs were treated with a targeted therapeutic (erlotinib according to the mutational status or chemotherapeutics based on the recommendation of the oncologists.We have established a robust system for the ex-vivo culture of MPEs and the application of drug tests in-vitro. The use of an antibody based magnetic cell separation system for epithelial cells before culture allowed treatment of effusions with only moderate tumor cell proportion. Experiments using drugs and drug-combinations revealed dose-dependent and specific growth inhibitory effects of targeted drugs.We developed a new approach for the ex-vivo culture of MPEs and the application of drug tests in-vitro using real-time measuring of cell growth, which precisely reproduced the effect of clinically established treatments by standard chemotherapy and targeted drugs. This sets the stage for future studies testing agents against specific targets from genomic profiling of metastatic tumor cells and multiple drug-combinations in a personalized manner.

Drug utilization profile in adult patients with refractory epilepsy at a tertiary referral center

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Priscila de Freitas-Lima

2013-11-01

Full Text Available Objective To evaluate the utilization profile of antiepileptic drugs in a population of adult patients with refractory epilepsy attending a tertiary center. Method Descriptive analyses of data were obtained from the medical records of 112 patients. Other clinical and demographic characteristics were also registered. Results Polytherapies with ≥3 antiepileptic drugs were prescribed to 60.7% of patients. Of the old agents, carbamazepine and clobazam were the most commonly prescribed (72.3% and 58.9% of the patients, respectively. Among the new agents, lamotrigine was the most commonly prescribed (36.6% of the patients. At least one old agent was identified in 103 out of the 104 polytherapies, while at least one new agent was prescribed to 70.5% of the population. The most prevalent combination was carbamazepine + clobazam + lamotrigine. The mean AED load found was 3.3 (range 0.4–7.7. Conclusion The pattern of use of individual drugs, although consistent with current treatment guidelines, is strongly influenced by the public health system.

Drug repurposing based on drug-drug interaction.

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Zhou, Bin; Wang, Rong; Wu, Ping; Kong, De-Xin

2015-02-01

Given the high risk and lengthy procedure of traditional drug development, drug repurposing is gaining more and more attention. Although many types of drug information have been used to repurpose drugs, drug-drug interaction data, which imply possible physiological effects or targets of drugs, remain unexploited. In this work, similarity of drug interaction was employed to infer similarity of the physiological effects or targets for the drugs. We collected 10,835 drug-drug interactions concerning 1074 drugs, and for 700 of them, drug similarity scores based on drug interaction profiles were computed and rendered using a drug association network with 589 nodes (drugs) and 2375 edges (drug similarity scores). The 589 drugs were clustered into 98 groups with Markov Clustering Algorithm, most of which were significantly correlated with certain drug functions. This indicates that the network can be used to infer the physiological effects of drugs. Furthermore, we evaluated the ability of this drug association network to predict drug targets. The results show that the method is effective for 317 of 561 drugs that have known targets. Comparison of this method with the structure-based approach shows that they are complementary. In summary, this study demonstrates the feasibility of drug repurposing based on drug-drug interaction data. © 2014 John Wiley & Sons A/S.

Core/shell PLGA microspheres with controllable in vivo release profile via rational core phase design.

Science.gov (United States)

Yu, Meiling; Yao, Qing; Zhang, Yan; Chen, Huilin; He, Haibing; Zhang, Yu; Yin, Tian; Tang, Xing; Xu, Hui

2018-02-27

Highly soluble drugs tend to release from preparations at high speeds, which make them need to be taken at frequent intervals. Additionally, some drugs need to be controlled to release in vivo at certain periods, so as to achieve therapeutic effects. Thus, the objective of this study is to design injectable microparticulate systems with controllable in vivo release profile. Biodegradable PLGA was used as the matrix material to fabricate microspheres using the traditional double emulsification-solvent evaporation method as well as improved techniques, with gel (5% gelatine or 25% F127) or LP powders as the inner phases. Their physicochemical properties were systemically investigated. Microspheres prepared by modified methods had an increase in drug loading (15.50, 16.72, 15.66%, respectively) and encapsulation efficiencies (73.46, 79.42, 74.40%, respectively) when compared with traditional methods (12.01 and 57.06%). The morphology of the particles was characterized by optical microscope (OM) and scanning electron microscopy (SEM), and the amorphous nature of the encapsulated drug was confirmed by differential scanning calorimetry (DSC) and X-ray diffraction (XRD) analysis. To evaluate their release behaviour, the in vitro degradation, in vitro release and in vivo pharmacodynamics were subsequently studied. Traditional microspheres prepared in this study with water as the inner phase had a relatively short release period within 16 d when compared with modified microspheres with 5% gelatine as the inner phase, which resulted in a smooth release profile and appropriate plasma LP concentrations over 21 d. Thus this type of modified microspheres can be better used in drugs requiring sustained release. The other two formulations containing 25% F127 and LP micropowders presented two-stage release profiles, resulting in fluctuant plasma LP concentrations which may be suitable for drugs requiring controlled release. All the results suggested that drug release rates from

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

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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.

Evaluations of dielectric property and drug release profile of 5-FU patches based on plasma charged electrets

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Wang, YUAN; Hejuan, LIANG; Ping, HUANG; Xiaoqiang, AN; Jian, JIANG; Lili, CUI

2018-05-01

In the present study, the electret 5-fluorouracil patch was developed, the effective surface potential, piezoelectric coefficient d 33, open-circuit thermally stimulated discharge (TSD) current spectra and shear adhesion of the patch were measured. The drug release profile of the patch was determined by using high performance liquid chromatography method. A stable potential difference which was positively dependent on the surface potential of the electret was generated on two sides of the patch. The measurements of d 33 coefficient, TSD current spectra and adhesion performance showed that the electrostatic field of the electret could cause polarization and cohesive strength decreasing of the matrix molecules, change the distribution and interaction of the drug molecules in patch, therefore to increase the release of drug from the transdermal patch.

Phylogenetic profiles of all membrane transport proteins of the malaria parasite highlight new drug targets

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January Weiner 3rd

2016-08-01

Full Text Available In order to combat the on-going malaria epidemic, discovery of new drug targets remains vital. Proteins that are essential to survival and specific to malaria parasites are key candidates. To survive within host cells, the parasites need to acquire nutrients and dispose of waste products across multiple membranes. Additionally, like all eukaryotes, they must redistribute ions and organic molecules between their various internal membrane bound compartments. Membrane transport proteins mediate all of these processes and are considered important mediators of drug resistance as well as drug targets in their own right. Recently, using advanced experimental genetic approaches and streamlined life cycle profiling, we generated a large collection of Plasmodium berghei gene deletion mutants and assigned essential gene functions, highlighting potential targets for prophylactic, therapeutic, and transmission-blocking anti-malarial drugs. Here, we present a comprehensive orthology assignment of all Plasmodium falciparum putative membrane transport proteins and provide a detailed overview of the associated essential gene functions obtained through experimental genetics studies in human and murine model parasites. Furthermore, we discuss the phylogeny of selected potential drug targets identified in our functional screen. We extensively discuss the results in the context of the functional assignments obtained using gene targeting available to date.

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

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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.

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.

Clinical relevance of cimetidine drug interactions.

Science.gov (United States)

Shinn, A F

1992-01-01

The excellent efficacy and tolerability profiles of H2-antagonists have established these agents as the leading class of antiulcer drugs. Attention has been focused on drug interactions with H2-antagonists as a means of product differentiation and because many patients are receiving multiple drug therapy. The main mechanism of most drug interactions involving cimetidine appears to be inhibition of the hepatic microsomal enzyme cytochrome P450, an effect which may be related to the different structures of H2-antagonists. Ranitidine appears to have less affinity than cimetidine for this system. There have been many published case reports and studies of drug interactions with cimetidine, but many of these have provided pharmacokinetic data only, with little information concerning the clinical significance of these findings. Nevertheless, the coadministration of cimetidine with drugs that have a narrow therapeutic margin (such as theophylline) may potentially result in clinically significant adverse effects. The monitoring of serum concentrations of drugs coadministered with cimetidine may reduce the risk of adverse events but does not abolish the problem. However, for most patients, concomitant administration of cimetidine with drugs possessing a wide therapeutic margin is unlikely to pose a significant problem.

1.6 μm DIAL Measurement and Back Trajectory Analysis of CO2 Concentration Profiles in the Lower-Atmosphere

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Shibata, Y.; Nagasawa, C.; Abo, M.

2016-12-01

Carbon dioxide (CO2) is the primary greenhouse gas emitted through human activities. In addition to the ground level CO2 network, vertical CO2 concentration profiles also play an important role for the estimation of the carbon budget and global warming in the inversion method. Especially, for the detailed analysis of forest carbon dynamics and CO2 fluxes of urban area, vertical CO2 concentration profiles with high spatial and temporal resolution in the lower atmosphere have been conducted by a differential absorption lidar (DIAL). We have observed several vertical profiles of CO2 concentrations for nighttime and daytime from 0.25 to 2.5 km altitude with range resolution of 300 m and integration time of 1 hour. In order to extract information on the origin of the CO2 masses, one day back trajectories were calculated by using a three dimensional (3-D) atmospheric transport model. In many cases, CO2 low concentration layers of over 1.5km altitude were flown by westerly winds from the forest. In another case, high concentration layers of CO2 were flown from the urban areas. As the spectra of absorption lines of any molecules are influenced basically by the temperature in the atmosphere, laser beams of three wavelengths around a CO2 absorption spectrum are transmitted alternately to the atmosphere for simultaneous measurements of CO2 concentration and temperature profiles. Moreover, a few processing algorithms of CO2-DIAL are also performed for improvement of measurement accuracy. For computation of trajectories and drawing their figures, the JRA-25 data provided by the cooperative research project for the JRA-25 long-term reanalysis of the Japan Meteorological Agency (JMA) and the Central Research Institute of Electric Power Industry (CRIEPI) and the NIPR trajectory model (Tomikawa and Sato, 2005; http://firp-nitram.nipr.ac.jp) were used. This work was financially supported by the System Development Program for Advanced Measurement and Analysis of the Japan Science and

Safety profile of drugs used in the treatment of osteoporosis: a systematical review of the literature

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M. Varenna

2013-10-01

Full Text Available The range of osteoporosis treatments is increasingly large and, like any disease, the pharmacological management of patients should involve a risk/benefit evaluation to attain the greatest reduction in risk of fracture with the lowest incidence of adverse events. The aim of this review is to critically appraise the literature about the safety issues of the main pharmacological treatments of osteoporosis. This document is the result of a consensus of experts based on a systematic review of regulatory documents, randomized controlled trials, metaanalyses, pharmacovigilance surveys and case series related to possible adverse drug reactions to osteoporosis treatment with calcium and vitamin D supplements, bisphosphonates, strontium ranelate, selective estrogen receptor modulators, denosumab, and teriparatide. As expected, randomized controlled trials showed only the most common adverse events due to the samples size and the short observation time. Case series and observational studies are able to provide data about uncommon side effects, but in some cases a sure cause-effect relationship needs still to be confirmed. Consistently with methodological limitations, the newer drugs have a tolerance profile that has not been fully explored yet. Osteoporosis treatments showed an overall good tolerance profile with rare serious adverse events that, however, must be well known by the clinician who prescribes these drugs. The concern about possible adverse events should be weighed against the reduction of morbidity and mortality associated with a significant fracture risk reduction.

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.

Possibility of Predicting Serotonin Transporter Occupancy From the In Vitro Inhibition Constant for Serotonin Transporter, the Clinically Relevant Plasma Concentration of Unbound Drugs, and Their Profiles for Substrates of Transporters.

Science.gov (United States)

Yahata, Masahiro; Chiba, Koji; Watanabe, Takao; Sugiyama, Yuichi

2017-09-01

Accurate prediction of target occupancy facilitates central nervous system drug development. In this review, we discuss the predictability of serotonin transporter (SERT) occupancy in human brain estimated from in vitro K i values for human SERT and plasma concentrations of unbound drug (C u,plasma ), as well as the impact of drug transporters in the blood-brain barrier. First, the geometric means of in vitro K i values were compared with the means of in vivo K i values (K i,u,plasma ) which were calculated as C u,plasma values at 50% occupancy of SERT obtained from previous clinical positron emission tomography/single photon emission computed tomography imaging studies for 6 selective serotonin transporter reuptake inhibitors and 3 serotonin norepinephrine reuptake inhibitors. The in vitro K i values for 7 drugs were comparable to their in vivo K i,u,plasma values within 3-fold difference. SERT occupancy was overestimated for 5 drugs (P-glycoprotein substrates) and underestimated for 2 drugs (presumably uptake transporter substrates, although no evidence exists as yet). In conclusion, prediction of human SERT occupancy from in vitro K i values and C u,plasma was successful for drugs that are not transporter substrates and will become possible in future even for transporter substrates, once the transporter activities will be accurately estimated from in vitro experiments. Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

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

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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

Drug diffusion across skin with diffusivity spatially modulated

Science.gov (United States)

Montoya Arroyave, Isabel

2014-05-01

A diffusion and delivery model of a drug across the skin with diffusivity spatially modulated is formulated and solved analytically using computer algebra. The model is developed using one-dimensional diffusion equation with a diffusivity which is a function of position in the skin; with an initial condition which is describing that the drug is initially contained inside a therapeutic patch; with a boundary condition according to which the change in concentration in the patch is minimal, such that assumption of zero flux at the patch-skin interface is valid; and with other boundary condition according to which the microcirculation in the capillaries just below the dermis carries the drug molecules away from the site at a very fast rate, maintaining the inner concentration at 0. The model is solved analytically by the method of the Laplace transform, with Bromwich integral and residue theorem. The concentration profile of the drug in the skin is expressed as an infinite series of Bessel functions. The corresponding total amount of delivered drug is expressed as an infinite series of decreasing exponentials. Also, the corresponding effective time for the therapeutic patch is determined. All computations were performed using computer algebra software, specifically Maple. The analytical results obtained are important for understanding and improving currentapplications of therapeutic patches. For future research it is interesting to consider more general models of spatial modulation of the diffusivity and the possible application of other computer algebra software such as Mathematica and Maxima.

Measurements of CO2 Concentration and Wind Profiles with A Scanning 1.6μm DIAL

Science.gov (United States)

Abo, M.; Shibata, Y.; Nagasawa, C.; Nagai, T.; Sakai, T.; Tsukamoto, M.

2012-12-01

Horizontal carbon dioxide (CO2) distribution and wind profiles are important information for understanding of the regional sink and source of CO2. The differential absorption lidar (DIAL) and the Doppler lidar with the range resolution is expected to bring several advantages over passive measurements. We have developed a new scanning 1.6μm DIAL and incoherent Doppler lidar system to perform simultaniously measurements of CO2 concentration and wind speed profiles in the atmosphere. The 1.6μm DIAL and Doppler lidar system consists of the Optical Parametric Generator (OPG) transmitter that excited by the LD pumped Nd:YAG laser with high repetition rate (500 Hz). The receiving optics include the near-infrared photomultiplier tube with high quantum efficiency operating at the photon counting mode, a fiber Bragg grating (FBG) filter to detct Doppler shift, and a 25 cm telescope[1][2]. Laser beam is transmitted coaxially and motorized scanning mirror system can scan the laser beam and field of view 0-360deg horizontally and 0-52deg vertically. We report the results of vertical CO2 scanning measurenents and vertical wind profiles. The scanning elevation angles were from 12deg to 24deg with angular step of 4deg and CO2 concentration profiles were obtained up to 1 km altitude with 200 m altitude resolution. We also obtained vertical wind vector profiles by measuring line-of-sight wind profiles at two azimuth angles with a fixed elevation angle 52deg. Vertical wind vector profiles were obtained up to 5 km altitude with 1 km altitude rasolution. This work was financially supported by the System Development Program for Advanced Measurement and Analysis of the Japan Science and Technology Agency. References [1] L. B. Vann, et al., "Narrowband fiber-optic phase-shifted Fabry-Perot Bragg grating filters for atmospheric water vapor lidar measurements", Appl. Opt., 44, pp. 7371-7377 (2005). [2] Y. Shibata, et al., "1.5μm incoherent Doppler lidar using a FBG filter", Proceedings

Metabolic profiles and lipoprotein lipid concentrations in non-obese and obese patients with polycystic ovarian disease.

Science.gov (United States)

Mahabeer, S; Naidoo, C; Norman, R J; Jialal, I; Reddi, K; Joubert, S M

1990-10-01

Clinical parameters, androgen status and lipoprotein lipid profiles were assessed in 10 non-obese and 10 obese patients with polycystic ovarian disease (PCOD) and reference subjects matched for age, height and weight. Both obese and non-obese women with PCOD had significantly higher androgen levels when compared to the reference groups. When comparison of lipoprotein lipid profiles were made between groups, non-obese women with PCOD had significantly higher total cholesterol, triglycerides and LDL-cholesterol levels than non-obese reference subjects. Obese PCOD women manifested significantly higher total cholesterol, LDL-cholesterol, cholesterol/HDL, and LDL/HDL values than did obese reference subjects. Correlations between serum androgens and lipoprotein lipid concentrations in PCOD and normal women were unhelpful. Both non-obese and obese patients with PCOD had significantly higher systolic and diastolic blood pressures (BPs) than the reference groups. Thus, both non-obese and obese women with PCOD manifest hyperandrogenaemia which may result in a male pattern of lipoprotein lipid concentrations.

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

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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.

Circulating Irisin Concentrations Are Associated with a Favourable Lipid Profile in the General Population.

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Simon Oelmann

Full Text Available Irisin is a myokine, which is mainly inversely associated with the risk for non-communicable diseases. Irisin improves cellular energy metabolism by uncoupling the mitochondrial respiratory chain resulting in increased energy expenditure using lipids. To date potential associations between irisin concentration and lipid profile are poorly understood. Therefore, this investigation aimed to evaluate potential associations between irisin and lipid levels in the general population.Data of 430 men and 537 women from the population-based Study of Health in Pomerania (SHIP-TREND with available irisin and lipid concentrations were used. Analyses of variance, linear and logistic regression models adjusted for age, HBA1c, waist circumference, physical activity, smoking, alcohol consumption, systolic blood pressure, ALAT were calculated.We detected significantly inverse associations between irisin and circulating levels of total [beta coefficient 0.21 (standard error 0.08, p = 0.01], low-density cholesterol [-0.16 (0.07, p = 0.03] and triglycerides [-0.17 (0.08, p = 0.02] for men. Females without lipid lowering medication had an inverse association between irisin and total cholesterol [-0.12 (0.06, p = 0.05]. Further, male subjects with irisin concentrations in the third tertile had an increased odds for elevated low-density cholesterol [odds ratio 1.96 (95% confidence interval 1.07-3.48, p = 0.03 and triglyceride [1.95 (1.09-3.47, p = 0.02] levels, even after exclusion of subjects with lipid lowering medication. In addition, our data revealed an annual rhythm of serum irisin levels with peak levels arise in winter and summer months.This is the first investigation to report a significant association between circulating irisin and a favourable lipid profile in the general population. This may infer that higher irisin concentrations are associated with a reduced risk for non-communicable diseases.

Blood cadmium concentration and lipid profile in Korean adults

International Nuclear Information System (INIS)

Kim, Kisok

2012-01-01

Although animal experiments have shown that cadmium exposure induces alterations in lipid profiles, no epidemiological study of this relationship has been performed. The objective of this study was to evaluate the association between blood cadmium concentration and blood lipid levels in Korean adults. A cross-sectional study comprising participants (n=3903) aged 20 years or older from the 2005, 2008, and 2009 Korea National Health and Nutrition Examination Surveys was conducted. Demographic characteristics and dietary intake were obtained from the participants by questionnaire, and cadmium and lipid levels were determined by analysis of blood samples. After adjusting for demographic and dietary factors, blood concentration of cadmium was positively associated with the risk of low high-density lipoprotein cholesterol (HDL-C) in a dose-dependent manner (p for trend <0.001). In addition, the odds ratios (ORs) of a high triglyceride to HDL-C ratio was significantly increased in the high blood cadmium groups [OR=1.36; 95% confidence interval (CI), 1.03–1.79 for fourth quintile and OR=1.41; 95% CI, 1.07–1.86 for fifth quintile] compared with the lowest quintile group. However, high blood cadmium was not associated with a risk of high total cholesterol, high low-density lipoprotein cholesterol, or high triglycerides. These data suggest that an increased cadmium body burden increases the risk of dyslipidemia, mainly due to the increased risk of low HDL-C and the high ratio of triglycerides to HDL-C.

Blood cadmium concentration and lipid profile in Korean adults

Energy Technology Data Exchange (ETDEWEB)

Kim, Kisok [Department of Public Health, Keimyung University, 1000 Shindang-dong, Daegu 704-701 (Korea, Republic of)

2012-01-15

Although animal experiments have shown that cadmium exposure induces alterations in lipid profiles, no epidemiological study of this relationship has been performed. The objective of this study was to evaluate the association between blood cadmium concentration and blood lipid levels in Korean adults. A cross-sectional study comprising participants (n=3903) aged 20 years or older from the 2005, 2008, and 2009 Korea National Health and Nutrition Examination Surveys was conducted. Demographic characteristics and dietary intake were obtained from the participants by questionnaire, and cadmium and lipid levels were determined by analysis of blood samples. After adjusting for demographic and dietary factors, blood concentration of cadmium was positively associated with the risk of low high-density lipoprotein cholesterol (HDL-C) in a dose-dependent manner (p for trend <0.001). In addition, the odds ratios (ORs) of a high triglyceride to HDL-C ratio was significantly increased in the high blood cadmium groups [OR=1.36; 95% confidence interval (CI), 1.03-1.79 for fourth quintile and OR=1.41; 95% CI, 1.07-1.86 for fifth quintile] compared with the lowest quintile group. However, high blood cadmium was not associated with a risk of high total cholesterol, high low-density lipoprotein cholesterol, or high triglycerides. These data suggest that an increased cadmium body burden increases the risk of dyslipidemia, mainly due to the increased risk of low HDL-C and the high ratio of triglycerides to HDL-C.

The radon concentration profile and the flux from a pilot-scale layered tailings pile

International Nuclear Information System (INIS)

Zettwoog, P.; Fourcade, N.; Campbell, F.E.; Caplan, H.

1982-01-01

A pilot tailings model was constructed to demonstrate the feasibility of the sub-aerial technique of tailing deposition for the proposed uranium mine and mill at Key Lake, Saskatchewan. A series of radon measurements were made on the model and results obtained for the radon concentration profile in the tailings, and for the flux from the surface. The results were compared with the model calculations of Zettwoog. (U.K.)

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

Vertical distribution of chlorophyll a concentration and phytoplankton community composition from in situ fluorescence profiles: a first database for the global ocean

Science.gov (United States)

Sauzède, R.; Lavigne, H.; Claustre, H.; Uitz, J.; Schmechtig, C.; D'Ortenzio, F.; Guinet, C.; Pesant, S.

2015-10-01

In vivo chlorophyll a fluorescence is a proxy of chlorophyll a concentration, and is one of the most frequently measured biogeochemical properties in the ocean. Thousands of profiles are available from historical databases and the integration of fluorescence sensors to autonomous platforms has led to a significant increase of chlorophyll fluorescence profile acquisition. To our knowledge, this important source of environmental data has not yet been included in global analyses. A total of 268 127 chlorophyll fluorescence profiles from several databases as well as published and unpublished individual sources were compiled. Following a robust quality control procedure detailed in the present paper, about 49 000 chlorophyll fluorescence profiles were converted into phytoplankton biomass (i.e., chlorophyll a concentration) and size-based community composition (i.e., microphytoplankton, nanophytoplankton and picophytoplankton), using a method specifically developed to harmonize fluorescence profiles from diverse sources. The data span over 5 decades from 1958 to 2015, including observations from all major oceanic basins and all seasons, and depths ranging from the surface to a median maximum sampling depth of around 700 m. Global maps of chlorophyll a concentration and phytoplankton community composition are presented here for the first time. Monthly climatologies were computed for three of Longhurst's ecological provinces in order to exemplify the potential use of the data product. Original data sets (raw fluorescence profiles) as well as calibrated profiles of phytoplankton biomass and community composition are available on open access at PANGAEA, Data Publisher for Earth and Environmental Science. Raw fluorescence profiles: http://doi.pangaea.de/10.1594/PANGAEA.844212 and Phytoplankton biomass and community composition: http://doi.pangaea.de/10.1594/PANGAEA.844485

Prediction of Drug-Drug Interactions with Bupropion and Its Metabolites as CYP2D6 Inhibitors Using a Physiologically-Based Pharmacokinetic Model.

Science.gov (United States)

Xue, Caifu; Zhang, Xunjie; Cai, Weimin

2017-12-21

The potential of inhibitory metabolites of perpetrator drugs to contribute to drug-drug interactions (DDIs) is uncommon and underestimated. However, the occurrence of unexpected DDI suggests the potential contribution of metabolites to the observed DDI. The aim of this study was to develop a physiologically-based pharmacokinetic (PBPK) model for bupropion and its three primary metabolites-hydroxybupropion, threohydrobupropion and erythrohydrobupropion-based on a mixed "bottom-up" and "top-down" approach and to contribute to the understanding of the involvement and impact of inhibitory metabolites for DDIs observed in the clinic. PK profiles from clinical researches of different dosages were used to verify the bupropion model. Reasonable PK profiles of bupropion and its metabolites were captured in the PBPK model. Confidence in the DDI prediction involving bupropion and co-administered CYP2D6 substrates could be maximized. The predicted maximum concentration (C max ) area under the concentration-time curve (AUC) values and C max and AUC ratios were consistent with clinically observed data. The addition of the inhibitory metabolites into the PBPK model resulted in a more accurate prediction of DDIs (AUC and C max ratio) than that which only considered parent drug (bupropion) P450 inhibition. The simulation suggests that bupropion and its metabolites contribute to the DDI between bupropion and CYP2D6 substrates. The inhibitory potency from strong to weak is hydroxybupropion, threohydrobupropion, erythrohydrobupropion, and bupropion, respectively. The present bupropion PBPK model can be useful for predicting inhibition from bupropion in other clinical studies. This study highlights the need for caution and dosage adjustment when combining bupropion with medications metabolized by CYP2D6. It also demonstrates the feasibility of applying the PBPK approach to predict the DDI potential of drugs undergoing complex metabolism, especially in the DDI involving inhibitory

An alkaline comet assay study on the antimalarial drug atovaquone in human peripheral blood lymphocytes: a study based on clinically relevant concentrations.

Science.gov (United States)

Dinter, Domagoj; Gajski, Goran; Garaj-Vrhovac, Vera

2013-01-01

Atovaquone, a hydroxynaphthoquinone, is an anti-parasite drug, selectively targeting the mitochondrial respiratory chain of malaria parasite. It is used for both the treatment and prevention of malaria, usually in a fixed combination with proguanil. Although atovaquone has not often been associated with severe adverse reactions in the recommended dosages and has a relatively favorable side effect profile, the present study was undertaken to evaluate its cytogenotoxic potential towards human peripheral blood lymphocytes. Two different concentrations of atovaquone found in plasma when used in fixed-dose combination with proguanile hydrochloride were used with and without S9 metabolic activation: 2950 ng ml(-1) used for prophylactic treatment and 11 800 ng ml(-1) used in treatment of malaria. The results showed that lymphocyte viability was not affected after the treatment, suggesting that atovaquone was not cytotoxic in the given concentrations. With the alkaline comet assay we demonstrated that in human peripheral blood lymphocytes no significant changes in comet parameters occurred after the treatment. There were no differences in tested parameters with the addition of S9 metabolic activation, indicating that atovaquone either has no metabolite or it is not toxic in the given concentrations. Since no effects were observed after the treatment, it is to be concluded that atovaquone is safe from the aspect of genototoxicity in the recommended dosages. Copyright © 2011 John Wiley & Sons, Ltd.

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.

Construction of Multi-Year Time-Series Profiles of Suspended Particulate Inorganic Matter Concentrations Using Machine Learning Approach

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Pannimpullath R. Renosh

2017-12-01

Full Text Available Hydro-sedimentary numerical models have been widely employed to derive suspended particulate matter (SPM concentrations in coastal and estuarine waters. These hydro-sedimentary models are computationally and technically expensive in nature. Here we have used a computationally less-expensive, well-established methodology of self-organizing maps (SOMs along with a hidden Markov model (HMM to derive profiles of suspended particulate inorganic matter (SPIM. The concept of the proposed work is to benefit from all available data sets through the use of fusion methods and machine learning approaches that are able to process a growing amount of available data. This approach is applied to two different data sets entitled “Hidden” and “Observable”. The hidden data are composed of 15 months (27 September 2007 to 30 December 2008 of hourly SPIM profiles extracted from the Regional Ocean Modeling System (ROMS. The observable data include forcing parameter variables such as significant wave heights ( H s and H s 50 (50 days from the Wavewatch 3-HOMERE database and barotropic currents ( U b a r and V b a r from the Iberian–Biscay–Irish (IBI reanalysis data. These observable data integrate hourly surface samples from 1 February 2002 to 31 December 2012. The time-series profiles of the SPIM have been derived from four different stations in the English Channel by considering 15 months of output hidden data from the ROMS as a statistical representation of the ocean for ≈11 years. The derived SPIM profiles clearly show seasonal and tidal fluctuations in accordance with the parent numerical model output. The surface SPIM concentrations of the derived model have been validated with satellite remote sensing data. The time series of the modeled SPIM and satellite-derived SPIM show similar seasonal fluctuations. The ranges of concentrations for the four stations are also in good agreement with the corresponding satellite data. The high accuracy of the

Mg concentration profile and its control in the low temperature grown Mg-doped GaN epilayer

Science.gov (United States)

Liu, S. T.; Yang, J.; Zhao, D. G.; Jiang, D. S.; Liang, F.; Chen, P.; Zhu, J. J.; Liu, Z. S.; Liu, W.; Xing, Y.; Zhang, L. Q.; Wang, W. J.; Li, M.; Zhang, Y. T.; Du, G. T.

2018-01-01

In this work, the Cp2Mg flux and growth pressure influence to Mg doping concentration and depth profiles is studied. From the SIMS measurement we found that a transition layer exists at the bottom region of the layer in which the Mg doping concentration changes gradually. The thickness of transition layer decreases with the increases of Mg doping concentration. Through analysis, we found that this is caused by Ga memory effect which the Ga atoms stay residual in MOCVD system will react with Mg source, leading a transition layer formation and improve the growth rate. And the Ga memory effect can be well suppressed by increasing Mg doping concentration and growth pressure and thus get a steep Mg doping at the bottom region of p type layer.

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

Global mass spectrometry and transcriptomics array based drug profiling provides novel insight into glucosamine induced endoplasmic reticulum stress

DEFF Research Database (Denmark)

Carvalho, Ana Sofia; Ribeiro, Helena; Voabil, Paula

2014-01-01

We investigated the molecular effects of glucosamine supplements, a popular and safe alternative to nonsteroidal anti-inflammatory drugs, for decreasing pain, inflammation, and maintaining healthy joints. Numerous studies have reported an array of molecular effects after glucosamine treatment. We...... questioned whether the differences in the effects observed in previous studies were associated with the focus on a specific subproteome or with the use of specific cell lines or tissues. To address this question, global mass spectrometry- and transcription array-based glucosamine drug profiling was performed....... Further, we hypothesize that O-HexNAcylation induced by glucosamine treatment enhances protein trafficking....

Evaluation of Drug-Drug Interaction Potential Between Sacubitril/Valsartan (LCZ696) and Statins Using a Physiologically Based Pharmacokinetic Model.

Science.gov (United States)

Lin, Wen; Ji, Tao; Einolf, Heidi; Ayalasomayajula, Surya; Lin, Tsu-Han; Hanna, Imad; Heimbach, Tycho; Breen, Christopher; Jarugula, Venkateswar; He, Handan

2017-05-01

Sacubitril/valsartan (LCZ696) has been approved for the treatment of heart failure. Sacubitril is an in vitro inhibitor of organic anion-transporting polypeptides (OATPs). In clinical studies, LCZ696 increased atorvastatin C max by 1.7-fold and area under the plasma concentration-time curve by 1.3-fold, but had little or no effect on simvastatin or simvastatin acid exposure. A physiologically based pharmacokinetics modeling approach was applied to explore the underlying mechanisms behind the statin-specific LCZ696 drug interaction observations. The model incorporated OATP-mediated clearance (CL int,T ) for simvastatin and simvastatin acid to successfully describe the pharmacokinetic profiles of either analyte in the absence or presence of LCZ696. Moreover, the model successfully described the clinically observed drug effect with atorvastatin. The simulations clarified the critical parameters responsible for the observation of a low, yet clinically relevant, drug-drug interaction DDI between sacubitril and atorvastatin and the lack of effect with simvastatin acid. Atorvastatin is administered in its active form and rapidly achieves C max that coincide with the low C max of sacubitril. In contrast, simvastatin requires a hydrolysis step to the acid form and therefore is not present at the site of interactions at sacubitril concentrations that are inhibitory. Similar models were used to evaluate the drug-drug interaction risk for additional OATP-transported statins which predicted to maximally result in a 1.5-fold exposure increase. Copyright © 2017. Published by Elsevier Inc.

Concentration- and time-dependent genotoxicity profiles of isoprene monoepoxides and diepoxide, and the cross-linking potential of isoprene diepoxide in cells

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Yan Li

2014-01-01

Full Text Available Isoprene, a possible carcinogen, is a petrochemical and a natural product being primarily produced by plants. It is biotransformed to 2-ethenyl-2-methyloxirane (IP-1,2-O and 2-(1-methylethenyloxirane (IP-3,4-O, both of which can be further metabolized to 2-methyl-2,2′-bioxirane (MBO. MBO is mutagenic, but IP-1,2-O and IP-3,4-O are not. While IP-1,2-O has been reported being genotoxic, the genotoxicity of IP-3,4-O and MBO, and the cross-linking potential of MBO have not been examined. In the present study, we used the comet assay to investigate the concentration- and time-dependent genotoxicity profiles of the three metabolites and the cross-linking potential of MBO in human hepatocyte L02 cells. For the incubation time of 1 h, all metabolites showed positive concentration-dependent profiles with a potency rank order of IP-3,4-O > MBO > IP-1,2-O. In human hepatocellular carcinoma (HepG2 and human leukemia (HL60 cells, IP-3,4-O was still more potent in inducing DNA breaks than MBO at high concentrations (>200 μM, although at low concentrations (≤200 μM IP-3,4-O exhibited slightly lower or similar potency to MBO. Interestingly, their time-dependent genotoxicity profiles (0.5–4 h in L02 cells were different from each other: IP-1,2-O and MBO (200 μM exhibited negative and positive profiles, respectively, with IP-3,4-O lying in between, namely, IP-3,4-O-caused DNA breaks did not change over the exposure time. Further experiments demonstrated that hydrolysis of IP-1,2-O contributed to the negative profile and MBO induced cross-links at high concentrations and long incubation times. Collectively, the results suggested that IP-3,4-O might play a significant role in the toxicity of isoprene.

Schizophrenia and the use of alcohol and other drugs: epidemiological profile

Directory of Open Access Journals (Sweden)

Jássia Lopes Freitas da Silveira

2014-09-01

Full Text Available This study aimed at characterizing the social demographic and clinical profile of patients with schizophrenia and alcohol and other drugs addiction of a Center of Psychosocial Attention III of the Central-Western region of the State of Minas Gerais, Brazil, from July 1st, 1997 to July 1st, 2013. It is a descriptive, observational and retrospective epidemiological study. The sample consisted of 1618 patients and the main results were: prevalence of male patients (60.4% and the age range was 21 - 30 years old (48.2%, presented more expressive abuse of alcohol (35.6% and cannabinoids (29.5% and the most frequent diagnosis of paranoid schizophrenia (41.7%. Understanding the factors associated to the coexistence of both conditions can provide a basis for the creation of interventional strategies to improve the prognosis of these patients.

Transcriptional profiling of the dose response: a more powerful approach for characterizing drug activities.

Directory of Open Access Journals (Sweden)

Rui-Ru Ji

2009-09-01

Full Text Available The dose response curve is the gold standard for measuring the effect of a drug treatment, but is rarely used in genomic scale transcriptional profiling due to perceived obstacles of cost and analysis. One barrier to examining transcriptional dose responses is that existing methods for microarray data analysis can identify patterns, but provide no quantitative pharmacological information. We developed analytical methods that identify transcripts responsive to dose, calculate classical pharmacological parameters such as the EC50, and enable an in-depth analysis of coordinated dose-dependent treatment effects. The approach was applied to a transcriptional profiling study that evaluated four kinase inhibitors (imatinib, nilotinib, dasatinib and PD0325901 across a six-logarithm dose range, using 12 arrays per compound. The transcript responses proved a powerful means to characterize and compare the compounds: the distribution of EC50 values for the transcriptome was linked to specific targets, dose-dependent effects on cellular processes were identified using automated pathway analysis, and a connection was seen between EC50s in standard cellular assays and transcriptional EC50s. Our approach greatly enriches the information that can be obtained from standard transcriptional profiling technology. Moreover, these methods are automated, robust to non-optimized assays, and could be applied to other sources of quantitative data.

Managing anthelmintic resistance-Variability in the dose of drug reaching the target worms influences selection for resistance?

Science.gov (United States)

Leathwick, Dave M; Luo, Dongwen

2017-08-30

The concentration profile of anthelmintic reaching the target worms in the host can vary between animals even when administered doses are tailored to individual liveweight at the manufacturer's recommended rate. Factors contributing to variation in drug concentration include weather, breed of animal, formulation and the route by which drugs are administered. The implications of this variability for the development of anthelmintic resistance was investigated using Monte-Carlo simulation. A model framework was established where 100 animals each received a single drug treatment. The 'dose' of drug allocated to each animal (i.e. the concentration-time profile of drug reaching the target worms) was sampled at random from a distribution of doses with mean m and standard deviation s. For each animal the dose of drug was used in conjunction with pre-determined dose-response relationships, representing single and poly-genetic inheritance, to calculate efficacy against susceptible and resistant genotypes. These data were then used to calculate the overall change in resistance gene frequency for the worm population as a result of the treatment. Values for m and s were varied to reflect differences in both mean dose and the variability in dose, and for each combination of these 100,000 simulations were run. The resistance gene frequency in the population after treatment increased as m decreased and as s increased. This occurred for both single and poly-gene models and for different levels of dominance (survival under treatment) of the heterozygote genotype(s). The results indicate that factors which result in lower and/or more variable concentrations of active reaching the target worms are more likely to select for resistance. The potential of different routes of anthelmintic administration to play a role in the development of anthelmintic resistance is discussed. Copyright © 2017 Elsevier B.V. All rights reserved.

Measured and modelled concentrations and vertical profiles of airborne particulate matter within the boundary layer of a street canyon

International Nuclear Information System (INIS)

Colls, J.J.; Micallef, A.

1999-01-01

Concentrations and vertical profiles of various fractions of airborne particulate matter (suspended particulate matter (SPM), PM 10 and PM 2.5 ) have been measured over the first three metres from ground in a street canyon. Measurements were carried out using automated near real-time apparatus called the Kinetic Sequential Sampling (KSS) system. KSS system is essentially an electronically-controlled lift carrying a real-time particle monitor for sampling air sequentially, at different heights within the breathing zone, which includes all heights within the surface layer of a street canyon at which people may breathe. Data is automatically logged at the different receptor levels, for the determination of the average vertical concentration profile of airborne particulate matter. For measuring the airborne particle concentration, a Grimm Dust Monitor 1.104/5 was used. The recorded data also allows for time series analysis of airborne particulate matter concentration at different heights. Time series data and hourly-average vertical concentration profiles in the boundary layer of the confines of a street are thought to be mainly determined by traffic emissions and traffic associated processes. Hence the measured data were compared with results of a street canyon emission-dispersion model in time and space. This Street Level Air Quality (SLAQ) model employs the plume-box technique and includes modules for simulating vehicle-generated effects such as thermally- and mechanically-generated turbulence and resuspension of road dust. Environmental processes, such as turbulence resulting from surface sensible heat and the formation of sulphate aerosol from sulphur dioxide exhaust emissions, are taken into account. The paper presents an outline description of the measuring technique and model used, and a comparison of the measured and modelled data

Amino acid profile of metabolisable protein in lactating dairy cows is affected by dry matter concentration in grass-clover silage

DEFF Research Database (Denmark)

Johansen, Marianne; Lund, Peter; Weisbjerg, Martin Riis

2018-01-01

Our previous study showed that supply of metabolisable protein (MP) to lactating dairy cows increased with increasing dry matter (DM) concentration in grass-clover silage. The aim of this study was to examine how amino acid (AA) profile of MP was affected by silage DM concentration. Eight grass-c...

Pharmacokinetics in Drug Discovery: An Exposure-Centred Approach to Optimising and Predicting Drug Efficacy and Safety.

Science.gov (United States)

Reichel, Andreas; Lienau, Philip

2016-01-01

The role of pharmacokinetics (PK) in drug discovery is to support the optimisation of the absorption, distribution, metabolism and excretion (ADME) properties of lead compounds with the ultimate goal to attain a clinical candidate which achieves a concentration-time profile in the body that is adequate for the desired efficacy and safety profile. A thorough characterisation of the lead compounds aiming at the identification of the inherent PK liabilities also includes an early generation of PK/PD relationships linking in vitro potency and target exposure/engagement with expression of pharmacological activity (mode-of-action) and efficacy in animal studies. The chapter describes an exposure-centred approach to lead generation, lead optimisation and candidate selection and profiling that focuses on a stepwise generation of an understanding between PK/exposure and PD/efficacy relationships by capturing target exposure or surrogates thereof and cellular mode-of-action readouts in vivo. Once robust PK/PD relationship in animal PD models has been constructed, it is translated to anticipate the pharmacologically active plasma concentrations in patients and the human therapeutic dose and dosing schedule which is also based on the prediction of the PK behaviour in human as described herein. The chapter outlines how the level of confidence in the predictions increases with the level of understanding of both the PK and the PK/PD of the new chemical entities (NCE) in relation to the disease hypothesis and the ability to propose safe and efficacious doses and dosing schedules in responsive patient populations. A sound identification of potential drug metabolism and pharmacokinetics (DMPK)-related development risks allows proposing of an effective de-risking strategy for the progression of the project that is able to reduce uncertainties and to increase the probability of success during preclinical and clinical development.

Real-time investigation of human topoisomerase I reaction kinetics using an optical sensor: a fast method for drug screening and determination of active enzyme concentrations.

Science.gov (United States)

Kristoffersen, Emil L; Jørgensen, Line A; Franch, Oskar; Etzerodt, Michael; Frøhlich, Rikke; Bjergbæk, Lotte; Stougaard, Magnus; Ho, Yi-Ping; Knudsen, Birgitta R

2015-06-07

Human DNA topoisomerase I (hTopI) is a nuclear enzyme that catalyzes relaxation of super helical tension that arises in the genome during essential DNA metabolic processes. This is accomplished through a common reaction mechanism shared among the type IB topoisomerase enzymes, including eukaryotic and poxvirus topoisomerase I. The mechanism of hTopI is specifically targeted in cancer treatment using camptothecin derivatives. These drugs convert the hTopI activity into a cellular poison, and hence the cytotoxic effects of camptothecin derivatives correlate with the hTopI activity. Therefore, fast and reliable techniques for high throughput measurements of hTopI activity are of high clinical interest. Here we demonstrate potential applications of a fluorophore-quencher based DNA sensor designed for measurement of hTopI cleavage-ligation activities, which are the catalytic steps affected by camptothecin. The kinetic analysis of the hTopI reaction with the DNA sensor exhibits a characteristic burst profile. This is the result of a two-step ping-pong reaction mechanism, where a fast first reaction, the one creating the signal, is followed by a slower second reaction necessary for completion of the catalytic cycle. Hence, the burst profile holds information about two reactions in the enzymatic mechanism. Moreover, it allows the amount of active enzyme in the reaction to be determined. The presented results pave the way for future high throughput drug screening and the potential of measuring active hTopI concentrations in clinical samples for individualized treatment.

Profile of drug administration errors in anesthesia among anesthesiologists from Santa Catarina

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Thomas Rolf Erdmann

2016-02-01

Full Text Available INTRODUCTION: Anesthesiology is the only medical specialty that prescribes, dilutes, and administers drugs without conferral by another professional. Adding to the high frequency of drug administration, a propitious scenario to errors is created. OBJECTIVE: Access the prevalence of drug administration errors during anesthesia among anesthesiologists from Santa Catarina, the circumstances in which they occurred, and possible associated factors. MATERIALS AND METHODS: An electronic questionnaire was sent to all anesthesiologists from Sociedade de Anestesiologia do Estado de Santa Catarina, with direct or multiple choice questions on responder demographics and anesthesia practice profile; prevalence of errors, type and consequence of error; and factors that may have contributed to the errors. RESULTS: Of the respondents, 91.8% reported they had committed administration errors, adding the total error of 274 and mean of 4.7 (6.9 errors per respondent. The most common error was replacement (68.4%, followed by dose error (49.1%, and omission (35%. Only 7% of respondents reported neuraxial administration error. Regarding circumstances of errors, they mainly occurred in the morning (32.7%, in anesthesia maintenance (49%, with 47.8% without harm to the patient and 1.75% with the highest morbidity and irreversible damage, and 87.3% of cases with immediate identification. As for possible contributing factors, the most frequent were distraction and fatigue (64.9% and misreading of labels, ampoules, or syringes (54.4%. CONCLUSION: Most respondents committed more than one error in anesthesia administration, mainly justified as a distraction or fatigue, and of low gravity.

Profiles determination of Cesium-137 concentration in the main areas of Goiania radiological accident

International Nuclear Information System (INIS)

Rocca, H.C.C.; Aoki, P.E.; Enokihara, C.T.; Rostelato, M.; Lepki, V.; Bambalas, E.

1988-07-01

This paper describes the profiles determination of cesium-137 concentration measured in function of depth and applied in seven areas considered as the main contamination focus. Since november 14th to december 17th 1987, 125 soil drillings were made and a total of 740 soil samples were prepared. Obtained data allowed to calculate the soil volume to be removed from contaminate areas. It was verified that after remotions the remaining activity was approximately 0,89Ci. (author) [pt

Understanding Drug Release Data through Thermodynamic Analysis.

Science.gov (United States)

Freire, Marjorie Caroline Liberato Cavalcanti; Alexandrino, Francisco; Marcelino, Henrique Rodrigues; Picciani, Paulo Henrique de Souza; Silva, Kattya Gyselle de Holanda E; Genre, Julieta; Oliveira, Anselmo Gomes de; Egito, Eryvaldo Sócrates Tabosa do

2017-06-13

Understanding the factors that can modify the drug release profile of a drug from a Drug-Delivery-System (DDS) is a mandatory step to determine the effectiveness of new therapies. The aim of this study was to assess the Amphotericin-B (AmB) kinetic release profiles from polymeric systems with different compositions and geometries and to correlate these profiles with the thermodynamic parameters through mathematical modeling. Film casting and electrospinning techniques were used to compare behavior of films and fibers, respectively. Release profiles from the DDSs were performed, and the mathematical modeling of the data was carried out. Activation energy, enthalpy, entropy and Gibbs free energy of the drug release process were determined. AmB release profiles showed that the relationship to overcome the enthalpic barrier was PVA-fiber > PVA-film > PLA-fiber > PLA-film. Drug release kinetics from the fibers and the films were better fitted on the Peppas-Sahlin and Higuchi models, respectively. The thermodynamic parameters corroborate these findings, revealing that the AmB release from the evaluated systems was an endothermic and non-spontaneous process. Thermodynamic parameters can be used to explain the drug kinetic release profiles. Such an approach is of utmost importance for DDS containing insoluble compounds, such as AmB, which is associated with an erratic bioavailability.

Understanding Drug Release Data through Thermodynamic Analysis

Science.gov (United States)

Freire, Marjorie Caroline Liberato Cavalcanti; Alexandrino, Francisco; Marcelino, Henrique Rodrigues; Picciani, Paulo Henrique de Souza; Silva, Kattya Gyselle de Holanda e; Genre, Julieta; de Oliveira, Anselmo Gomes; do Egito, Eryvaldo Sócrates Tabosa

2017-01-01

Understanding the factors that can modify the drug release profile of a drug from a Drug-Delivery-System (DDS) is a mandatory step to determine the effectiveness of new therapies. The aim of this study was to assess the Amphotericin-B (AmB) kinetic release profiles from polymeric systems with different compositions and geometries and to correlate these profiles with the thermodynamic parameters through mathematical modeling. Film casting and electrospinning techniques were used to compare behavior of films and fibers, respectively. Release profiles from the DDSs were performed, and the mathematical modeling of the data was carried out. Activation energy, enthalpy, entropy and Gibbs free energy of the drug release process were determined. AmB release profiles showed that the relationship to overcome the enthalpic barrier was PVA-fiber > PVA-film > PLA-fiber > PLA-film. Drug release kinetics from the fibers and the films were better fitted on the Peppas–Sahlin and Higuchi models, respectively. The thermodynamic parameters corroborate these findings, revealing that the AmB release from the evaluated systems was an endothermic and non-spontaneous process. Thermodynamic parameters can be used to explain the drug kinetic release profiles. Such an approach is of utmost importance for DDS containing insoluble compounds, such as AmB, which is associated with an erratic bioavailability. PMID:28773009

A Novel Drug-Mouse Phenotypic Similarity Method Detects Molecular Determinants of Drug Effects.

Directory of Open Access Journals (Sweden)

Jeanette Prinz

2016-09-01

Full Text Available The molecular mechanisms that translate drug treatment into beneficial and unwanted effects are largely unknown. We present here a novel approach to detect gene-drug and gene-side effect associations based on the phenotypic similarity of drugs and single gene perturbations in mice that account for the polypharmacological property of drugs. We scored the phenotypic similarity of human side effect profiles of 1,667 small molecules and biologicals to profiles of phenotypic traits of 5,384 mouse genes. The benchmarking with known relationships revealed a strong enrichment of physical and indirect drug-target connections, causative drug target-side effect links as well as gene-drug links involved in pharmacogenetic associations among phenotypically similar gene-drug pairs. The validation by in vitro assays and the experimental verification of an unknown connection between oxandrolone and prokineticin receptor 2 reinforces the ability of this method to provide new molecular insights underlying drug treatment. Thus, this approach may aid in the proposal of novel and personalized treatments.

Comparison of gene expression and fatty acid profiles in concentrate and forage finished beef.

Science.gov (United States)

Buchanan, J W; Garmyn, A J; Hilton, G G; VanOverbeke, D L; Duan, Q; Beitz, D C; Mateescu, R G

2013-01-01

Fatty acid profiles and intramuscular expression of genes involved in fatty acid metabolism were characterized in concentrate- (CO) and forage- (FO) based finishing systems. Intramuscular samples from the adductor were taken at slaughter from 99 heifers finished on a CO diet and 58 heifers finished on a FO diet. Strip loins were obtained at fabrication to evaluate fatty acid profiles of LM muscle for all 157 heifers by using gas chromatography fatty acid methyl ester analysis. Composition was analyzed for differences by using the General Linear Model (GLM) procedure in SAS. Differences in fatty acid profile included a greater atherogenic index, greater percentage total MUFA, decreased omega-3 to omega-6 ratio, decreased percentage total PUFA, and decreased percentage omega-3 fatty acids in CO- compared with FO-finished heifers (P0.05). Upregulation was observed for PPARγ, fatty acid synthase (FASN), and fatty acid binding protein 4 (FABP4) in FO-finished compared with CO-finished heifers in both atherogenic index categories (P<0.05). Upregulation of diglyceride acyl transferase 2 (DGAT2) was observed in FO-finished heifers with a HAI (P<0.05). Expression of steroyl Co-A desaturase (SCD) was upregulated in CO-finished heifers with a LAI, and downregulated in FO-finished heifers with a HAI (P<0.05). Expression of adiponectin (ADIPOQ) was significantly downregulated in CO-finished heifers with a HAI compared with all other categories (P<0.05). The genes identified in this study which exhibit differential regulation in response to diet or in animals with extreme fatty acid profiles may provide genetic markers for selecting desirable fatty acid profiles in future selection programs.

Oxygen 18 concentration profile measurements near the surface by 18O(p,α)15N resonance reaction

International Nuclear Information System (INIS)

Amsel, G.; David, D.

1975-01-01

The method of spectrum reduction in nuclear reaction microanalysis does not allow to obtain depth resolutions better than the order of 2000A. Resolutions of the order of 200A may be obtained by using the narrow resonance technique, when applied to thin films. The latter technique was extended to thick targets, with deep concentration profiles presenting a sharp gradient near the surface. This method is presented and illustrated by the study of 18 O profiles in oxygen diffusion measurements in growing ZrO 2 , using the 629keV resonance of the reaction 18 O(p,α) 15 N [fr

Stability-indicating HPLC-DAD/UV-ESI/MS impurity profiling of the anti-malarial drug lumefantrine.

Science.gov (United States)

Verbeken, Mathieu; Suleman, Sultan; Baert, Bram; Vangheluwe, Elien; Van Dorpe, Sylvia; Burvenich, Christian; Duchateau, Luc; Jansen, Frans H; De Spiegeleer, Bart

2011-02-28

Lumefantrine (benflumetol) is a fluorene derivative belonging to the aryl amino alcohol class of anti-malarial drugs and is commercially available in fixed combination products with β-artemether. Impurity characterization of such drugs, which are widely consumed in tropical countries for malaria control programmes, is of paramount importance. However, until now, no exhaustive impurity profile of lumefantrine has been established, encompassing process-related and degradation impurities in active pharmaceutical ingredients (APIs) and finished pharmaceutical products (FPPs). Using HPLC-DAD/UV-ESI/ion trap/MS, a comprehensive impurity profile was established based upon analysis of market samples as well as stress, accelerated and long-term stability results. In-silico toxicological predictions for these lumefantrine related impurities were made using Toxtree® and Derek®. Several new impurities are identified, of which the desbenzylketo derivative (DBK) is proposed as a new specified degradant. DBK and the remaining unspecified lumefantrine related impurities are predicted, using Toxtree® and Derek®, to have a toxicity risk comparable to the toxicity risk of the API lumefantrine itself. From unstressed, stressed and accelerated stability samples of lumefantrine API and FPPs, nine compounds were detected and characterized to be lumefantrine related impurities. One new lumefantrine related compound, DBK, was identified and characterized as a specified degradation impurity of lumefantrine in real market samples (FPPs). The in-silico toxicological investigation (Toxtree® and Derek®) indicated overall a toxicity risk for lumefantrine related impurities comparable to that of the API lumefantrine itself.

Thermal Profile of the Lunar Interior Constrained by Revised Estimates of Concentrations of Heat Producing Elements

Science.gov (United States)

Fuqua-Haviland, H.; Panovska, S.; Mallik, A.; Bremner, P. M.; McDonough, W. F.

2017-12-01

Constraining the heat producing element (HPE) concentrations of the Moon is important for understanding the thermal state of the interior. The lunar HPE budget is debated to be suprachondritic [1] to chondritic [2]. The Moon is differentiated, thus, each reservoir has a distinct HPE signature complicating this effort. The thermal profile of the lunar interior has been constructed using HPE concentrations of an ordinary chondrite (U = 0.0068 ppm; Th = 0.025 ppm; K = 17 ppm) which yields a conservative low estimate [2, 3, 4]. A later study estimated the bulk lunar mantle HPE concentrations (U = 0.039 ppm; Th = 0.15 ppm; K = 212 ppm) based on measurements of Apollo pyroclastic glasses [5] assuming that these glasses represent the least fractionated, near-primary lunar mantle melts, hence, are the best proxies for capturing mantle composition. In this study, we independently validate the revised estimate by using HPE concentrations [5] to construct a conductive lunar thermal profile, or selenotherm. We compare our conductive profile to the range of valid temperatures. We demonstrate the HPE concentrations reported by [5], when used in a simple 1D spherical thermal conduction equation, yield an impossibly hot mantle with temperatures in excess of 4,000 K (Fig 1). This confirms their revised estimate is not representative of the bulk lunar mantle, and perhaps only representative of a locally enriched mantle domain. We believe that their Low-Ti avg. source estimate (Th = 0.055 ppm, Th/U=4; K/U=1700), with the least KREEP assimilation is the closest representation of the bulk lunar mantle, producing 3E-12 W/kg of heat. This estimate is close to that of the Earth (5E-12 W/kg), indicating that the bulk Earth and lunar mantles are similar in their HPE constituents. We have used the lunar mantle heat production, in conjunction with HPE estimates of the Fe-Ti-rich cumulates (high Ti-source estimate from [5]) and measurements of crustal ferroan anorthite [6], to capture the

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.

Formulation and In-vitro Evaluation of Tretinoin Microemulsion as a Potential Carrier for Dermal Drug Delivery.

Science.gov (United States)

Mortazavi, Seyed Alireza; Pishrochi, Sanaz; Jafari Azar, Zahra

2013-01-01

In this study, tretinoin microemulsion has been formulated based on phase diagram studies by changing the amounts and proportions of inactive ingredients, such as surfactants, co-surfactants and oils. The effects of these variables have been determined on microemulsion formation, particle size of the dispersed phase and release profile of tretinoin from microemulsion through dialysis membrane. In released studies, static Franz diffusion cells mounted with dialysis membrane were used. Sampling was conducted every 3 h at room temperature over a period of 24 h. The amount of released drug was measured with UV-spectrophotometer and the percentage of drug released was calculated. Based on the results obtained, the oil phase concentration had a proportional effect on particle size which can consequently influence on drug release. The particle size and the amount of released drug were affected by the applied surfactants. The components of the optimized microemulsion formulation were 15% olive oil, 12% propylene glycol (as co-surfactant), 33% Tween(®)80 (as surfactant) and 40% distilled water, which was tested for viscosity and rheological behavior. The prepared tretinoin microemulsion showed pseudoplastic-thixotropic behavior. The profile of drug release follows zero order kinetics. The optimized tretinoin microemulsion showed enhanced in-vitro release profile compared to the commercial gels and creams.

Drug Interactions between some antiepileptic and certain hypocholesterolaemic drugs in irradiated animals

International Nuclear Information System (INIS)

Shaaban, D.M.L.

2015-01-01

Drug Interactions between antiepileptic drug such as phenytoin and certain hypercholesterolaemia drug namely rosuvastatin were investigated on several biological parameters. Phenytoin (60 mg/kg i.p) and rosuvastatin (1.25 mg/kg i.p) were given either alone and in combination to normal and irradiated animals to investigate drug interactions between the test drugs. Anticonvulsant activity was evaluated using pentylenetetrazole in a dose (80 mg/kg i.p) in normal and irradiated mice. Brain neurotransmitters (glutamate and GABA) were investigated. Lipid profile (total cholesterol (TC), Triacylglycerol (TG), High density lipoprotein-cholesterol (HDL-C) and low density lipoprotein- cholesterol (LDL-C) were determined. Liver functions such as serum Aspartate amino transferase (AST) and serum alanine amino transferase (ALT) were also estimated. Oxidative stress bio markers namely serum malondialdehyde (MDA), serum nitric oxide (NO) and blood superoxide dismutase activity (SOD) were studied. Histopathological examinations of brain and liver tissues were performed. Administration of phenytoin concurrently with rosuvastatin is not recommended in patients receiving radiotherapy as dangerous side effects on liver functions and lipid profile may occur. The interactions between the two drugs in normal rats improve liver functions and lipid peroxidation. Apart from the action of the combination on total cholesterol, it improves lipid profile pattern. Rosuvastatin administration in combination with phenytoin may have additive anticonvulsant activity.

Molecular characterization and drug susceptibility profile of a Mycobacterium avium subspecies avium isolate from a dog with disseminated infection.

Science.gov (United States)

Armas, Federica; Furlanello, Tommaso; Camperio, Cristina; Trotta, Michele; Novari, Gianluca; Marianelli, Cinzia

2016-01-12

Mycobacterium avium complex (MAC) infections have been described in many mammalian species including humans and pets. We isolated and molecularly typed the causative agent of a rare case of disseminated mycobacteriosis in a dog. We identified the pathogen as a M. avium subspecies avium by sequencing the partial genes gyrB and rpsA. Considering the zoonotic potential of this infection, and in an attempt to ensure the most effective treatment for the animal, we also determined the drug susceptibility profile of the isolate to the most common drugs used to treat MAC disease in humans. The pathogen was tested in vitro against the macrolide clarithromycin, as well as against amikacin, ciprofloxacin, rifampicin, ethambutol and linezolid by the resazurin microdilution assay. It was found to be sensitive to all tested drugs save ethambutol. Despite the fact that the pathogen was sensitive to the therapies administered, the dog's overall clinical status worsened, and the animal died shortly after antimicrobial susceptibility results became available. Nucleotide sequencing of the embB gene, the target gene most commonly associated with ethambutol resistance, showed new missense mutations when compared to sequences available in public databases. In conclusion, we molecularly identified the MAC pathogen and determined its drug susceptibility profile in a relatively short period of time (seven days). We also characterized new genetic mutations likely to have been involved in the observed ethambutol resistance. Our results confirm the usefulness of both the gyrB and the rpsA genes as biomarkers for an accurate identification and differentiation of MAC pathogens.

[Comparison of family functioning profile in adolescents with and without drug-dependency in a high school].

Science.gov (United States)

Cruz-Salmerón, Víctor Hugo; Martínez-Martínez, Martha Leticia; Garibay-López, Leticia; Camacho-Calderón, Nicolás

2011-02-01

To compare the family functioning profile (FFP) in adolescents addicted to drugs and those not addicted to drugs. Cross-sectional study comparative. A high school in Querétaro State, Mexico. Study of 63 adolescents with and without addiction, of both sexes between the ages of 13 and 19, enrolled in high school; two groups formed, one not addicted to drugs (systematic probabilistic sampling was carried out); and compared with drug addicts (database). FFP(Alpha Cronbach 91). Descriptive and inferential statistical analysis. Adolescents with drug addiction (n=20), average age 17.5±0.4 (range 16-19), and group of non-addicts (n=43), average age 16.9±0.1 (range 15-18) and P=0.000. All the adolescents lived in an urban area with a predominantly simple nuclear modern, working family type. Half (50%) of addicted adolescents came from broken families P=0.002. The dispersion phase was a protective factor in preventing drug addiction in adolescents (P=0.003 OR 0.6 95% Cl;1.8-21.0). Significant statistical differences were observed in authority (OR=29.7, 95% Cl; 5.8-150.5), supervision (OR 10.3, 95% Cl; 2.8-37.2) and support (OR 0.04, 95% Cl; 5.5-109.8). The overall family dysfunctionality, (P=0.000, OR 1.8, 95% Cl; 1.3-2.3). Dysfunctional families are a risk factor for drug addiction in adolescents, when there is insufficient authority and supervision within the family. On the other hand, family support, as well as the dispersion phase, are protective factors. Copyright © 2010 Elsevier España, S.L. All rights reserved.

Calculation of concentration profiles and their experimental verification with a pulsed sieve-plate column and the reactive material system of uranyl nitrate, nitric acid/tributyl phosphate, kerosine

International Nuclear Information System (INIS)

Ihle, E.

1985-01-01

The present study is concerned with the calculation of stationary and non-stationary concentration profiles as well as with the starting and disturbance behaviour of a pulsed sieve-plate extraction column. It investigates into the material system HNO 3 /uranyl nitrate in water with 30 per cent by volume of tributyl phosphate in kerosine. During the measurements of the concentration profiles for HNO 3 transition, which were effected in the direction of extraction and reextraction, it was shown that the concentration profiles measured in the mixer-settler range, in spite of a sixfold enlargement of the specific heat transfer area, do not differ essentially from those measured in the dispersion range. During the measurements of concentration profiles for HNO 3 /uranium transition, which were effected in the direction of coextraction and co-reextraction only for mixer-settler range, it was discovered that with increasing phase ratios, there is a depletion of the uranium concentration in the aqueous phase. If the phase ratio is further raised, it is the nitric acid, and not the uranium, that is depleted. (orig./PW) [de

Micropatch-arrayed pads for non-invasive spatial and temporal profiling of topical drugs on skin surface.

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Dutkiewicz, Ewelina P; Chiu, Hsien-Yi; Urban, Pawel L

2015-11-01

Micropatch-arrayed pads (MAPAs) are presented as a facile and sensitive sampling method for spatial profiling of topical agents adsorbed on the surface of skin. MAPAs are 28 × 28 mm sized pieces of polytetrafluoroethylene containing plurality of cavities filled with agarose hydrogel. They are affixed onto skin for 10 min with the purpose to collect drugs applied topically. Polar compounds are absorbed by the hydrogel micropatches. The probes are subsequently scanned by an automated nanospray desorption electrospray ionization mass spectrometry system operated in the tapping dual-polarity mode. When the liquid junction gets into contact with every micropatch, polar compounds absorbed in the hydrogel matrix are desorbed and transferred to the ion source. A 3D-printed interface prevents evaporation of hydrogel micropatches assuring good reproducibility and sensitivity. MAPAs have been applied to follow dispersion of topical drugs applied to human skin in vivo and to porcine skin ex vivo, in the form of self-adhesive patches. Spatiotemporal characteristics of the drug dispersion process have been revealed using this non-invasive test. Differences between drug dispersion in vivo and ex vivo could be observed. We envision that MAPAs can be used to investigate spatiotemporal kinetics of various topical agents utilized in medical treatment. Copyright © 2015 John Wiley & Sons, Ltd.

Understanding Drug Release Data through Thermodynamic Analysis

Directory of Open Access Journals (Sweden)

Marjorie Caroline Liberato Cavalcanti Freire

2017-06-01

Full Text Available Understanding the factors that can modify the drug release profile of a drug from a Drug-Delivery-System (DDS is a mandatory step to determine the effectiveness of new therapies. The aim of this study was to assess the Amphotericin-B (AmB kinetic release profiles from polymeric systems with different compositions and geometries and to correlate these profiles with the thermodynamic parameters through mathematical modeling. Film casting and electrospinning techniques were used to compare behavior of films and fibers, respectively. Release profiles from the DDSs were performed, and the mathematical modeling of the data was carried out. Activation energy, enthalpy, entropy and Gibbs free energy of the drug release process were determined. AmB release profiles showed that the relationship to overcome the enthalpic barrier was PVA-fiber > PVA-film > PLA-fiber > PLA-film. Drug release kinetics from the fibers and the films were better fitted on the Peppas–Sahlin and Higuchi models, respectively. The thermodynamic parameters corroborate these findings, revealing that the AmB release from the evaluated systems was an endothermic and non-spontaneous process. Thermodynamic parameters can be used to explain the drug kinetic release profiles. Such an approach is of utmost importance for DDS containing insoluble compounds, such as AmB, which is associated with an erratic bioavailability.

[Optimization of cluster analysis based on drug resistance profiles of MRSA isolates].

Science.gov (United States)

Tani, Hiroya; Kishi, Takahiko; Gotoh, Minehiro; Yamagishi, Yuka; Mikamo, Hiroshige

2015-12-01

We examined 402 methicillin-resistant Staphylococcus aureus (MRSA) strains isolated from clinical specimens in our hospital between November 19, 2010 and December 27, 2011 to evaluate the similarity between cluster analysis of drug susceptibility tests and pulsed-field gel electrophoresis (PFGE). The results showed that the 402 strains tested were classified into 27 PFGE patterns (151 subtypes of patterns). Cluster analyses of drug susceptibility tests with the cut-off distance yielding a similar classification capability showed favorable results--when the MIC method was used, and minimum inhibitory concentration (MIC) values were used directly in the method, the level of agreement with PFGE was 74.2% when 15 drugs were tested. The Unweighted Pair Group Method with Arithmetic mean (UPGMA) method was effective when the cut-off distance was 16. Using the SIR method in which susceptible (S), intermediate (I), and resistant (R) were coded as 0, 2, and 3, respectively, according to the Clinical and Laboratory Standards Institute (CLSI) criteria, the level of agreement with PFGE was 75.9% when the number of drugs tested was 17, the method used for clustering was the UPGMA, and the cut-off distance was 3.6. In addition, to assess the reproducibility of the results, 10 strains were randomly sampled from the overall test and subjected to cluster analysis. This was repeated 100 times under the same conditions. The results indicated good reproducibility of the results, with the level of agreement with PFGE showing a mean of 82.0%, standard deviation of 12.1%, and mode of 90.0% for the MIC method and a mean of 80.0%, standard deviation of 13.4%, and mode of 90.0% for the SIR method. In summary, cluster analysis for drug susceptibility tests is useful for the epidemiological analysis of MRSA.

Abbreviated kinetic profiles in area-under-the-curve monitoring of cyclosporine therapy.

Science.gov (United States)

Grevel, J; Kahan, B D

1991-11-01

Abbreviated kinetic profiles can reduce the number of phlebotomies and drug assays, and thereby the cost of area-under-the-curve (AUC) monitoring. In the present investigation, we used two independent data sets: group 1, 101 AUC profiles from 77 stable renal-transplant patients, which included a 5-h sample in addition to the usual 0-, 2-, 4-, 6-, 10-, 14-, and 24-h samples; and group 2, 100 profiles from 50 stable renal-transplant patients before and after a change in their daily oral dose of cyclosporine. Group I demonstrated a fair correlation between cyclosporine trough concentrations and the AUC calculated from a complete set of seven concentrations (r2 = 0.820 and 0.758 for the 24- and 0-h samples, respectively). Stepwise multiple linear-regression analysis revealed that the abbreviated set of three time points (2, 6, and 14 h) explained 96% of the variance in AUC values calculated from the full set of seven samples; additional time points increased the accuracy only slightly. For group 2, we examined the difference between the observed and the predicted concentrations by linear extrapolation; the error in the observed AUC value, compared with the predicted value calculated from seven time points (-13.2% to -1.2%), was similar to the error from just three time points (-11.5% to 4.5%). Abbreviated AUC profiles involving three time points used with a model equation seem to provide a reliable alternative to full seven-point profiles.

Amphiphilic block copolymers for drug delivery.

Science.gov (United States)

Adams, Monica L; Lavasanifar, Afsaneh; Kwon, Glen S

2003-07-01

Amphiphilic block copolymers (ABCs) have been used extensively in pharmaceutical applications ranging from sustained-release technologies to gene delivery. The utility of ABCs for delivery of therapeutic agents results from their unique chemical composition, which is characterized by a hydrophilic block that is chemically tethered to a hydrophobic block. In aqueous solution, polymeric micelles are formed via the association of ABCs into nanoscopic core/shell structures at or above the critical micelle concentration. Upon micellization, the hydrophobic core regions serve as reservoirs for hydrophobic drugs, which may be loaded by chemical, physical, or electrostatic means, depending on the specific functionalities of the core-forming block and the solubilizate. Although the Pluronics, composed of poly(ethylene oxide)-block-poly(propylene oxide)-block-poly(ethylene oxide), are the most widely studied ABC system, copolymers containing poly(L-amino acid) and poly(ester) hydrophobic blocks have also shown great promise in delivery applications. Because each ABC has unique advantages with respect to drug delivery, it may be possible to choose appropriate block copolymers for specific purposes, such as prolonging circulation time, introduction of targeting moieties, and modification of the drug-release profile. ABCs have been used for numerous pharmaceutical applications including drug solubilization/stabilization, alteration of the pharmacokinetic profile of encapsulated substances, and suppression of multidrug resistance. The purpose of this minireview is to provide a concise, yet detailed, introduction to the use of ABCs and polymeric micelles as delivery agents as well as to highlight current and past work in this area. Copyright 2003 Wiley-Liss, Inc. and the American Pharmacists Association

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

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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

Spectroscopic Analysis of Ion Concentration Profile at Electrode/Electrolyte Interface by Interferometry

Science.gov (United States)

Moore, David; Saraf, Ravi

2014-03-01

Owing to the difference in Fermi levels at an electrode/electrolyte interface, ions form an electrical double layer (EDL) with ion concentrations well over 10-fold compared to bulk. The concentration profile of the EDL intrinsically affects the electrochemical reaction rates at the electrode, which is of great significance in many applications, such as batteries and biosensors. Conventionally, using cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS), the electrical properties of the EDL are represented as ``equivalent circuits'' consisting of the resistance to charge transfer (Rct), the double layer capacitance (Cdl) and a ``Warburg (constant phase) diffusion element'' that represents the long range diffusion of ions to the electrode. The translation to the well-understood physical structure can be lost as complicated effects are often lumped together. For example, the effect of subtle modification of the electrode surface by say, redox compounds, enzymes, or polymers is not directly measured, and must be inferred by capacitance changes. An interferometer method will be described to directly measure changes in concentration at the interface during redox process. This method in concert with CV or EIS performed concomitantly will lead to more information to model the diffuse layer for improved understanding of the kinetics of the reaction at different distances from the electrode. Applications to DNA and polymer adsorption binding will be discussed.

Profiling the nucleobase and structure selectivity of anticancer drugs and other DNA alkylating agents by RNA sequencing.

Science.gov (United States)

Gillingham, Dennis; Sauter, Basilius

2018-05-06

Drugs that covalently modify DNA are components of most chemotherapy regimens, often serving as first-line treatments. Classically the chemical reactivity of DNA alkylators has been determined in vitro with short oligonucleotides. Here we use next generation RNA sequencing to report on the chemoselectivity of alkylating agents. We develop the method with the well-known clinically used DNA modifiying drugs streptozotocin and temozolomide, and then apply the technique to profile RNA modification with uncharacterized alkylation reactions such as with powerful electrophiles like trimethylsilyldiazomethane. The multiplexed and massively parallel format of NGS offers analyses of chemical reactivity in nucleic acids to be accomplished in less time with greater statistical power. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Evaluation of the whole body physiologically based pharmacokinetic (WB-PBPK) modeling of drugs.

Science.gov (United States)

Munir, Anum; Azam, Shumaila; Fazal, Sahar; Bhatti, A I

2018-08-14

The Physiologically based pharmacokinetic (PBPK) modeling is a supporting tool in drug discovery and improvement. Simulations produced by these models help to save time and aids in examining the effects of different variables on the pharmacokinetics of drugs. For this purpose, Sheila and Peters suggested a PBPK model capable of performing simulations to study a given drug absorption. There is a need to extend this model to the whole body entailing all another process like distribution, metabolism, and elimination, besides absorption. The aim of this scientific study is to hypothesize a WB-PBPK model through integrating absorption, distribution, metabolism, and elimination processes with the existing PBPK model.Absorption, distribution, metabolism, and elimination models are designed, integrated with PBPK model and validated. For validation purposes, clinical records of few drugs are collected from the literature. The developed WB-PBPK model is affirmed by comparing the simulations produced by the model against the searched clinical data. . It is proposed that the WB-PBPK model may be used in pharmaceutical industries to create of the pharmacokinetic profiles of drug candidates for better outcomes, as it is advance PBPK model and creates comprehensive PK profiles for drug ADME in concentration-time plots. Copyright © 2018 Elsevier Ltd. All rights reserved.

Gene expression profiling of a Zn-tolerant and a Zn-sensitive Suillus luteus isolate exposed to increased external zinc concentrations

OpenAIRE

MULLER, Ludo; Craciun, A. R.; RUYTINX, Joske; LAMBAERTS, Marc; Verbruggen, N.; VANGRONSVELD, Jaco; COLPAERT, Jan

2007-01-01

Complementary DNA (cDNA)-amplified fragment-length polymorphism (AFLP) was applied to analyze transcript profiles of a Zn-tolerant and a Zn-sensitive isolate of the ectomycorrhizal basidiomycete Suillus luteus, both cultured with and without increased external zinc concentrations. From the obtained transcript profiles that covered approximately 2% of the total expected complement of genes in S. luteus, 144 nonredundant, differentially expressed transcript-derived fragments (TDFs), falling in ...

Deep Learning Applications for Predicting Pharmacological Properties of Drugs and Drug Repurposing Using Transcriptomic Data.

Science.gov (United States)

Aliper, Alexander; Plis, Sergey; Artemov, Artem; Ulloa, Alvaro; Mamoshina, Polina; Zhavoronkov, Alex

2016-07-05

Deep learning is rapidly advancing many areas of science and technology with multiple success stories in image, text, voice and video recognition, robotics, and autonomous driving. In this paper we demonstrate how deep neural networks (DNN) trained on large transcriptional response data sets can classify various drugs to therapeutic categories solely based on their transcriptional profiles. We used the perturbation samples of 678 drugs across A549, MCF-7, and PC-3 cell lines from the LINCS Project and linked those to 12 therapeutic use categories derived from MeSH. To train the DNN, we utilized both gene level transcriptomic data and transcriptomic data processed using a pathway activation scoring algorithm, for a pooled data set of samples perturbed with different concentrations of the drug for 6 and 24 hours. In both pathway and gene level classification, DNN achieved high classification accuracy and convincingly outperformed the support vector machine (SVM) model on every multiclass classification problem, however, models based on pathway level data performed significantly better. For the first time we demonstrate a deep learning neural net trained on transcriptomic data to recognize pharmacological properties of multiple drugs across different biological systems and conditions. We also propose using deep neural net confusion matrices for drug repositioning. This work is a proof of principle for applying deep learning to drug discovery and development.

Evaluation of hydrophobic materials as matrices for controlled-release drug delivery.

Science.gov (United States)

Quadir, Mohiuddin Abdul; Rahman, M Sharifur; Karim, M Ziaul; Akter, Sanjida; Awkat, M Talat Bin; Reza, Md Selim

2003-07-01

The present study was undertaken to evaluate the effect of different insoluble and erodable wax-lipid based materials and their content level on the release profile of drug from matrix systems. Matrix tablets of theophylline were prepared using carnauba wax, bees wax, stearic acid, cetyl alcohol, cetostearyl alcohol and glyceryl monostearate as rate-retarding agents by direct compression process. The release of theophylline from these hydrophobic matrices was studied over 8-hours in buffer media of pH 6.8. Statistically significant difference was found among the drug release profile from different matrices. The release kinetics was found to be governed by the type and content of hydrophobic materials in the matrix. At lower level of wax matrices (25%), a potential burst release was observed with all the materials being studied. Bees wax could not exert any sustaining action while an extensive burst release was found with carnauba wax at this hydrophobic load. Increasing the concentration of fat-wax materials significantly decreased the burst effect of drug from the matrix. At higher hydrophobic level (50% of the matrix), the rate and extent of drug release was significantly reduced due to increased tortuosity and reduced porosity of the matrix. Cetostearyl alcohol imparted the strongest retardation of drug release irrespective of fat-wax level. Numerical fits indicate that the Higuchi square root of time model was the most appropriate one for describing the release profile of theophylline from hydrophobic matrices. The release mechanism was also explored and explained with biexponential equation. Application of this model indicates that Fickian or case I kinetics is the predominant mechanism of drug release from these wax-lipid matrices. The mean dissolution time (MDT) was calculated for all the formulations and the highest MDT value was obtained with cetostearyl matrix. The greater sustaining activity of cetostearyl alcohol can be attributed to some level of

Study of Copolymer Composition on Drug Loading Efficiency of Enalapril in Polymersomes and Cytotoxicity of Drug Loaded Nanoparticles.

Science.gov (United States)

Danafar, H; Manjili, H K; Najafi, M

2016-09-01

Enalapril was used for hypertension and congestive heart failure. Di-block mPEG-PCL copolymers were synthesized and used to prepare of polymersomes for controlled release of enalapril as a hydrophilic drug. The various methods such as HNMR, FTIR, GPC, DSC, PCS and AFM performed for characterization of the polymersomes. The results of AFM showed that the polymersomes had spherical structure and the size of nanoparticles was 97 nm. Drug-loading efficiency of nanoparticles from copolymers with compositions of mPEG1-PCL1, mPEG2-PCL2, and mPEG3-PCL3 were 14.43%, 19.8%, and 12.33% respectively. The release profile of enalapril for drug loaded nanoparticles prepared from mPEG3-PCL3 was very fast and release profile for the nanoparticles prepared from mPEG1-PCL1 and mPEG2-PCL2 was sustained. The IC 50 value of enalapril was determined to be 8 μM while EPM/m-PEG-PCL nanoparticles did not show significant toxicity at equal concentrations in comparison with enalapril drug. Therapeutic preparations of mPEG-PCL micelle are calibrated by the mouse LD 50 assay. A dose-finding scheme of the polymeric micelle showed a safe dose of mPEG-PCL micelles was approximately 330 mg/kg in mice. The relationship between the numbers of animals, number of doses, duration of the assay used to estimate the LD 50 and the precision of the assay were investigated. Overall, the results was showed that m-PEG-PCL polymersomes can be considered as a promising carrier for hydrophilic drugs. © Georg Thieme Verlag KG Stuttgart · New York.

Effects of elevated atmospheric CO2 concentration and temperature on the soil profile methane distribution and diffusion in rice-wheat rotation system.

Science.gov (United States)

Yang, Bo; Chen, Zhaozhi; Zhang, Man; Zhang, Heng; Zhang, Xuhui; Pan, Genxing; Zou, Jianwen; Xiong, Zhengqin

2015-06-01

The aim of this experiment was to determine the impacts of climate change on soil profile concentrations and diffusion effluxes of methane in a rice-wheat annual rotation ecosystem in Southeastern China. We initiated a field experiment with four treatments: ambient conditions (CKs), CO2 concentration elevated to ~500 μmol/mol (FACE), temperature elevated by ca. 2°C (T) and combined elevation of CO2 concentration and temperature (FACE+T). A multilevel sampling probe was designed to collect the soil gas at four different depths, namely, 7 cm, 15 cm, 30 cm and 50 cm. Methane concentrations were higher during the rice season and decreased with depth, while lower during the wheat season and increased with depth. Compared to CK, mean methane concentration was increased by 42%, 57% and 71% under the FACE, FACE+T and T treatments, respectively, at the 7 cm depth during the rice season (pCO2 concentration and temperature could significantly increase soil profile methane concentrations and their effluxes from a rice-wheat field annual rotation ecosystem (p<0.05). Copyright © 2015. Published by Elsevier B.V.

Global transcriptional profiling of longitudinal clinical isolates of Mycobacterium tuberculosis exhibiting rapid accumulation of drug resistance.

Directory of Open Access Journals (Sweden)

Anirvan Chatterjee

Full Text Available The identification of multidrug resistant (MDR, extensively and totally drug resistant Mycobacterium tuberculosis (Mtb, in vulnerable sites such as Mumbai, is a grave threat to the control of tuberculosis. The current study aimed at explaining the rapid expression of MDR in Directly Observed Treatment Short Course (DOTS compliant patients, represents the first study comparing global transcriptional profiles of 3 pairs of clinical Mtb isolates, collected longitudinally at initiation and completion of DOTS. While the isolates were drug susceptible (DS at onset and MDR at completion of DOTS, they exhibited identical DNA fingerprints at both points of collection. The whole genome transcriptional analysis was performed using total RNA from H37Rv and 3 locally predominant spoligotypes viz. MANU1, CAS and Beijing, hybridized on MTBv3 (BuG@S microarray, and yielded 36, 98 and 45 differentially expressed genes respectively. Genes encoding transcription factors (sig, rpoB, cell wall biosynthesis (emb genes, protein synthesis (rpl and additional central metabolic pathways (ppdK, pknH, pfkB were found to be down regulated in the MDR isolates as compared to the DS isolate of the same genotype. Up regulation of drug efflux pumps, ABC transporters, trans-membrane proteins and stress response transcriptional factors (whiB in the MDR isolates was observed. The data indicated that Mtb, without specific mutations in drug target genes may persist in the host due to additional mechanisms like drug efflux pumps and lowered rate of metabolism. Furthermore this population of Mtb, which also showed reduced DNA repair activity, would result in selection and stabilization of spontaneous mutations in drug target genes, causing selection of a MDR strain in the presence of drug pressures. Efflux pump such as drrA may play a significant role in increasing fitness of low level drug resistant cells and assist in survival of Mtb till acquisition of drug resistant mutations with

Drug-drug interactions involving antidepressants: focus on desvenlafaxine.

Science.gov (United States)

Low, Yvette; Setia, Sajita; Lima, Graca

2018-01-01

Psychiatric and physical conditions often coexist, and there is robust evidence that associates the frequency of depression with single and multiple physical conditions. More than half of patients with depression may have at least one chronic physical condition. Therefore, antidepressants are often used in cotherapy with other medications for the management of both psychiatric and chronic physical illnesses. The risk of drug-drug interactions (DDIs) is augmented by complex polypharmacy regimens and extended periods of treatment required, of which possible outcomes range from tolerability issues to lack of efficacy and serious adverse events. Optimal patient outcomes may be achieved through drug selection with minimal potential for DDIs. Desvenlafaxine is a serotonin-norepinephrine reuptake inhibitor approved for the treatment of adults with major depressive disorder. Pharmacokinetic studies of desvenlafaxine have shown a simple metabolic profile unique among antidepressants. This review examines the DDI profiles of antidepressants, particularly desvenlafaxine, in relation to drugs of different therapeutic areas. The summary and comparison of information available is meant to help clinicians in making informed decisions when using desvenlafaxine in patients with depression and comorbid chronic conditions.

Application of PBPK modelling in drug discovery and development at Pfizer.

Science.gov (United States)

Jones, Hannah M; Dickins, Maurice; Youdim, Kuresh; Gosset, James R; Attkins, Neil J; Hay, Tanya L; Gurrell, Ian K; Logan, Y Raj; Bungay, Peter J; Jones, Barry C; Gardner, Iain B

2012-01-01

Early prediction of human pharmacokinetics (PK) and drug-drug interactions (DDI) in drug discovery and development allows for more informed decision making. Physiologically based pharmacokinetic (PBPK) modelling can be used to answer a number of questions throughout the process of drug discovery and development and is thus becoming a very popular tool. PBPK models provide the opportunity to integrate key input parameters from different sources to not only estimate PK parameters and plasma concentration-time profiles, but also to gain mechanistic insight into compound properties. Using examples from the literature and our own company, we have shown how PBPK techniques can be utilized through the stages of drug discovery and development to increase efficiency, reduce the need for animal studies, replace clinical trials and to increase PK understanding. Given the mechanistic nature of these models, the future use of PBPK modelling in drug discovery and development is promising, however, some limitations need to be addressed to realize its application and utility more broadly.

The prediction of concentration profiles for a NIMCIX column absorbing uranium from aqueous solution

International Nuclear Information System (INIS)

Wright, R.S.

1979-01-01

A procedure is proposed for the prediction of concentration profiles for a countercurrent ion-exchange absorption column, use being made of equilibrium and kinetic data derived from small-scale batch tests. A comparison is presented between the predictions and the measured performance of a column (2,5 m in diameter) absorbing uranium from solution. The method is shown to be adequate for design purposes provided that the data used are from tests in which the solution and resin conditions approximate those for which the plant is being designed [af

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

Science.gov (United States)

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.

Imipenem in burn patients: pharmacokinetic profile and PK/PD target attainment.

Science.gov (United States)

Gomez, David S; Sanches-Giraud, Cristina; Silva, Carlindo V; Oliveira, Amanda M Ribas Rosa; da Silva, Joao Manoel; Gemperli, Rolf; Santos, Silvia R C J

2015-03-01

Unpredictable pharmacokinetics (PK) in burn patients may result in plasma concentrations below concentrations that are effective against common pathogens. The present study evaluated the imipenem PK profile and pharmacokinetic/pharmacodynamics (PK/PD) correlation in burn patients. Fifty-one burn patients, 38.7 years of age (mean), 68.0 kg, 36.3% total burn surface area (TBSA), of whom 84% (43/51) exhibited thermal injury, 63% inhalation injury and 16% electrical injury (8/51), all of whom were receiving imipenem treatment were investigated. Drug plasma monitoring, PK study (120 sets of plasma levels) and PK/PD correlation were performed in a series of blood samples. Only 250 μl of plasma samples were required for drug plasma measurements using the ultra filtration technique for the purification of biological matrix and quantification using liquid chromatography. Probability of target attainment (PTA) was calculated using a PD target of 40% free drug concentrations above the minimum inhibitory concentration (40%fT>MIC). Significant differences in PK parameters (medians), such as biological half-life (2.2 vs 5.5 h), plasma clearance (16.2 vs 1.4 l h(-1)) and volume of distribution (0.86 vs 0.19 l kg(-1)), were registered in burn patients via comparisons of set periods with normal renal function against periods of renal failure. Correlations between creatinine clearance and total body plasma clearance were also obtained. In addition, the PK profile did not change according to TBSA during sets when renal function was preserved. PTA was >89% for MIC values up to 4 mg l(-1). In conclusion, imipenem efficacy for the control of hospital infection on the basis of PK/PD correlation was guaranteed for burn in patients at the recommended dose regimens for normal renal function (31.1±9.7 mg kg(-1) daily), but the daily dose must be reduced to 17.2±9.7 mg kg(-1) during renal failure to avoid neurotoxicity.

An augmented space recursive method for the first principles study of concentration profiles at CuNi alloy surfaces

International Nuclear Information System (INIS)

Dasgupta, I.; Mookerjee, A.

1995-07-01

We present here a first principle method for the calculation of effective cluster interactions for semi-infinite solid alloys required for the study of surface segregation and surface ordering on disordered surfaces. Our method is based on the augmented space recursion coupled with the orbital peeling method of Burke in the framework of the TB-LMTO. Our study of surface segregation in CuNi alloys demonstrates strong copper segregation and a monotonic concentration profile throughout the concentration range. (author). 35 refs, 4 figs, 2 tabs

Secondary metabolite profiles and antifungal drug susceptibility of Aspergillus fumigatus and closely related species, Aspergillus lentulus, Aspergillus udagawae, and Aspergillus viridinutans.

Science.gov (United States)

Tamiya, Hiroyuki; Ochiai, Eri; Kikuchi, Kazuyo; Yahiro, Maki; Toyotome, Takahito; Watanabe, Akira; Yaguchi, Takashi; Kamei, Katsuhiko

2015-05-01

The incidence of Aspergillus infection has been increasing in the past few years. Also, new Aspergillus fumigatus-related species, namely Aspergillus lentulus, Aspergillus udagawae, and Aspergillus viridinutans, were shown to infect humans. These fungi exhibit marked morphological similarities to A. fumigatus, albeit with different clinical courses and antifungal drug susceptibilities. The present study used liquid chromatography/time-of-flight mass spectrometry to identify the secondary metabolites secreted as virulence factors by these Aspergillus species and compared their antifungal susceptibility. The metabolite profiles varied widely among A. fumigatus, A. lentulus, A. udagawae, and A. viridinutans, producing 27, 13, 8, and 11 substances, respectively. Among the mycotoxins, fumifungin, fumiquinazoline A/B and D, fumitremorgin B, gliotoxin, sphingofungins, pseurotins, and verruculogen were only found in A. fumigatus, whereas auranthine was only found in A. lentulus. The amount of gliotoxin, one of the most abundant mycotoxins in A. fumigatus, was negligible in these related species. In addition, they had decreased susceptibility to antifungal agents such as itraconazole and voriconazole, even though metabolites that were shared in the isolates showing higher minimum inhibitory concentrations than epidemiological cutoff values were not detected. These strikingly different secondary metabolite profiles may lead to the development of more discriminative identification protocols for such closely related Aspergillus species as well as improved treatment outcomes. Copyright © 2015 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

Chemical weathering of a marine terrace chronosequence, Santa Cruz, California I: Interpreting rates and controls based on soil concentration-depth profiles

Science.gov (United States)

White, A.F.; Schulz, M.S.; Vivit, D.V.; Blum, A.E.; Stonestrom, David A.; Anderson, S.P.

2008-01-01

The spatial and temporal changes in element and mineral concentrations in regolith profiles in a chronosequence developed on marine terraces along coastal California are interpreted in terms of chemical weathering rates and processes. In regoliths up to 15 m deep and 226 kyrs old, quartz-normalized mass transfer coefficients indicate non-stoichiometric preferential release of Sr > Ca > Na from plagioclase along with lesser amounts of K, Rb and Ba derived from K-feldspar. Smectite weathering results in the loss of Mg and concurrent incorporation of Al and Fe into secondary kaolinite and Fe-oxides in shallow argillic horizons. Elemental losses from weathering of the Santa Cruz terraces fall within the range of those for other marine terraces along the Pacific Coast of North America. Residual amounts of plagioclase and K-feldspar decrease with terrace depth and increasing age. The gradient of the weathering profile bs is defined by the ratio of the weathering rate, R to the velocity at which the profile penetrates into the protolith. A spreadsheet calculator further refines profile geometries, demonstrating that the non-linear regions at low residual feldspar concentrations at shallow depth are dominated by exponential changes in mineral surface-to-volume ratios and at high residual feldspar concentrations, at greater depth, by the approach to thermodynamic saturation. These parameters are of secondary importance to the fluid flux qh, which in thermodynamically saturated pore water, controls the weathering velocity and mineral losses from the profiles. Long-term fluid fluxes required to reproduce the feldspar weathering profiles are in agreement with contemporary values based on solute Cl balances (qh = 0.025-0.17 m yr-1). During saturation-controlled and solute-limited weathering, the greater loss of plagioclase relative to K-feldspar is dependent on the large difference in their respective solubilities instead of the small difference between their respective

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

Science.gov (United States)

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.

Use of nuclear methods for the analysis of materials and the determination of concentration profiles

International Nuclear Information System (INIS)

Darras, R.

1976-01-01

The possibilities of the activation analysis and nuclear reaction analysis are presented. These methods allow the oligo-elements and impurities (in trace amounts) to be determined in materials with accuracy and a high sensitivity. They can also be applied to the determination of major elements in a small amount of materials. Surface analysis and concentration profile determination are possible when the nature and energy of the incident particles are judiciously selected. Exemples of analysis of steels, pure iron and refractories are given [fr

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

Science.gov (United States)

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.

The pharmacokinetics of enteral antituberculosis drugs in patients requiring intensive care.

Science.gov (United States)

Koegelenberg, C F N; Nortje, A; Lalla, U; Enslin, A; Irusen, E M; Rosenkranz, B; Seifart, H I; Bolliger, C T

2013-04-05

There is a paucity of data on the pharmacokinetics of fixed-dose combination enteral antituberculosis treatment in critically ill patients. To establish the pharmacokinetic profile of a fixed-dose combination of rifampicin, isoniazid, pyrazinamide and ethambutol given according to weight via a nasogastric tube to patients admitted to an intensive care unit (ICU). We conducted a prospective, observational study on 10 patients (mean age 32 years, 6 male) admitted to an ICU and treated for tuberculosis (TB). Serum concentrations of the drugs were determined at eight predetermined intervals over 24 hours by means of high-performance liquid chromatography. The therapeutic maximum plasma concentration (Cmax) for rifampicin at time to peak concentration was achieved in only 4 patients, whereas 2 did not achieve therapeutic Cmax for isoniazid. No patient reached sub-therapeutic Cmax for pyrazinamide (6 were within and 4 above therapeutic range). Three patients reached sub-therapeutic Cmax for ethambutol, and 6 patients were within and 1 above the therapeutic range. Patients with a sub-therapeutic rifampicin level had a higher mean Acute Physiology and Chronic Health Evaluation II (APACHE II) score (p=0.03) and a lower estimated glomerular filtration rate (GFR) (p=0.03). A fixed-dose combination tablet, crushed and mixed with water, given according to weight via a nasogastric tube to patients with TB admitted to an ICU resulted in sub-therapeutic rifampicin plasma concentrations in the majority of patients, whereas the other drugs had a more favourable pharmacokinetic profile. Patients with a sub-therapeutic rifampicin concentration had a higher APACHE II score and a lower estimated GFR, which may contribute to suboptimal outcomes in critically ill patients. Studies in other settings have reported similar proportions of patients with 'sub-therapeutic' rifampicin concentrations.

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

Data-driven prediction of adverse drug reactions induced by drug-drug interactions.

Science.gov (United States)

Liu, Ruifeng; AbdulHameed, Mohamed Diwan M; Kumar, Kamal; Yu, Xueping; Wallqvist, Anders; Reifman, Jaques

2017-06-08

The expanded use of multiple drugs has increased the occurrence of adverse drug reactions (ADRs) induced by drug-drug interactions (DDIs). However, such reactions are typically not observed in clinical drug-development studies because most of them focus on single-drug therapies. ADR reporting systems collect information on adverse health effects caused by both single drugs and DDIs. A major challenge is to unambiguously identify the effects caused by DDIs and to attribute them to specific drug interactions. A computational method that provides prospective predictions of potential DDI-induced ADRs will help to identify and mitigate these adverse health effects. We hypothesize that drug-protein interactions can be used as independent variables in predicting ADRs. We constructed drug pair-protein interaction profiles for ~800 drugs using drug-protein interaction information in the public domain. We then constructed statistical models to score drug pairs for their potential to induce ADRs based on drug pair-protein interaction profiles. We used extensive clinical database information to construct categorical prediction models for drug pairs that are likely to induce ADRs via synergistic DDIs and showed that model performance deteriorated only slightly, with a moderate amount of false positives and false negatives in the training samples, as evaluated by our cross-validation analysis. The cross validation calculations showed an average prediction accuracy of 89% across 1,096 ADR models that captured the deleterious effects of synergistic DDIs. Because the models rely on drug-protein interactions, we made predictions for pairwise combinations of 764 drugs that are currently on the market and for which drug-protein interaction information is available. These predictions are publicly accessible at http://avoid-db.bhsai.org . We used the predictive models to analyze broader aspects of DDI-induced ADRs, showing that ~10% of all combinations have the potential to induce ADRs

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

Science.gov (United States)

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.

Systematic evaluation of commercially available ultra-high performance liquid chromatography columns for drug metabolite profiling: optimization of chromatographic peak capacity.

Science.gov (United States)

Dubbelman, Anne-Charlotte; Cuyckens, Filip; Dillen, Lieve; Gross, Gerhard; Hankemeier, Thomas; Vreeken, Rob J

2014-12-29

The present study investigated the practical use of modern ultra-high performance liquid chromatography (UHPLC) separation techniques for drug metabolite profiling, aiming to develop a widely applicable, high-throughput, easy-to-use chromatographic method, with a high chromatographic resolution to accommodate simultaneous qualitative and quantitative analysis of small-molecule drugs and metabolites in biological matrices. To this end, first the UHPLC system volume and variance were evaluated. Then, a mixture of 17 drugs and various metabolites (molecular mass of 151-749Da, logP of -1.04 to 6.7), was injected on six sub-2μm particle columns. Five newest generation core shell technology columns were compared and tested against one column packed with porous particles. Two aqueous (pH 2.7 and 6.8) and two organic mobile phases were evaluated, first with the same flow and temperature and subsequently at each column's individual limit of temperature and pressure. The results demonstrated that pre-column dead volume had negligible influence on the peak capacity and shape. In contrast, a decrease in post-column volume of 57% resulted in a substantial (47%) increase in median peak capacity and significantly improved peak shape. When the various combinations of stationary and mobile phases were used at the same flow rate (0.5mL/min) and temperature (45°C), limited differences were observed between the median peak capacities, with a maximum of 26%. At higher flow though (up to 0.9mL/min), a maximum difference of almost 40% in median peak capacity was found between columns. The finally selected combination of solid-core particle column and mobile phase composition was chosen for its selectivity, peak capacity, wide applicability and peak shape. The developed method was applied to rat hepatocyte samples incubated with the drug buspirone and demonstrated to provide a similar chromatographic resolution, but a 6 times higher signal-to-noise ratio than a more traditional UHPLC

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.

Measurement of concentration profile during charging of Li battery anode materials in LiClO4-PC electrolyte

International Nuclear Information System (INIS)

Nishikawa, K.; Fukunaka, Y.; Sakka, T.; Ogata, Y.H.; Selman, J.R.

2007-01-01

Li metal was galvanostatically electrodeposited on a horizontally positioned, downward-facing Li metal cathode in 0.5 M LiClO 4 -PC electrolyte. The refractive index profile corresponding to the transient Li + ion concentration profile formed in the electrolyte solution upon applying a current step was measured in-situ by holographic interferometry. The configuration of the electrolytic cell was such that mass transfer was governed only by transient diffusion and migration, in the absence of convection. Between the moment of closing the current circuit and the time at which the interference fringes started to shift, an incubation period was observed. Such an incubation period had earlier been observed in lithium electrodeposition at a vertical planar Li metal cathode. The incubation period for the horizontal Li cathode was roughly half that for a vertical one. To study the effect of the electrode material on the incubation period, interferometry measurements were also made at an electrodeposited Ni-Sn alloy electrode. The concentration profile formed near the Ni-Sn alloy electrode during lithiation (alloying or intercalation of Li + into the electrode) agrees well with predictions made by means of the one-dimensional diffusion equation. Only very short incubation period was detected, but the magnitude was negligibly smaller than that of Li metal electrodeposition. The incubation period therefore appears to be characteristic for Li metal electrode only

Design and characterisation of matrix tablets of highly water soluble drug

Directory of Open Access Journals (Sweden)

Vijayalakshmi Prakya

2012-04-01

Full Text Available Tramadol HCL is a centrally acting opioid analgesic. Although the drug has a higher plasma half life, the steady state plasma concentration is not achieved with frequent dosing of q.i.d at 6 hour intervals. Therefore, the objective of the present work was to formulate a 100mg strength Tramadol matrix tablets to extend the drug release and thus decrease the dosing frequency and achieve steady state plasma concentration. Initially, preformulation studies were carried out to rule out any incompatibility between the drug and the chosen polymer(s after exposing physical mixtures of the drug and the polymer(s to 40 and deg;C/75% RH for three months. A suitable method was developed for drug estimation at 271nm by a UV double beam spectrophotometer. Next, various batches of tablets were designed using different polymers such as Ethylcellulose, Carnauba wax, HPMC-K100M, Carbopol-974P and Kollidon-SR. Direct compression technique was used except for the formulation containing carnauba wax for which melt granulation was done followed by compression. Formulations F-1 to F-15 contained single polymers in increasing concentrations in drug:polymer ratios of 1:1, 1:2 and 1:3 where it was observed that the drug release extended with increasing polymer concentrations. Carbopol-974P extended drug release better followed by HPMC-K100M and Carnauba wax compared to other polymers. A combination of these polymers was also used at various ratios to get formulations F-16 to F-20 and observed that the polymer combinations controlled drug release better. The type of fillers like lactose and microcrystalline cellulose had no effect on the physiochemical characters as well as on the drug release profiles. The in vitro release data from the best formulation fitted well in Higuchi as well as Peppas model, the and #8216;n and #8217; value, which confirmed that the release mechanism shifted from initial dissolution to later extended diffusion in which both diffusion and erosion

Commercial viability of CNS drugs: balancing the risk/reward profile.

Science.gov (United States)

Johnson, Ginger S

2014-01-01

CNS has historically been a formidable therapeutic area in which to innovate owing to biological (e.g., complex neurobiology, difficulty reaching the target), as well as clinical (e.g., subjective clinical endpoints, high placebo response, lack of biomarkers) challenges. In the current market where many of the larger diseases are dominated by a generic standard of care, commercial challenges now make the triple threat of scientific-clinical-commercial risk too much for many players to tackle. However, opportunities do exist for smaller biotech companies to concentrate on narrowly focused patient populations associated with high unmet need for which risk can be tightly defined. In CNS, there are two major areas to balance the risk/reward profile and create commercially viable opportunities: To realize value, all companies (start-ups and big players) must define, measure and quantify clear and meaningful value to all stakeholders: physicians, patients, caregivers and payers. © 2013.

Antifungal susceptibility profiles of 1698 yeast reference strains revealing potential emerging human pathogens.

Directory of Open Access Journals (Sweden)

Marie Desnos-Ollivier

Full Text Available New molecular identification techniques and the increased number of patients with various immune defects or underlying conditions lead to the emergence and/or the description of novel species of human and animal fungal opportunistic pathogens. Antifungal susceptibility provides important information for ecological, epidemiological and therapeutic issues. The aim of this study was to assess the potential risk of the various species based on their antifungal drug resistance, keeping in mind the methodological limitations. Antifungal susceptibility profiles to the five classes of antifungal drugs (polyens, azoles, echinocandins, allylamines and antimetabolites were determined for 1698 yeast reference strains belonging to 992 species (634 Ascomycetes and 358 Basidiomycetes. Interestingly, geometric mean minimum inhibitory concentrations (MICs of all antifungal drugs tested were significantly higher for Basidiomycetes compared to Ascomycetes (p<0.001. Twenty four strains belonging to 23 species of which 19 were Basidiomycetes seem to be intrinsically "resistant" to all drugs. Comparison of the antifungal susceptibility profiles of the 4240 clinical isolates and the 315 reference strains belonging to 53 shared species showed similar results. Even in the absence of demonstrated in vitro/in vivo correlation, knowing the in vitro susceptibility to systemic antifungal agents and the putative intrinsic resistance of yeast species present in the environment is important because they could become opportunistic pathogens.

The Potential of The Synergy of Sunphotometer and Lidar Data to Validate Vertical Profiles of The Aerosol Mass Concentration Estimated by An Air Quality Model

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Siomos N.

2016-01-01

Full Text Available Vertical profiles of the aerosol mass concentration derived by the Lidar/Radiometer Inversion Code (LIRIC, that uses combined sunphotometer and lidar data, were used in order to validate the aerosol mass concentration profiles estimated by the air quality model CAMx. Lidar and CIMEL measurements performed at the Laboratory of Atmospheric Physics of the Aristotle University of Thessaloniki, Greece (40.5N, 22.9E from the period 2013-2014 were used in this study.

Development of Bioadhesive Chitosan Superporous Hydrogel Composite Particles Based Intestinal Drug Delivery System

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Hitesh Chavda

2013-01-01

Full Text Available Bioadhesive superporous hydrogel composite (SPHC particles were developed for an intestinal delivery of metoprolol succinate and characterized for density, porosity, swelling, morphology, and bioadhesion studies. Chitosan and HPMC were used as bioadhesive and release retardant polymers, respectively. A 32 full factorial design was applied to optimize the concentration of chitosan and HPMC. The drug loaded bioadhesive SPHC particles were filled in capsule, and the capsule was coated with cellulose acetate phthalate and evaluated for drug content, in vitro drug release, and stability studies. To ascertain the drug release kinetics, the drug release profiles were fitted for mathematical models. The prepared system remains bioadhesive up to eight hours in intestine and showed Hixson-Crowell release with anomalous nonfickian type of drug transport. The application of SPHC polymer particles as a biomaterial carrier opens a new insight into bioadhesive drug delivery system and could be a future platform for other molecules for intestinal delivery.

Demystifying "oxi" cocaine: Chemical profiling analysis of a "new Brazilian drug" from Acre State.

Science.gov (United States)

da Silva Junior, Ronaldo C; Gomes, Cezar S; Goulart Júnior, Saulo S; Almeida, Fernanda V; Grobério, Tatiane S; Braga, Jez W B; Zacca, Jorge J; Vieira, Maurício L; Botelho, Elvio D; Maldaner, Adriano O

2012-09-10

Recent information from various sources suggests that a new illicit drug, called "oxi", is being spread across Brazil. It would be used in the smoked form and it would look like to crack cocaine: usually small yellowish or light brown stones. As fully released in the media, "oxi" would differ from crack cocaine in the sense that crack would contain carbonate or bicarbonate salts whereas "oxi" would include the addition of calcium oxide and kerosene (or gasoline). In this context, this work presents a chemical profiling comparative study between "oxi" street samples seized by the Civil Police of the State of Acre (CP/AC) and samples associated with both international and interstate drug trafficking seized by the Brazilian Federal Police in Acre (FP/AC). The outcome of this work assisted Brazilian authorities to stop inaccurate and alarmist releases on this issue. It may be of good use by the forensic community in order to better understand matters in their efforts to guide local law enforcement agencies in case such claims reach the international illicit market. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Inorganic Profiling of Amoxicillin Drugs in Ghana Using Proton Induced X-Ray Emission (Pixe) Analysis

International Nuclear Information System (INIS)

Abdul-Wahab, Zurika

2017-07-01

Induced X-ray Emission (PIXE) analysis of the amoxicillin standard reference material revealed ten (10 ) elements which include Al, S, K, Ca, V, Cr, Mn, Fe, Ni, and Zn. Sulphur was identified as the major element in the standard reference material and recorded concentration value of 396,805 ppm. Samples from Kwame Nkrumah Circle, a locally manufactured brand recorded the lowest sulphur concentrations of 251,745 ppm, compared to all drugs analysed using PIXE; imported amoxicillin (395,753 ppm) and Okaishi locally manufactured (384,710 ppm). Additionally, the elements Cr, Mn and Fe were found to be relatively higher in the Kwame Nkrumah Circle sample hence raising concerns over the quality of the Kwame Nkrumah Circle brand. When a physical parameter test was performed on all samples, all brands with the exception of Kwame Nkrumah Circle passed the disintegration and dissolution test deeming the Kwame Nkrumah Circle brand substandard. After an HPLC test was performed for all samples, it was discovered that all the drugs analysed passed the acceptance criteria (90-120%) for drugs set by the British Pharmacopoeia; with the Kwame Nkrumah Circle brand recording a value of 97% relatively lower than all the other samples which range from 113 to 117%. Sulphur as an active principle ingredient was correlated with the other identified elements. Strong correlations with correlation coefficients within the range 0.9936 – 0.9978 were found with the elements Cr, Mn, and Fe. Hence the elements S, Cr, Mn, and Fe lend themselves as element signature for amoxicillin medical drug. This was done to discover element signatures that will facilitate differentiating between genuine and counterfeit amoxicillin drugs. Considering the simplicity in sample preparation, the non-distractive nature of PIXE analysis, and also fast turn out in producing results. PIXE offers a considerable advantage when analysing antibiotic drugs on a large scale. (author)

Plutonium, americium, and uranium concentrations in Nevada Test Site soil profiles

International Nuclear Information System (INIS)

Essington, E.H.; Gilbert, R.O.; Eberhardt, L.L.; Fowler, E.B.

1975-01-01

Many soil profile samples were collected by the Nevada Applied Ecology Group from five nuclear safety test sites on the Nevada Test Site and Tonopah Test Range in Nevada, U.S.A. The profile samples were analyzed for 239 Pu, 240 Pu, 241 Am, and in some cases 235 U and 238 U, in order to estimate the depth of radionuclide penetration and level of contamination at specific sampling depths after an extended period of time since deposition on the surface. Nearly 70 individual profiles were examined. About one-half of the profiles exhibited a smooth leaching pattern with more than 95 percent of the plutonium in the top 5 cm. Other profile patterns are discussed relative to mechanical disturbance of the profile after the initial deposition, accumulation of plutonium in specific zones within the soil profile, and occurrence of large amounts of plutonium in the deepest parts of the soil profile. The implications of these observations are discussed with respect to redistribution of radioactivity by wind, water, and burrowing animals, ingestion by burrowing and grazing animals, uptake by vegetation, and cleanup operations. (auth)

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

Science.gov (United States)

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.

Science.gov (United States)

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.

The control of beads diameter of bead-on-string electrospun nanofibers and the corresponding release behaviors of embedded drugs

Energy Technology Data Exchange (ETDEWEB)

Li, Tingxiao [Key Laboratory of Textile Science and Technology (Donghua University), Ministry of Education of China, Shanghai 201620 (China); College of Textiles, Donghua University, Shanghai 201620 (China); Ding, Xin, E-mail: xding@dhu.edu.cn [Key Laboratory of Textile Science and Technology (Donghua University), Ministry of Education of China, Shanghai 201620 (China); College of Textiles, Donghua University, Shanghai 201620 (China); Tian, Lingling, E-mail: lingling_tian@nus.edu.sg [Center of Nanofibers & Nanotechnology, Department of Mechanical Engineering, National University of Singapore, 117576 (Singapore); Hu, Jiyong; Yang, Xudong [Key Laboratory of Textile Science and Technology (Donghua University), Ministry of Education of China, Shanghai 201620 (China); College of Textiles, Donghua University, Shanghai 201620 (China); Ramakrishna, Seeram [Center of Nanofibers & Nanotechnology, Department of Mechanical Engineering, National University of Singapore, 117576 (Singapore); Guangdong-Hongkong-Macau Institute of CNS Regeneration (GHMICR), Jinan University, Guangzhou 510632 (China)

2017-05-01

Bead-on-string nanofibers, with appropriate control of the beads diameter, are potential fibrous structures for efficient encapsulation of particle drugs in micron scales and could achieve controlled drug release for tissue engineering applications. In this study, the beads diameter of electrospun bead-on-string nanofibers was controlled by adjusting the concentration of spinning polymer, poly (lactic-co-glycolic acid) (PLGA), and the solvent ratio of chloroform to acetone. The images of the scanning electron microscopy (SEM) suggested that bead-on-string nanofibers could be successfully obtained only with a certain range of PLGA solution concentration. Moreover, with the decrease in the solvent ratio of chloroform to acetone, the range was left-shifted towards a smaller concentration. In addition, increase in the PLGA solution concentration within the range the beads diameter became greater and the shape of the beads changed from oval to slender when increasing the PLGA concentration within the range. The bead-on-string nanofibers with different beads diameter were further used to load micro-particle drugs of tetracycline hydrochloride, as a model drug, to examine the release behavior of nanofibers scaffold. The release profiles of drug loaded bead-on-string nanofibers demonstrated the possibility to alleviate the burst drug release by means of beads diameter control. - Highlights: • Bead diameter of bead-on-string electrospun nanofibers was controlled by varying solvent ratio and polymer concentration. • The effect of the addition of particle drugs on BD of bead-on-string electrospun nanofibers was studied. • The corresponding release behaviors of nanofibers with different BD loading micro-particle drugs were investigated. • Bead-on-string nanofibers with bigger BD could alleviate the initial burst release.

The control of beads diameter of bead-on-string electrospun nanofibers and the corresponding release behaviors of embedded drugs

International Nuclear Information System (INIS)

Li, Tingxiao; Ding, Xin; Tian, Lingling; Hu, Jiyong; Yang, Xudong; Ramakrishna, Seeram

2017-01-01

Bead-on-string nanofibers, with appropriate control of the beads diameter, are potential fibrous structures for efficient encapsulation of particle drugs in micron scales and could achieve controlled drug release for tissue engineering applications. In this study, the beads diameter of electrospun bead-on-string nanofibers was controlled by adjusting the concentration of spinning polymer, poly (lactic-co-glycolic acid) (PLGA), and the solvent ratio of chloroform to acetone. The images of the scanning electron microscopy (SEM) suggested that bead-on-string nanofibers could be successfully obtained only with a certain range of PLGA solution concentration. Moreover, with the decrease in the solvent ratio of chloroform to acetone, the range was left-shifted towards a smaller concentration. In addition, increase in the PLGA solution concentration within the range the beads diameter became greater and the shape of the beads changed from oval to slender when increasing the PLGA concentration within the range. The bead-on-string nanofibers with different beads diameter were further used to load micro-particle drugs of tetracycline hydrochloride, as a model drug, to examine the release behavior of nanofibers scaffold. The release profiles of drug loaded bead-on-string nanofibers demonstrated the possibility to alleviate the burst drug release by means of beads diameter control. - Highlights: • Bead diameter of bead-on-string electrospun nanofibers was controlled by varying solvent ratio and polymer concentration. • The effect of the addition of particle drugs on BD of bead-on-string electrospun nanofibers was studied. • The corresponding release behaviors of nanofibers with different BD loading micro-particle drugs were investigated. • Bead-on-string nanofibers with bigger BD could alleviate the initial burst release.

Drugs for Pain Management in Shock Wave Lithotripsy

Directory of Open Access Journals (Sweden)

Christian Bach

2011-01-01

Full Text Available Objective. With this review, we provide a comprehensive overview of the main aspects and currently used drugs for analgesia in shockwave lithotripsy. Evidence Acquisition. We reviewed current literature, concentrating on newer articles and high-quality reviews in international journals. Results. No standardized protocols for pain control in SWL exist, although it is crucial for treatment outcome. General and spinal anaesthesia show excellent pain control but are only recommended for selected cases. The newer opioids and nonsteroidal anti-inflammatory drugs are able to deliver good analgesia. Interest in inhalation anaesthesia with nitrous oxide, local anaesthesia with deep infiltration of the tissue, and dermal anaesthesia with EMLA or DMSO has recently rekindled, showing good results in terms of pain control and a favourable side effect profile. Tamsulosin and paracetamol are further well-known drugs being currently investigated. Conclusion. Apart from classically used drugs like opioids and NSARs, medicaments like nitrous oxide, paracetamol, DMSA, or refined administration techniques for infiltration anaesthesia show a good effectiveness in pain control for SWL.

Studying the personality profile of drug addicts by utilizing two models of Cloninger and Eysneck

Directory of Open Access Journals (Sweden)

2008-11-01

Full Text Available Objectives: Identifying personality factors of tendency to drugs can be helpful in better recognition and treatment of drug-dependency and also by providing consulting and psychological services can relatively prevents from vulnerable people to be addicted. This research therefore aims to investigate personality profile of substance dependent by using personality models of Cloninger and Eysenck. Methods: 100 substance-dependent and 100 normal men selected by available sampling method and completed Temperament and Character Inventory of Cloninger (TCI and Eysenck Personality Questionnaire _ Revised (EPQ-R. Also, some democratic information regarding substance- dependents collected. Research data were analyzed by inferential and descriptive statistics. Findings: This research showed that there are significant differences in temperament dimensions of novelty seeking and harm avoidance and character dimensions of self-direction and cooperativeness of Cloninger model and neuroticism and psychosis dimensions of Eysenck model between substance- dependent men and normal men. Results: Comparing in normal men, substance dependent men gained higher scores at novelty seeking and neuroticism and psychosis, and lower scores at self-direction and cooperativeness.

Measurement of laser power for photo-triggered drug delivery in vivo

Energy Technology Data Exchange (ETDEWEB)

Wang, R.; Zhang, X. L.; Liu, F.; Zhang, Z. L.; Chen, Y. J.; Zhao, E. M.; Liu, L., E-mail: liulu@hrbeu.edu.cn [Key Lab of In-Fiber Integrated Optics, Ministry Education of China, Harbin Engineering University, Harbin 150001 (China); School of Science, Harbin Engineering University, Harbin 150001 (China)

2016-07-14

Thus far, despite many investigations have been carried out for photo-triggered drug delivery systems, most of them suffer from an intrinsic drawback of without real-time monitoring mechanism. Incident intensity of light is a feasible parameter to monitor the drug release profiles. However, it is difficult to measure the incident laser power irradiated onto the photo-triggered carriers in drug delivery systems during in vivo therapy. We design an online measurement method based on the fluorescence intensity ratio (FIR) technique through upconversion nanoparticles. FIR value varies with temperature of sample due to the thermal effect induced by the incident laser, which validates the laser power measurement. Effects of rare earth doping concentration, as well as experimental conditions including laser spots and wavelengths on the measurement behavior were also investigated.

Vertical profiles of aerosol mass concentration derived by unmanned airborne in situ and remote sensing instruments during dust events

Science.gov (United States)

Mamali, Dimitra; Marinou, Eleni; Sciare, Jean; Pikridas, Michael; Kokkalis, Panagiotis; Kottas, Michael; Binietoglou, Ioannis; Tsekeri, Alexandra; Keleshis, Christos; Engelmann, Ronny; Baars, Holger; Ansmann, Albert; Amiridis, Vassilis; Russchenberg, Herman; Biskos, George

2018-05-01

In situ measurements using unmanned aerial vehicles (UAVs) and remote sensing observations can independently provide dense vertically resolved measurements of atmospheric aerosols, information which is strongly required in climate models. In both cases, inverting the recorded signals to useful information requires assumptions and constraints, and this can make the comparison of the results difficult. Here we compare, for the first time, vertical profiles of the aerosol mass concentration derived from light detection and ranging (lidar) observations and in situ measurements using an optical particle counter on board a UAV during moderate and weak Saharan dust episodes. Agreement between the two measurement methods was within experimental uncertainty for the coarse mode (i.e. particles having radii > 0.5 µm), where the properties of dust particles can be assumed with good accuracy. This result proves that the two techniques can be used interchangeably for determining the vertical profiles of aerosol concentrations, bringing them a step closer towards their systematic exploitation in climate models.

Vertical profiles of lung deposited surface area concentration of particulate matter measured with a drone in a street canyon.

Science.gov (United States)

Kuuluvainen, Heino; Poikkimäki, Mikko; Järvinen, Anssi; Kuula, Joel; Irjala, Matti; Dal Maso, Miikka; Keskinen, Jorma; Timonen, Hilkka; Niemi, Jarkko V; Rönkkö, Topi

2018-05-23

The vertical profiles of lung deposited surface area (LDSA) concentration were measured in an urban street canyon in Helsinki, Finland, by using an unmanned aerial system (UAS) as a moving measurement platform. The street canyon can be classified as an avenue canyon with an aspect ratio of 0.45 and the UAS was a multirotor drone especially modified for emission measurements. In the experiments of this study, the drone was equipped with a small diffusion charge sensor capable of measuring the alveolar LDSA concentration of particles. The drone measurements were conducted during two days on the same spatial location at the kerbside of the street canyon by flying vertically from the ground level up to an altitude of 50 m clearly above the rooftop level (19 m) of the nearest buildings. The drone data were supported by simultaneous measurements and by a two-week period of measurements at nearby locations with various instruments. The results showed that the averaged LDSA concentrations decreased approximately from 60 μm 2 /cm 3 measured close to the ground level to 36-40 μm 2 /cm 3 measured close to the rooftop level of the street canyon, and further to 16-26 μm 2 /cm 3 measured at 50 m. The high-resolution measurement data enabled an accurate analysis of the functional form of vertical profiles both in the street canyon and above the rooftop level. In both of these regions, exponential fits were used and the parameters obtained from the fits were thoroughly compared to the values found in literature. The results of this study indicated that the role of turbulent mixing caused by traffic was emphasized compared to the street canyon vortex as a driving force of the dispersion. In addition, the vertical profiles above the rooftop level showed a similar exponential decay compared to the profiles measured inside the street canyon. Copyright © 2018 Elsevier Ltd. All rights reserved.

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...

Addiction research centres and the nurturing of creativity: National Drug Dependence Treatment Centre, India--a profile.

Science.gov (United States)

Ray, Rajat; Dhawan, Anju; Chopra, Anita

2013-10-01

The National Drug Dependence Treatment Centre (NDDTC) is a part of the All India Institute of Medical Sciences, a premier autonomous medical university in India. This article provides an account of its origin and its contribution to the field of substance use disorder at the national and international levels. Since its establishment, the NDDTC has played a major role in the development of various replicable models of care, the training of post-graduate students of psychiatry, research, policy development and planning. An assessment of the magnitude of drug abuse in India began in the early 1990s and this was followed by a National Survey on Extent, Patterns and Trends of Drug Abuse in 2004. Several models of clinical care have been developed for population subgroups in diverse settings. The centre played an important role in producing data and resource material which helped to scale up opioid substitution treatment in India. A nationwide database on the profile of patients seeking treatment (Drug Abuse Monitoring System) at government drug treatment centres has also been created. The centre has provided valuable inputs for the Government of India's programme planning. Besides clinical studies, research has also focused on pre-clinical studies. Capacity-building is an important priority, with training curricula and resource material being developed for doctors and paramedical staff. Many of these training programmes are conducted in collaboration with other institutions in the country. The NDDTC has received funding from several national and international organizations for research and scientific meetings, and, most recently (2012), it has been designated as a World Health Organization Collaborating Centre on Substance Abuse. © 2012 The Authors, Addiction © 2012 Society for the Study of Addiction.

Exploration of a Doxorubicin-Polymer Conjugate in Lipid-Polymer Hybrid Nanoparticle Drug Delivery

Science.gov (United States)

Lough, Emily

Nanoparticle (NP) drug delivery is a major focus in the research community because of its potential to use existing drugs in safer and more effective ways. Chemotherapy encapsulation in NPs shields the drug from the rest of the body while it is within the NP, with less systemic exposure leading to fewer off-target effects of the drug. However, passive loading of drugs into NPs is a suboptimal method, often leading to burst release upon administration. This work explores the impact of incorporating the drug-polymer conjugate doxorubicin-poly (lactic-co-glycolic) acid (Dox-PLGA) into a lipid-polymer hybrid nanoparticle (LPN). The primary difference in using a drug-polymer conjugate for NP drug delivery is the drug's release kinetics. Dox-PLGA LPNs showed a more sustained and prolonged release profile over 28 days compared to LPNs with passively loaded, unconjugated doxorubicin. This sustained release translates to cytotoxicity; when systemic circulation was simulated using dialysis, Dox-PLGA LPNs retained their cytotoxicity at a higher level than the passively loaded LPNs. The in vivo implication of preserving cytotoxic potency through a slower release profile is that the majority of Dox delivered via Dox-PLGA LPNs will be kept within the LPN until it reaches the tumor. This will result in fewer systemic side effects and more effective treatments given the higher drug concentration at the tumor site. An intriguing clinical application of this drug delivery approach lies in using Dox-PLGA LPNs to cross the blood-brain barrier (BBB). The incorporation of Dox-PLGA is hypothesized to have a protective effect on the BBB as its slow release profile will prevent drug from harming the BBB. Using induced pluripotent stem cells differentiated to human brain microvascular endothelial cells that comprise the BBB, the Dox-PLGA LPNs were shown to be less destructive to the BBB than their passively loaded counterparts. Dox-PLGA LPNs showed superior cytotoxicity against plated tumor

Profiling evolutionary landscapes underlying drug resistance

DEFF Research Database (Denmark)

Hickman, Rachel

bacterial communities i.e. biofilms or dormant metabolic states. Antibiotic drugs are currently our best medicine to treat (against) bacterial pathogens due to antibiotics unique properties of being small molecules that are soluble and act systemically. These qualities allow for many modern medical...

Towards Better Precision Medicine: PacBio Single-Molecule Long Reads Resolve the Interpretation of HIV Drug Resistant Mutation Profiles at Explicit Quasispecies (Haplotype) Level.

Science.gov (United States)

Huang, Da Wei; Raley, Castle; Jiang, Min Kang; Zheng, Xin; Liang, Dun; Rehman, M Tauseef; Highbarger, Helene C; Jiao, Xiaoli; Sherman, Brad; Ma, Liang; Chen, Xiaofeng; Skelly, Thomas; Troyer, Jennifer; Stephens, Robert; Imamichi, Tomozumi; Pau, Alice; Lempicki, Richard A; Tran, Bao; Nissley, Dwight; Lane, H Clifford; Dewar, Robin L

2016-01-01

Development of HIV-1 drug resistance mutations (HDRMs) is one of the major reasons for the clinical failure of antiretroviral therapy. Treatment success rates can be improved by applying personalized anti-HIV regimens based on a patient's HDRM profile. However, the sensitivity and specificity of the HDRM profile is limited by the methods used for detection. Sanger-based sequencing technology has traditionally been used for determining HDRM profiles at the single nucleotide variant (SNV) level, but with a sensitivity of only ≥ 20% in the HIV population of a patient. Next Generation Sequencing (NGS) technologies offer greater detection sensitivity (~ 1%) and larger scope (hundreds of samples per run). However, NGS technologies produce reads that are too short to enable the detection of the physical linkages of individual SNVs across the haplotype of each HIV strain present. In this article, we demonstrate that the single-molecule long reads generated using the Third Generation Sequencer (TGS), PacBio RS II, along with the appropriate bioinformatics analysis method, can resolve the HDRM profile at a more advanced quasispecies level. The case studies on patients' HIV samples showed that the quasispecies view produced using the PacBio method offered greater detection sensitivity and was more comprehensive for understanding HDRM situations, which is complement to both Sanger and NGS technologies. In conclusion, the PacBio method, providing a promising new quasispecies level of HDRM profiling, may effect an important change in the field of HIV drug resistance research.

Profile of rheumatology patients willing to report adverse drug reactions: bias from selective reporting

Directory of Open Access Journals (Sweden)

Protić D

2016-02-01

Full Text Available Dragana Protić,1 Nada Vujasinović-Stupar,2 Zoran Bukumirić,3 Slavica Pavlov-Dolijanović,4 Snežana Baltić,5 Slavica Mutavdžin,6 Ljiljana Markovic-Denić,7 Marija Zdravković,8 Zoran Todorović1 1Department of Pharmacology, Clinical Pharmacology and Toxicology, Faculty of Medicine, University of Belgrade, Belgrade, Serbia; 2Department 2, Institute of Rheumatology, Faculty of Medicine, University of Belgrade, Belgrade, Serbia; 3Institute for Medical Statistics and Informatics, Faculty of Medicine, University of Belgrade, Belgrade, Serbia; 4Department 5, Institute of Rheumatology, Faculty of Medicine, University of Belgrade, Belgrade, Serbia; 5Department 5, Institute of Rheumatology, Belgrade, Serbia; 6Institute of Physiology “Rihard Burjan”, Faculty of Medicine, University of Belgrade, Belgrade, Serbia; 7Institute of Epidemiology, Faculty of Medicine, University of Belgrade, Belgrade, Serbia; 8Department of Cardiology, Medical Center “Bežanijska kosa”, Faculty of Medicine, University of Belgrade, Belgrade, Serbia Background: Adverse drug reactions (ADRs have a significant impact on human health and health care costs. The aims of our study were to determine the profile of rheumatology patients willing to report ADRs and to identify bias in such a reporting system. Methods: Semi-intensive ADRs reporting system was used in our study. Patients willing to participate (N=261 completed the questionnaire designed for the purpose of the study at the hospital admission. They were subsequently classified into two groups according to their ability to identify whether they had experienced ADRs during the previous month. Group 1 included 214 out of 261 patients who were able to identify ADRs, and group 2 consisted of 43 out of 261 patients who were not able to identify ADRs in their recent medical history. Results: Group 1 patients were more significantly aware of their diagnosis than the patients from group 2. Marginal significance was found

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.

Science.gov (United States)

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.

Science.gov (United States)

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.

Analysis of the Mechanism of Prolonged Persistence of Drug Interaction between Terbinafine and Amitriptyline or Nortriptyline.

Science.gov (United States)

Mikami, Akiko; Hori, Satoko; Ohtani, Hisakazu; Sawada, Yasufumi

2017-01-01

The purpose of the study was to quantitatively estimate and predict drug interactions between terbinafine and tricyclic antidepressants (TCAs), amitriptyline or nortriptyline, based on in vitro studies. Inhibition of TCA-metabolizing activity by terbinafine was investigated using human liver microsomes. Based on the unbound K i values obtained in vitro and reported pharmacokinetic parameters, a pharmacokinetic model of drug interaction was fitted to the reported plasma concentration profiles of TCAs administered concomitantly with terbinafine to obtain the drug-drug interaction parameters. Then, the model was used to predict nortriptyline plasma concentration with concomitant administration of terbinafine and changes of area under the curve (AUC) of nortriptyline after cessation of terbinafine. The CYP2D6 inhibitory potency of terbinafine was unaffected by preincubation, so the inhibition seems to be reversible. Terbinafine competitively inhibited amitriptyline or nortriptyline E-10-hydroxylation, with unbound K i values of 13.7 and 12.4 nM, respectively. Observed plasma concentrations of TCAs administered concomitantly with terbinafine were successfully simulated with the drug interaction model using the in vitro parameters. Model-predicted nortriptyline plasma concentration after concomitant nortriptylene/terbinafine administration for two weeks exceeded the toxic level, and drug interaction was predicted to be prolonged; the AUC of nortriptyline was predicted to be increased by 2.5- or 2.0- and 1.5-fold at 0, 3 and 6 months after cessation of terbinafine, respectively. The developed model enables us to quantitatively predict the prolonged drug interaction between terbinafine and TCAs. The model should be helpful for clinical management of terbinafine-CYP2D6 substrate drug interactions, which are difficult to predict due to their time-dependency.

Electrostimulated Release of Neutral Drugs from Polythiophene Nanoparticles: Smart Regulation of Drug-Polymer Interactions.

Science.gov (United States)

Puiggalí-Jou, Anna; Micheletti, Paolo; Estrany, Francesc; Del Valle, Luis J; Alemán, Carlos

2017-09-01

Poly(3,4-ethylenedioxythiophene) (PEDOT) nanoparticles are loaded with curcumin and piperine by in situ emulsion polymerization using dodecyl benzene sulfonic acid both as a stabilizer and a doping agent. The loaded drugs affect the morphology, size, and colloidal stability of the nanoparticles. Furthermore, kinetics studies of nonstimulated drug release have evidenced that polymer···drug interactions are stronger for curcumin than for piperine. This observation suggests that drug delivery systems based on combination of the former drug with PEDOT are much appropriated to show an externally tailored release profile. This is demonstrated by comparing the release profiles obtained in presence and absence of electrical stimulus. Results indicate that controlled and time-programmed release of curcumin is achieved in a physiological medium by applying a negative voltage of -1.25 V to loaded PEDOT nanoparticles. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Biocompatible fluorescent zein nanoparticles for simultaneous bioimaging and drug delivery application

International Nuclear Information System (INIS)

Girija Aswathy, Ravindran; Sivakumar, Balasubramanian; Brahatheeswaran, Dhandayudhapani; Fukuda, Takahiro; Yoshida, Yasuhiko; Maekawa, Toru; Sakthi Kumar, D

2012-01-01

We report the synthesis of 5-fluorouracil (5-FU) loaded biocompatible fluorescent zein nanoparticles. Zein is the storage protein in corn kernels that has a variety of unique characteristics and functionalities that makes zein valuable in various commercial applications. It is classified as generally recognized as safe (GRAS) by the Food and Drug Administration (FDA). We synthesized zein nanoparticles of around 800 nm in size and conjugated with quantum dot ZnS:Mn. The nanoparticle was in turn encapsulated with the drug 5-FU. The luminescent properties of these nanoparticles were studied by using fluorescence microscopy. The nanoparticles were characterized and the drug release profile was studied. The biocompatibility of zein nanoparticle and the cytotoxicity with drug-loaded nanoparticle was studied in L929 and MCF-7 cell lines. The nanoparticles were successfully employed for cellular imaging. In vitro drug release studies were also performed. The biocompatibility of the nanoparticle showed that nanoparticles at higher concentrations are compatible for cells and are expected to be promising agents for the targeted delivery of drugs in the near future

Profile of isokinetic eccentric-to-concentric strength ratios of shoulder rotator muscles in elite female team handball players.

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Andrade, Marilia Dos Santos; Fleury, Anna Maria; de Lira, Claudio Andre Barbosia; Dubas, Joao Paulo; da Silva, Antonio Carlos

2010-05-01

The purpose of this study was to establish the isokinetic profile of shoulder rotator muscles strength in female handball players. Twenty-seven handball players performed concentric and eccentric strength tests of both dominant and non-dominant upper limbs on an isokinetic dynamometer. Internal and external rotator muscles peak torque was assessed at 1.05, 3.14, and 5.23 rad . s(-1) in concentric mode and at 3.14 and 5.23 rad . s(-1) in eccentric mode. Concentric balance ratio and functional ratio were obtained. Bi-lateral deficiency was compared. Concentric strength for internal and external rotation was significantly greater for the dominant than for the non-dominant limb for all speeds (P muscles were stronger in the dominant than the non-dominant limb (P stronger than the non-dominant side, balance concentric ratios remained the same, with only the functional strength ratio different at 5.23 rad . s(-1). Our results suggest that concentric strength exercises be used for internal and external rotators on the non-dominant side, and functional exercise that improves eccentric rotation strength for prevention programmes.

Polychlorinated biphenyl (PCB) contamination in Galveston Bay, Texas: Comparing concentrations and profiles in sediments, passive samplers, and fish.

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Oziolor, Elias M; Apell, Jennifer N; Winfield, Zach C; Back, Jeffrey A; Usenko, Sascha; Matson, Cole W

2018-05-01

The industrialized portion of the Houston Ship Channel (HSC) is heavily contaminated with anthropogenic contaminants, most prominent of which are the polychlorinated biphenyls (PCBs). This contamination has driven adaptive evolution in a keystone species for Galveston Bay, the Gulf killifish (Fundulus grandis). We investigated the geographical extent of PCB impacts by sampling 12 sites, ranging from the heavily industrialized upper portion of the HSC to Galveston Island. At each site, PCB concentrations and profiles were determined in three environmental compartments: sediment, water (polyethylene passive samplers), and fish tissue (resident Gulf killifish). We observed a steep gradient of PCB contamination, ranging from 4.00 to 100,000 ng/g organic carbon in sediment, 290-110,000 ng/g lipid in fish, and 4.5-2300 ng/g polyethylene in passive samplers. The PCB congener profiles in Gulf killifish at the most heavily contaminated sites were shifted toward the higher chlorinated PCBs and were highly similar to the sediment contamination profiles. In addition, while magnitude of total PCB concentrations in sediment and total fish contamination levels were highly correlated between sites, the relative PCB congener profiles in fish and passive samplers were more alike. This strong correlation, along with a lack of dependency of biota-sediment accumulation factors with total contamination rates, confirm the likely non-migratory nature of Gulf killifish and suggest their contamination levels are a good site-specific indicator of contamination in the Galveston Bay area. The spatial gradient of PCB contamination in Galveston Bay was evident in all three matrices studied and was observed effectively using Gulf killifish contamination as an environmentally relevant bioindicator of localized contamination in this environment. Copyright © 2018 Elsevier Ltd. All rights reserved.

Predicting transporter-mediated drug interactions: Commentary on: "Pharmacokinetic evaluation of a drug transporter cocktail consisting of digoxin, furosemide, metformin and rosuvastatin" and "Validation of a microdose probe drug cocktail for clinical drug interaction assessments for drug transporters and CYP3A".

Science.gov (United States)

Zhang, L; Sparreboom, A

2017-04-01

Transporters, expressed in various tissues, govern the absorption, distribution, metabolism, and excretion of drugs, and consequently their inherent safety and efficacy profiles. Drugs may interact with a transporter as a substrate and/or an inhibitor. Understanding transporter-mediated drug-drug interactions (DDIs), in addition to enzyme-mediated DDIs, is an integral part of risk assessment in drug development and regulatory review because the concomitant use of more than one medication in patients is common. © 2016 ASCPT.

Correlates of Sex Trading among Drug-Involved Women in Committed Intimate Relationships: A Risk Profile.

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Jiwatram-Negrón, Tina; El-Bassel, Nabila

2015-01-01

Despite a slight decline in new human immunodeficiency virus (HIV) infections in New York, marked increases and concentrated epidemics continue among subsets of the population, including women engaged in sex trading. We examined the prevalence and correlates of sex trading among 346 low-income, HIV-negative women in HIV-concordant intimate relationships. Women and their long-term main partners were recruited to participate in an HIV prevention intervention. Baseline data were used in this article. Of the 346 women in the study, 28% reported sex trading during the prior 90 days. Multivariate analyses showed increased relative risk of sex trading by lifetime experience of severe intimate partner violence (IPV), drug, and alcohol use, and marginal significance for mental health hospitalization, partner drug dependency, and homelessness. These findings suggest an urgent need for HIV prevention and intervention efforts targeted toward women in intimate relationships who trade sex for money or drugs, with an emphasis on IPV, mental health, history of incarceration, and substance abuse. Copyright © 2015 Jacobs Institute of Women's Health. Published by Elsevier Inc. All rights reserved.

Enhanced drug encapsulation and extended release profiles of calcium-alginate nanoparticles by using tannic acid as a bridging cross-linking agent.

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Abulateefeh, Samer R; Taha, Mutasem O

2015-01-01

Calcium alginate nanoparticles (NPs) suffer from sub-optimal stability in bio-relevant media leading to low drug encapsulation efficiency and uncontrolled release profiles. To sort out these drawbacks, a novel approach is proposed herein based on introducing tannic acid into these NPs to act as a bridging cross-linking aid agent. Calcium-alginate NPs were prepared by the ionotropic gelation method and loaded with diltiazem hydrochloride as a model drug. These NPs were characterized in terms of particle size, zeta potential, and morphology, and results were explained in accordance with Fourier-transform infrared (FTIR) spectroscopy and differential scanning calorimetry (DSC). The incorporation of tannic acid led to more than four folds increase in drug encapsulation efficiency (i.e. from 15.3% to 69.5%) and reduced burst drug release from 44% to around 10% within the first 30 min. These findings suggest the possibility of improving the properties of Ca-alginate NPs by incorporating cross-linking aid agents under mild conditions.

Linseed oil supplemented concentrate fed to Brahman crossbred fattening steers on carcass quality traits and intramuscular fatty acid profiles

Directory of Open Access Journals (Sweden)

Pitunart Noosen

2017-02-01

Full Text Available The objective of this study was to determine the linseed oil supplemented concentrate fed to Brahman crossbred fattening steers on carcass quality trait and intramuscular fatty acid (FA profiles. All steers were fed 14% CP concentrate. The treatments included: (1 7 kg/d concentrate; (2 4 kg/d concentrate supplemented with 200 g/d palm oil (PO; (3 4 kg/d concentrate supplemented with 100 g/d PO and 100 g/d linseed oil (LSO; and (4 4 kg/d concentrate supplemented with 200 g/d LSO. The animals in the treatment 1 were fed ad libitum rice straw (RS, whereas the animals in other treatments were fed ad libitum fresh grass (FG. Dietary treatments had no effect on nutrient intake while oil supplement decreased dry matter intake (DMI. Inclusion of LSO did not negatively affect carcass quality, but increasing amount of LSO supplement increased the n-3 fatty acids and lowered the n-6/n-3 ratio in beef

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.

Therapeutic drug monitoring in pediatric IBD: current application and future perspectives.

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Lega, Sara; Bramuzzo, Matteo; Dubinsky, Marla

2017-09-11

As the paradigm for IBD management is evolving from symptom control to the more ambitious goal of complete deep remission, the concept of personalized medicine, as a mean to deliver individualized treatment with the best effectiveness and safety profile, is becoming paramount. Therapeutic drug monitoring (TDM) is an essential part of personalized medicine wherein serum drug concentrations are used to guide drug dosing on an individual basis. The concept of TDM has been introduced in the field of IBD along with thiopurines, over a decade ago, and evolved around anti-TNFs therapies. In the era of biologics, TDM entered the clinical field to assist clinicians managing anti-TNF failure and its role is now moving toward the concept of "proactive" TDM with the goal to optimize drug exposure and prevent loss of response. Research in TDM is rapidly expanding: while the role of TDM with new biologics is under investigation, preliminary data suggest that software-systems support tools could be an opportunity to guide dosing choices and maximize the cost-benefit profile of therapies in the near future. The review discusses the current knowledge that poses the rationale for the use of TDM and the present and future role of TDM-based approaches in the management of pediatric IBD. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Drug release from enzyme-mediated in situ-forming hydrogel based on gum tragacanth-tyramine conjugate.

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Dehghan-Niri, Maryam; Tavakol, Moslem; Vasheghani-Farahani, Ebrahim; Ganji, Fariba

2015-05-01

In the present study, injectable hydrogels based on gum tragacanth-tyramine conjugate were prepared by enzymatic oxidation of tyramine radicals in the presence of hydrogen peroxide. Then, in vitro release of bovine serum albumin and insulin as model protein drugs from this polymeric network was investigated. Also, to improve the properties of this hydrogel, a blended hydrogel composed of tyramine-conjugated gelatin and tyramine-conjugated tragacanth was prepared. Experimental results showed that the gelation time ranged from 3 to 28 s depending on the polymer and enzyme concentrations. Results of morphological investigation of hydrogels indicated that the average pore size of hydrogels varied from 120 to 160 µm. Swelling degree of hydrogels and the rate of drug release decreased by increasing of hydrogen peroxide and polymer concentrations. The release profile of drug from hydrogels followed Higuchi and Fickian diffusion mechanism. Finally, it was shown that the swelling characteristics and drug release behavior of this polymeric network could be improved by blending it with tyramine-conjugated gelatin. © The Author(s) 2015 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

Vitamin E concentrations in adults with HIV/AIDS on highly active antiretroviral therapy.

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Itinoseki Kaio, Daniella J Itinoseki; Rondó, Patricia Helen C; Luzia, Liania Alves; Souza, José Maria P; Firmino, Aline Vale; Santos, Sigrid Sousa

2014-09-15

HIV/AIDS patients are probably more predisposed to vitamin E deficiency, considering that they are more exposed to oxidative stress. Additionally, there are an extensive number of drugs in the highly active antiretroviral therapy (HAART) regimens that may interfere with vitamin E concentrations. The objective of this study was to compare serum concentrations of alpha-tocopherol in 182 HIV/AIDS patients receiving different HAART regimens. The patients were divided into three groups according to regimen: nucleoside analog reverse-transcriptase inhibitors (NRTIs) + non-nucleoside analog reverse-transcriptase inhibitors (NNRTIs); NRTIs + protease inhibitors + ritonavir; NRTIs + other classes. Alpha-tocopherol was assessed by high-performance liquid chromatography. Multiple linear regression analysis was used to evaluate the effects of HAART regimen, time of use, and compliance with the regimen on alpha-tocopherol concentrations. Alpha-tocopherol concentrations were on average 4.12 μmol/L lower for the NRTIs + other classes regimen when compared to the NRTIs + NNRTIs regimen (p = 0.037). A positive association (p < 0.001) was observed between alpha-tocopherol and cholesterol concentrations, a finding due, in part, to the relationship between liposoluble vitamins and lipid profile. This study demonstrated differences in alpha-tocopherol concentrations between patients using different HAART regimens, especially regimens involving the use of new drugs. Long-term prospective cohort studies are needed to monitor vitamin E status in HIV/AIDS patients since the beginning of treatment.

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.

Characterization of naproxen-loaded solid SMEDDSs prepared by spray drying: the effect of the polysaccharide carrier and naproxen concentration.

Science.gov (United States)

Čerpnjak, Katja; Zvonar, Alenka; Vrečer, Franc; Gašperlin, Mirjana

2015-05-15

The purpose of this study was to prepare solid SMEDDS (sSMEDDS) particles produced by spray-drying using maltodextrin (MD), hypromellose (HPMC), and a combination of the two as a solid carrier. Naproxen (NPX) as the model drug was dissolved (at 6% concentration) or partially suspended (at 18% concentration) in a liquid SMEDDS composed of Miglyol(®) 812, Peceol™, Gelucire(®) 44/14, and Solutol(®) HS 15. Among the sSMEDDSs tested, the MD-based sSMEDDSs (with a granular, smooth-surfaced, microspherical appearance) preserved the self-microemulsifying properties of liquid SMEDDSs and exhibited dissolution profiles similar to those of liquid SMEDDSs, irrespective of the concentration of NPX. In contrast, HPMC-based sSMEDDSs (irregular-shaped microparticles) exhibited slightly prolonged release times due to the polymeric nature of the carrier. Differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), and Raman mapping analysis confirmed molecularly dissolved NPX (at 6% of drug loading), whereas at 18% NPX loading drug is partially molecularly dissolved and partially in the crystalline state. Copyright © 2015. Published by Elsevier B.V.

Macrolide drug interactions: an update.

Science.gov (United States)

Pai, M P; Graci, D M; Amsden, G W

2000-04-01

To describe the current drug interaction profiles for the commonly used macrolides in the US and Europe, and to comment on the clinical impact of these interactions. A MEDLINE search (1975-1998) was performed to identify all pertinent studies, review articles, and case reports. When appropriate information was not available in the literature, data were obtained from the product manufacturers. All available data were reviewed to provide an unbiased account of possible drug interactions. Data for some of the interactions were not available from the literature, but were available from abstracts or company-supplied materials. Although the data were not always explicit, the best attempt was made to deliver pertinent information that clinical practitioners would need to formulate practice opinions. When more in-depth information was supplied in the form of a review or study report, a thorough explanation of pertinent methodology was supplied. Several clinically significant drug interactions have been identified since the approval of erythromycin. These interactions usually were related to the inhibition of the cytochrome P450 enzyme systems, which are responsible for the metabolism of many drugs. The decreased metabolism by the macrolides has in some instances resulted in potentially severe adverse events. The development and marketing of newer macrolides are hoped to improve the drug interaction profile associated with this class. However, this has produced variable success. Some of the newer macrolides demonstrated an interaction profile similar to that of erythromycin; others have improved profiles. The most success in avoiding drug interactions related to the inhibition of cytochrome P450 has been through the development of the azalide subclass, of which azithromycin is the first and only to be marketed. Azithromycin has not been demonstrated to inhibit the cytochrome P450 system in studies using a human liver microsome model, and to date has produced none of the

Validation of a microdose probe drug cocktail for clinical drug interaction assessments for drug transporters and CYP3A.

Science.gov (United States)

Prueksaritanont, T; Tatosian, D A; Chu, X; Railkar, R; Evers, R; Chavez-Eng, C; Lutz, R; Zeng, W; Yabut, J; Chan, G H; Cai, X; Latham, A H; Hehman, J; Stypinski, D; Brejda, J; Zhou, C; Thornton, B; Bateman, K P; Fraser, I; Stoch, S A

2017-04-01

A microdose cocktail containing midazolam, dabigatran etexilate, pitavastatin, rosuvastatin, and atorvastatin has been established to allow simultaneous assessment of a perpetrator impact on the most common drug metabolizing enzyme, cytochrome P450 (CYP)3A, and the major transporters organic anion-transporting polypeptides (OATP)1B, breast cancer resistance protein (BCRP), and MDR1 P-glycoprotein (P-gp). The clinical utility of these microdose cocktail probe substrates was qualified by conducting clinical drug interaction studies with three inhibitors with different in vitro inhibitory profiles (rifampin, itraconazole, and clarithromycin). Generally, the pharmacokinetic profiles of the probe substrates, in the absence and presence of the inhibitors, were comparable to their reported corresponding pharmacological doses, and/or in agreement with theoretical expectations. The exception was dabigatran, which resulted in an approximately twofold higher magnitude for microdose compared to conventional dosing, and, thus, can be used to flag a worst-case scenario for P-gp. Broader application of the microdose cocktail will facilitate a more comprehensive understanding of the roles of drug transporters in drug disposition and drug interactions. © 2016 American Society for Clinical Pharmacology and Therapeutics.

Toward a generic approach for : Stress testing of drug substances and drug products

NARCIS (Netherlands)

Klick, Silke; Muijselaar, Pim G.; Waterval, Joop; Eichinger, Thomas; Korn, Christian; Gerding, Thijs K.; Debets, Alexander J.; Sänger-Van De Griend, Cari; Van Den Beld, Cas; Somsen, Govert W.; De Jong, Gerhardus J.

The Impurity Profiling Group has developed a generic approach for conducting stress testing on drug substances and drug products. The proposed strategy is evaluated and verified with historical data and new experiments. Results demonstrate that the proposed approach is reasonable and generates

Total hepatocellular disposition profiling of rosuvastatin and pitavastatin in sandwich-cultured human hepatocytes.

Science.gov (United States)

Kanda, Katsuhiro; Takahashi, Ryosuke; Yoshikado, Takashi; Sugiyama, Yuichi

2018-04-09

This study describes the total disposition profiling of rosuvastatin (RSV) and pitavastatin (PTV) using a single systematic procedure called D-PREX (Disposition Profile Exploration) in sandwich-cultured human hepatocytes (SCHH). The biliary excretion fractions of both statins were clearly observed, which were significantly decreased dependent on the concentration of Ko143, an inhibitor for breast cancer resistance protein (BCRP). Ko143 also decreased the basolateral efflux fraction of RSV, whereas that of PTV was not significantly affected. To understand these phenomena, effects of Ko143 on biliary excretion (BCRP and multidrug resistance-associated protein (MRP) 2) and basolateral efflux (MRP3 and MRP4) transporters were examined using transporter-expressing membrane vesicles. BCRP, MRP3 and MRP4-mediated transport of RSV was observed, and Ko143 inhibited these transporters except MRP3. BCRP and MRP4 also mediated the transport of PTV, but the Ko143-mediated inhibition was only clear for BCRP. These results might explain the Ko143-mediated complete and partial inhibition of the biliary excretion and the basolateral efflux of RSV, respectively, in SCHH. In conclusion, D-PREX with sequential sampling of supernatants prior to cell lysis enables the evaluation of total drug disposition profiles resulting from complex interplays of intracellular pathways, which would provide high-throughput evaluation of drug disposition during drug discovery. Copyright © 2018 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.

Routine drug and food interactions during antihelminthic treatment of neurocysticercosis: a reason for the variable efficacy of albendazole and praziquantel?

Science.gov (United States)

Romo, Matthew L; Carpio, Arturo; Kelvin, Elizabeth A

2014-04-01

Neurocysticercosis (NC) or infection of the central nervous system with Taenia solium larvae is a leading cause of preventable seizures and epilepsy in endemic regions across the globe. Albendazole and praziquantel are commonly used antihelminthic agents to treat NC; however, viable cysts persist in the majority of patients, putting them at risk for future seizures and other neurological complications. Because of their pharmacokinetic profiles, albendazole and praziquantel have the potential to interact with many different drugs. During antihelminthic treatment, antiepileptic drugs and corticosteroids are commonly co-administered to manage seizures and cerebral edema; however, the most commonly used agents from these drug classes are known to significantly alter plasma concentrations of albendazole and praziquantel. The overarching issue with drug interactions during the treatment of NC is whether or not they have clinical relevance, as the plasma concentrations of albendazole and praziquantel have not been directly linked with eradication of viable cysts. Future studies should attempt to evaluate the validity of a causal relationship between antihelminthic plasma concentrations and outcomes so that drug interactions can be better understood and managed and so that treatment can be optimized. © 2014, The American College of Clinical Pharmacology.

Evaluation of Potential Drug-Drug Interaction Between Delayed-Release Dimethyl Fumarate and a Commonly Used Oral Contraceptive (Norgestimate/Ethinyl Estradiol) in Healthy Women.

Science.gov (United States)

Zhu, Bing; Nestorov, Ivan; Zhao, Guolin; Meka, Venkata; Leahy, Mark; Kam, Jeanelle; Sheikh, Sarah I

2017-11-01

Delayed-release dimethyl fumarate (DMF) is an oral therapy for relapsing multiple sclerosis with anti-inflammatory and neuroprotective properties. This 2-period crossover study was conducted to evaluate the potential for drug-drug interaction between DMF (240 mg twice daily) and a combined oral contraceptive (OC; norgestimate 250 μg, ethinyl estradiol 35 μg). Forty-six healthy women were enrolled; 32 completed the study. After the lead-in period (OC alone), 41 eligible participants were randomized 1:1 to sequence 1 (OC and DMF coadministration in period 1; OC alone in period 2) or sequence 2 (regimens reversed). Mean concentration profiles of plasma norelgestromin (primary metabolite of norgestimate) and ethinyl estradiol were superimposable following OC alone and OC coadministered with DMF, with 90% confidence intervals of geometric mean ratios for area under the plasma concentration-time curve over the dosing interval and peak plasma concentration contained within the 0.8-1.25 range. Low serum progesterone levels during combined treatment confirmed suppression of ovulation. The pharmacokinetics of DMF (measured via its primary active metabolite, monomethyl fumarate) were consistent with historical data when DMF was administered alone. No new safety concerns were identified. These results suggest that norgestimate/ethinyl estradiol-based OCs may be used with DMF without dose modification. © 2017, The Authors. Clinical Pharmacology in Drug Development Published by Wiley Periodicals, Inc. on behalf of The American College of Clinical Pharmacology.

Smart surface coating of drug nanoparticles with cross-linkable polyethylene glycol for bio-responsive and highly efficient drug delivery

Science.gov (United States)

Wei, Weijia; Zhang, Xiujuan; Chen, Xianfeng; Zhou, Mengjiao; Xu, Ruirui; Zhang, Xiaohong

2016-04-01

Many drug molecules can be directly used as nanomedicine without the requirement of any inorganic or organic carriers such as silica and liposome nanostructures. This new type of carrier-free drug nanoparticles (NPs) has great potential in clinical treatment because of its ultra-high drug loading capacity and biodegradability. For practical applications, it is essential for such nanomedicine to possess robust stability and minimal premature release of therapeutic molecules during circulation in the blood stream. To meet this requirement, herein, we develop GSH-responsive and crosslinkable amphiphilic polyethylene glycol (PEG) molecules to modify carrier-free drug NPs. These PEG molecules can be cross-linked on the surface of the NPs to endow them with greater stability and the cross-link is sensitive to intracellular environment for bio-responsive drug release. With this elegant design, our experimental results show that the liberation of DOX from DOX-cross-linked PEG NPs is dramatically slower than that from DOX-non-cross-linked PEG NPs, and the DOX release profile can be controlled by tuning the concentration of the reducing agent to break the cross-link between PEG molecules. More importantly, in vivo studies reveal that the DOX-cross-linked PEG NPs exhibit favorable blood circulation half-life (>4 h) and intense accumulation in tumor areas, enabling effective anti-cancer therapy. We expect this work will provide a powerful strategy for stabilizing carrier-free nanomedicines and pave the way to their successful clinical applications in the future.Many drug molecules can be directly used as nanomedicine without the requirement of any inorganic or organic carriers such as silica and liposome nanostructures. This new type of carrier-free drug nanoparticles (NPs) has great potential in clinical treatment because of its ultra-high drug loading capacity and biodegradability. For practical applications, it is essential for such nanomedicine to possess robust stability

SU-D-201-04: Study On the Impact of Tumor Shape and Size On Drug Delivery to Pancreatic Tumors

International Nuclear Information System (INIS)

Soltani, M; Bazmara, H; Sefidgar, M; Subramaniam, R; Rahmim, A

2015-01-01

Purpose: Drug delivery to solid tumors can be expressed physically using transport phenomena such as convection and diffusion for the drug of interest within extracellular matrices. We aimed to carefully model these phenomena, and to investigate the effect of tumor shape and size on drug delivery to solid tumors in the pancreas. Methods: In this study, multiple tumor geometries as obtained from clinical PET/CT images were considered. An advanced numerical method was used to simultaneously solve fluid flow and solute transport equations. Data from n=45 pancreatic cancer patients with non-resectable locoregional disease were analyzed, and geometrical information from the tumors including size, shape, and aspect ratios were classified. To investigate effect of tumor shape, tumors with similar size but different shapes were selected and analyzed. Moreover, to investigate effect of tumor size, tumors with similar shapes but different sizes, ranging from 1 to 77 cm 3 , were selected and analyzed. A hypothetical tumor similar to one of the analyzed tumors, but scaled to reduce its size below 0.2 cm 3 , was also analyzed. Results: The results showed relatively similar average drug concentration profiles in tumors with different sizes. Generally, smaller tumors had higher absolute drug concentration. In the hypothetical tumor, with volume less than 0.2 cm 3 , the average drug concentration was 20% higher in comparison to its counterparts. For the various real tumor geometries, however, the maximum difference between average drug concentrations was 10% for the smallest and largest tumors. Moreover, the results demonstrated that for pancreatic tumors the shape is not significant. The negligible difference of drug concentration in different tumor shapes was due to the minimum effect of convection in pancreatic tumors. Conclusion: In tumors with different sizes, smaller tumors have higher drug delivery; however, the impact of tumor shape in the case of pancreatic tumors is not

SU-D-201-04: Study On the Impact of Tumor Shape and Size On Drug Delivery to Pancreatic Tumors

Energy Technology Data Exchange (ETDEWEB)

Soltani, M [ohns Hopkins University School of Medicine, Baltimore, Maryland, and KNT university, Tehran (Iran, Islamic Republic of); Bazmara, H [KNT university, Tehran (Iran, Islamic Republic of); Sefidgar, M [IKI University, Qazvin (Iran, Islamic Republic of); Subramaniam, R; Rahmim, A [Johns Hopkins University School of Medicine, Baltimore, MD (United States)

2015-06-15

Purpose: Drug delivery to solid tumors can be expressed physically using transport phenomena such as convection and diffusion for the drug of interest within extracellular matrices. We aimed to carefully model these phenomena, and to investigate the effect of tumor shape and size on drug delivery to solid tumors in the pancreas. Methods: In this study, multiple tumor geometries as obtained from clinical PET/CT images were considered. An advanced numerical method was used to simultaneously solve fluid flow and solute transport equations. Data from n=45 pancreatic cancer patients with non-resectable locoregional disease were analyzed, and geometrical information from the tumors including size, shape, and aspect ratios were classified. To investigate effect of tumor shape, tumors with similar size but different shapes were selected and analyzed. Moreover, to investigate effect of tumor size, tumors with similar shapes but different sizes, ranging from 1 to 77 cm{sup 3}, were selected and analyzed. A hypothetical tumor similar to one of the analyzed tumors, but scaled to reduce its size below 0.2 cm{sup 3}, was also analyzed. Results: The results showed relatively similar average drug concentration profiles in tumors with different sizes. Generally, smaller tumors had higher absolute drug concentration. In the hypothetical tumor, with volume less than 0.2 cm{sup 3}, the average drug concentration was 20% higher in comparison to its counterparts. For the various real tumor geometries, however, the maximum difference between average drug concentrations was 10% for the smallest and largest tumors. Moreover, the results demonstrated that for pancreatic tumors the shape is not significant. The negligible difference of drug concentration in different tumor shapes was due to the minimum effect of convection in pancreatic tumors. Conclusion: In tumors with different sizes, smaller tumors have higher drug delivery; however, the impact of tumor shape in the case of pancreatic

The impact of preparation parameters on typical attributes of chitosan-heparin nanohydrogels: particle size, loading efficiency, and drug release.

Science.gov (United States)

Shahbazi, Mohammad-Ali; Hamidi, Mehrdad

2013-11-01

Today, developing an optimized nanoparticle (NP) preparation procedure is of paramount importance in all nanoparticulate drug delivery researches, leading to expanding more operative and clinically validated nanomedicines. In this study, a one-at-a-time experimental approach was used for evaluating the effect of various preparation factors on size, loading, and drug release of hydrogel NPs prepared with ionotropic gelation between heparin and chitosan. The size, loading efficiency (LE) and drug release profile of the NPs were evaluated when the chitosan molecular weight, chitosan concentration, heparin addition time to chitosan solution, heparin concentration, pH value of chitosan solution, temperature, and mixing rate were changed separately while other factors were in optimum condition. The results displayed that size and LE are highly influenced by chitosan concentration, getting an optimum of 63 ± 0.57 and 75.19 ± 2.65, respectively, when chitosan concentration was 0.75 mg/ml. Besides, heparin addition time of 3 min leaded to 74.1 ± 0.79 % LE with no sensible effect on size and release profile. In addition, pH 5.5 showed a minimum size of 63 ± 1.87, maximum LE of 73.81 ± 3.13 and the slowest drug release with 63.71 ± 3.84 % during one week. Although LE was not affected by temperature, size and release reduced to 63 ± 0 and 74.21 ± 1.99% when temperature increased from 25°C to 55°C. Also, continuous increase of mixer rate from 500 to 3500 rpm resulted in constant enhancement of LE from 58.3 ± 3.6 to 74.4 ± 2.59 as well as remarkable decrease in size from 148 ± 4.88 to 63 ± 2.64.

Dosing strategy based on prevailing aminoglycoside minimum inhibitory concentration in India: Evidence and issues

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Balaji Veeraraghavan

2017-01-01

Full Text Available Aminoglycosides are important agents used for treating drug-resistant infections. The current dosing regimen of aminoglycosides does not achieve sufficient serum level concentration for the infected bacterial pathogen interpreted as susceptible based on laboratory testing. Minimum inhibitory concentration was determined for nearly 2000 isolates of Enterobacteriaceae and Pseudomonas aeruginosa by broth microdilution method. Results were interpreted based on CLSI and EUCAST interpretative criteria and the inconsistencies in the susceptibility profile were noted. This study provides insights into the inconsistencies existing in the laboratory interpretation and the corresponding clinical success rates. This urges the need for revising clinical breakpoints for amikacin, to resolve under dosing leading to clinical failure.

Optimal Anti-cancer Drug Profiles for Effective Penetration of the Anti-cancer Drug Market by Generic Drugs in Japan.

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Shibata, Shoyo; Matsushita, Maiko; Saito, Yoshimasa; Suzuki, Takeshi

2017-01-01

The increased use of generic drugs is a good indicator of the need to reduce the increasing costs of prescription drugs. Since there are more expensive drugs compared with other therapeutic areas, "oncology" is an important one for generic drugs. The primary objective of this article was to quantify the extent to which generic drugs in Japan occupy each level of the Anatomical Therapeutic Chemical (ATC) classification system. The dataset used in this study was created from publicly available information obtained from the IMS Japan Pharmaceutical Market database. Data on the total amount of sales and number of prescriptions for anti-cancer drugs between 2010 and 2016 in Japan were selected. The data were categorized according to the third level of the ATC classification system. All categories of the ATC classification system had increased market shares in Japan between 2010 and 2016. The barriers to market entry were relatively low in L01F (platinum anti-neoplastics), L01C (plant-based neoplastics), L02B (cytostatic hormone antagonists), and L01D (anti-neoplastic antibiotics) but were high in L02A (cytostatic hormones), L01H (protein kinase inhibitors), and L01B (anti-metabolites). Generic cancer drugs could bring savings to Japanese health care systems. Therefore, their development should be directed toward niche markets, such as L02A, L01H, and L01B, and not competitive markets.

The role of silicon interstitials in the deactivation and reactivation of high concentration boron profiles

Energy Technology Data Exchange (ETDEWEB)

Aboy, Maria [Campus Miguel Delibes, University of Valladolid, 47011 Valladolid (Spain)]. E-mail: marabo@tel.uva.es; Pelaz, Lourdes [Campus Miguel Delibes, University of Valladolid, 47011 Valladolid (Spain); Marques, Luis A. [Campus Miguel Delibes, University of Valladolid, 47011 Valladolid (Spain); Lopez, Pedro [Campus Miguel Delibes, University of Valladolid, 47011 Valladolid (Spain); Barbolla, Juan [Campus Miguel Delibes, University of Valladolid, 47011 Valladolid (Spain); Venezia, V.C. [Philips Research Leuven, Leuven (Belgium); Duffy, R. [Philips Research Leuven, Leuven (Belgium); Griffin, Peter B. [Stanford University, Stanford, CA (United States)

2004-12-15

Boron cluster formation and dissolution in high concentration B profiles and the role of Si interstitials in these processes are analyzed by kinetic non-lattice Monte Carlo atomistic simulations. For this purpose, we use theoretical structures as simplifications of boron implants into preamorphized Si, followed by low-temperature solid phase epitaxial (SPE) regrowth or laser thermal annealing process. We observe that in the presence of high B concentrations (above 10{sup 20} cm{sup -3}), significant deactivation occurs during high temperature anneal, even in the presence of only equilibrium Si interstitials. The presence of additional Si interstitials from an end of range (EOR) damage region accelerates the deactivation process and makes B deactivation slightly higher. We show that B deactivation and reactivation processes can be clearly correlated to the evolution of Si interstitial defects at the EOR. The minimum level of activation occurs when the Si interstitial defects at EOR dissolve or form very stable defects.

Cumulative organic anion transporter-mediated drug-drug interaction potential of multiple components in salvia miltiorrhiza (danshen) preparations.

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Wang, Li; Venitz, Jürgen; Sweet, Douglas H

2014-12-01

To evaluate organic anion transporter-mediated drug-drug interaction (DDI) potential for individual active components of Danshen (Salvia miltiorrhiza) vs. combinations using in vitro and in silico approaches. Inhibition profiles for single Danshen components and combinations were generated in stably-expressing human (h)OAT1 and hOAT3 cells. Plasma concentration-time profiles for compounds were estimated from in vivo human data using an i.v. two-compartment model (with first-order elimination). The cumulative DDI index was proposed as an indicator of DDI potential for combination products. This index was used to evaluate the DDI potential for Danshen injectables from 16 different manufacturers and 14 different lots from a single manufacturer. The cumulative DDI index predicted in vivo inhibition potentials, 82% (hOAT1) and 74% (hOAT3), comparable with those observed in vitro, 72 ± 7% (hOAT1) and 81 ± 10% (hOAT3), for Danshen component combinations. Using simulated unbound Cmax values, a wide range in cumulative DDI index between manufacturers, and between lots, was predicted. Many products exhibited a cumulative DDI index > 1 (50% inhibition). Danshen injectables will likely exhibit strong potential to inhibit hOAT1 and hOAT3 function in vivo. The proposed cumulative DDI index might improve prediction of DDI potential of herbal medicines or pharmaceutical preparations containing multiple components.

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

Ethanol-drug absorption interaction: potential for a significant effect on the plasma pharmacokinetics of ethanol vulnerable formulations.

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Lennernäs, Hans

2009-01-01

Generally, gastric emptying of a drug to the small intestine is controlled by gastric motor activity and is the main factor affecting the onset of absorption. Accordingly, the emptying rate from the stomach is mainly affected by the digestive state, the properties of the pharmaceutical formulation and the effect of drugs, posture and circadian rhythm. Variability in the gastric emptying of drugs is reflected in variability in the absorption rate and the shape of the plasma pharmacokinetic profile. When ethanol interacts with an oral controlled release product, such that the mechanism controlling drug release is impaired, the delivery of the dissolved dose into the small intestine and the consequent absorption may result in dangerously high plasma concentrations. For example, the maximal plasma concentration of hydromorphone has individually been shown to be increased as much as 16 times through in vivo testing as a result of this specific pharmacokinetic ethanol-drug formulation interaction. Thus, a pharmacokinetic ethanol-drug interaction is a very serious safety concern when substantially the entire dose from a controlled release product is rapidly emptied into the small intestine (dose dumping), having been largely dissolved in a strong alcoholic beverage in the stomach during a sufficient lag-time in gastric emptying. Based on the literature, a two hour time frame for screening the in vitro dissolution profile of a controlled release product in ethanol concentrations of up to 40% is strongly supported and may be considered as the absolute minimum standard. It is also evident that the dilution, absorption and metabolism of ethanol in the stomach are processes with a minor effect on the local ethanol concentration and that ethanol exposure will be highly dependent on the volume and ethanol concentration of the fluid ingested, together with the rate of intake and gastric emptying. When and in which patients a clinically significant dose dumping will happen is

Synthesis, characterization, release kinetics and toxicity profile of drug-loaded starch nanoparticles.

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El-Naggar, Mehrez E; El-Rafie, M H; El-sheikh, M A; El-Feky, Gina S; Hebeish, A

2015-11-01

The current research work focuses on the medical application of the cost-effective cross-linked starch nanoparticles, for the transdermal delivery using Diclofenac sodium (DS) as a model drug. The prepared DS-cross-linked starch nanoparticles were synthesized using nanoprecipitation technique at different concentrations of sodium tripolyphosphate (STPP) in the presence of Tween 80 as a surfactant. The resultant cross-linked starch nanoparticles loaded with DS were characterized using world-class facilities such as TEM, DLS, FT-IR, XRD, and DSc. The efficiency of DS loading was also evaluated via entrapment efficiency as well as in vitro release and histopathological study on rat skin. The optimum nanoparticles formulation selected by the JMP(®) software was the formula that composed of 5% maize starch, 57.7mg DS and 0.5% STPP and 0.4% Tween 80, with particle diameter of about 21.04nm, polydispersity index of 0.2 and zeta potential of -35.3mV. It is also worth noting that this selected formula shows an average entrapment efficiency of 95.01 and sustained DS release up to 6h. The histophathological studies using the best formula on rat skin advocate the use of designed transdermal DS loaded cross-linked starch nanoparticles as it is safe and non-irritant to rat skin. The overall results indicate that, the starch nanoparticles could be considered as a good carrier for DS drug regarding the enhancement in its controlled release and successful permeation, thus, offering a promising nanoparticulate system for the transdermal delivery non-steroidal anti-inflammatory drug (NSAID). Copyright © 2015 Elsevier B.V. All rights reserved.

Surface bioengineering of diatomite based nanovectors for efficient intracellular uptake and drug delivery

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Terracciano, Monica; Shahbazi, Mohammad-Ali; Correia, Alexandra; Rea, Ilaria; Lamberti, Annalisa; de Stefano, Luca; Santos, Hélder A.

2015-11-01

Diatomite is a natural porous silica material of sedimentary origin. Due to its peculiar properties, it can be considered as a valid surrogate of synthetic porous silica for nano-based drug delivery. In this work, we exploit the potential of diatomite nanoparticles (DNPs) for drug delivery with the aim of developing a successful dual-biofunctionalization method by polyethylene glycol (PEG) coverage and cell-penetrating peptide (CPP) bioconjugation, to improve the physicochemical and biological properties of the particles, to enhance the intracellular uptake in cancer cells, and to increase the biocompatibility of 3-aminopropyltriethoxysilane (APT) modified-DNPs. DNPs-APT-PEG-CPP showed hemocompatibility for up to 200 μg mL-1 after 48 h of incubation with erythrocytes, with a hemolysis value of only 1.3%. The cytotoxicity of the modified-DNPs with a concentration up to 200 μg mL-1 and incubation with MCF-7 and MDA-MB-231 breast cancer cells for 24 h, demonstrated that PEGylation and CPP-bioconjugation can strongly reduce the cytotoxicity of DNPs-APT. The cellular uptake of the modified-DNPs was also evaluated using the above mentioned cancer cell lines, showing that the CPP-bioconjugation can considerably increase the DNP cellular uptake. Moreover, the dual surface modification of DNPs improved both the loading of a poorly water-soluble anticancer drug, sorafenib, with a loading degree up to 22 wt%, and also enhanced the drug release profiles in aqueous solutions. Overall, this work demonstrates that the biofunctionalization of DNPs is a promising platform for drug delivery applications in cancer therapy as a result of its enhanced stability, biocompatibility, cellular uptake, and drug release profiles.Diatomite is a natural porous silica material of sedimentary origin. Due to its peculiar properties, it can be considered as a valid surrogate of synthetic porous silica for nano-based drug delivery. In this work, we exploit the potential of diatomite nanoparticles

Printing Tablets with Fully Customizable Release Profiles for Personalized Medicine.

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Sun, Yajuan; Soh, Siowling

2015-12-16

Personalizing the release profiles of drugs is important for different people with different medical and biological conditions. A technically simple and low-cost method to fabricate fully customizable tablets that can deliver drugs with any type of release profile is described. The customization is intuitively straightforward: the desired profile can simply be "drawn" and printed by a 3D printer. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Quantitative detection of mass concentration of sand-dust storms via wind-profiling radar and analysis of Z- M relationship

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Wang, Minzhong; Ming, Hu; Ruan, Zheng; Gao, Lianhui; Yang, Di

2018-02-01

With the aim to achieve quantitative monitoring of sand-dust storms in real time, wind-profiling radar is applied to monitor and study the process of four sand-dust storms in the Tazhong area of the Taklimakan Desert. Through evaluation and analysis of the spatial-temporal distribution of reflectivity factor, it is found that reflectivity factor ranges from 2 to 18 dBz under sand-dust storm weather. Using echo power spectrum of radar vertical beams, sand-dust particle spectrum and sand-dust mass concentration at the altitude of 600 ˜ 1500 m are retrieved. This study shows that sand-dust mass concentration reaches 700 μg/m3 under blowing sand weather, 2000 μg/m3 under sand-dust storm weather, and 400 μg/m3 under floating dust weather. The following equations are established to represent the relationship between the reflectivity factor and sand-dust mass concentration: Z = 20713.5 M 0.995 under floating dust weather, Z = 22988.3 M 1.006 under blowing sand weather, and Z = 24584.2 M 1.013 under sand-dust storm weather. The retrieval results from this paper are almost consistent with previous monitoring results achieved by former researchers; thus, it is implied that wind-profiling radar can be used as a new reference device to quantitatively monitor sand-dust storms.

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

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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 passive air sampler for characterizing the vertical concentration profile of gaseous phase polycyclic aromatic hydrocarbons in near soil surface air

International Nuclear Information System (INIS)

Zhang Yuzhong; Deng Shuxing; Liu Yanan; Shen Guofeng; Li Xiqing; Cao Jun; Wang Xilong; Reid, Brian; Tao Shu

2011-01-01

Air-soil exchange is an important process governing the fate of polycyclic aromatic hydrocarbons (PAHs). A novel passive air sampler was designed and tested for measuring the vertical concentration profile of 4 low molecular weight PAHs in gaseous phase (PAH LMW4 ) in near soil surface air. Air at various heights from 5 to 520 mm above the ground was sampled by polyurethane foam disks held in down-faced cartridges. The samplers were tested at three sites: A: an extremely contaminated site, B: a site near A, and C: a background site on a university campus. Vertical concentration gradients were revealed for PAH LMW4 within a thin layer close to soil surface at the three sites. PAH concentrations either decreased (Site A) or increased (Sites B and C) with height, suggesting either deposition to or evaporation from soils. The sampler is a useful tool for investigating air-soil exchange of gaseous phase semi-volatile organic chemicals. - Research highlights: → Design, field test and calibration of the novel passive air sampler, PAS-V-I. → Vertical concentration gradients of PAH LMW4 within a thin layer close to soil. → Comparison of results between PAS-V-I measurement and fugacity approach. → Potential application of PAS-V-I and further modifications. - A novel passive sampling device was developed and tested for measuring vertical concentration profile of gaseous phase polycyclic aromatic hydrocarbons in near soil surface air.

In vitro dissolution profile study of mucolytic drug ambroxol hydrochloride from solid oral dosage form by UHPLC-MS/MS

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Vujović Maja M.

2017-01-01

Full Text Available In this paper a simplified dissolution test was performed for the release of ambroxol from tablets according to the European Pharmacopoeia. In vitro, three different dissolution media; 0.1 M HCl pH 1.2, acetate buffer (ABS pH 4.5 and phosphate buffer (PBS pH 6.8 were used for the simulation of the gastrointestinal conditions at temperature of 37.0±0.5°C. The drug release was evaluated by a new ultra - high performance liquid chromatography (UHPLC - tandem mass spectrometry (MS/MS method. The method was validated to meet requirements as per ICH guidelines which include linearity, specificity, precision, accuracy and robustness. The corresponding dissolution profiles showed more than 80% drug release within 30 minutes without significant differences. Further, the developed and validated UHPLC-MS/MS method could find a useful application in the process of production, quality control and bioavailability/bioequivalence studies of new pharmaceutical formulations of drugs in order to achieve a safe therapeutic efficacy. [Projekat Ministarstva nauke Republike Srbije, br. 175045

Bioavailability assessment of hydroxymethylglutaryl coenzyme A reductase inhibitor utilizing pulsatile drug delivery system: a pilot study.

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Taha, Ehab I

2016-09-01

Chronotherapy or pulsatile drug delivery system could be achieved by increasing drug plasma concentration exactly at the time of disease incidence. Cholesterol synthesis shows a circadian rhythm being high at late night and early in the morning. Simvastatin (SIM) inhibits hydroxymethylglutaryl coenzyme A reductase, which is responsible for cholesterol synthesis. In this study, SIM lipid-based formulation filled in gelatin capsules and coated with aqueous Eudragit® S100 dispersion was prepared for chronotherapeutic treatment of hypercholesterolemia. The pharmacokinetic parameters of SIM capsules were studied in human volunteers after a single oral dose and compared with that of Zocor® tablets as a reference in a randomized cross-over study. Pharmacokinetic parameters such as AUC 0-∞ , C max , T max , t 1/2 and elimination rate constant were determined from plasma concentration-time profile for both formulations. The tested formulation had the ability to delay drug absorption and provide higher drug concentrations from 3 up to 10 h after oral administration compared to that of commercial tablets. The data in this study revealed that the prepared formulation could be effective in chronotherapeutic treatment of hypercholesterolemia. Moreover, the tested formulation was found to enhance SIM bioavailability by 29% over the reference tablets.

Drug Target Interference in Immunogenicity Assays: Recommendations and Mitigation Strategies.

Science.gov (United States)

Zhong, Zhandong Don; Clements-Egan, Adrienne; Gorovits, Boris; Maia, Mauricio; Sumner, Giane; Theobald, Valerie; Wu, Yuling; Rajadhyaksha, Manoj

2017-11-01

Sensitive and specific methodology is required for the detection and characterization of anti-drug antibodies (ADAs). High-quality ADA data enables the evaluation of potential impact of ADAs on the drug pharmacokinetic profile, patient safety, and efficacious response to the drug. Immunogenicity assessments are typically initiated at early stages in preclinical studies and continue throughout the drug development program. One of the potential bioanalytical challenges encountered with ADA testing is the need to identify and mitigate the interference mediated by the presence of soluble drug target. A drug target, when present at sufficiently high circulating concentrations, can potentially interfere with the performance of ADA and neutralizing antibody (NAb) assays, leading to either false-positive or, in some cases, false-negative ADA and NAb assay results. This publication describes various mechanisms of assay interference by soluble drug target, as well as strategies to recognize and mitigate such target interference. Pertinent examples are presented to illustrate the impact of target interference on ADA and NAb assays as well as several mitigation strategies, including the use of anti-target antibodies, soluble versions of the receptors, target-binding proteins, lectins, and solid-phase removal of targets. Furthermore, recommendations for detection and mitigation of such interference in different formats of ADA and NAb assays are provided.

Self-double-emulsifying drug delivery system (SDEDDS): a new way for oral delivery of drugs with high solubility and low permeability.

Science.gov (United States)

Qi, Xiaole; Wang, Lishuang; Zhu, Jiabi; Hu, Zhenyi; Zhang, Jie

2011-05-16

Water-in-oil-in-water (w/o/w) double emulsions are potential for enhancing oral bioavailability of drugs with high solubility and low permeability, but their industrial application is limited due to the instability. Herein, we developed a novel formulation, self-double-emulsifying drug delivery systems (SDEDDS) by formulating mixtures of hydrophilic surfactants and water-in-oil (w/o) emulsions, which were easier to be stable through formulations optimization. SDEDDS can spontaneously emulsify to water-in-oil-in-water (w/o/w) double emulsions in the mixed aqueous gastrointestinal environment, with drugs encapsulated in the internal water phase of the double emulsions. We employed SDEDDS to improve the oral absorption of pidotimod, a peptide-like drug with high solubility and low permeability. The optimized pidotimod-SDEDDS were found to be stable up to 6 months under 25°C. Plasma concentration-time profiles from pharmacokinetic studies in rats dosed with SDEDDS showed 2.56-fold (p<0.05) increased absorption of pidotimod, compared to the pidotimod solution. Histopathologic studies confirmed that SDEDDS exerted absorption promoting effect without serious local damages. These studies demonstrate that SDEDDS may be a promising strategy for peroral delivery of peptide and peptidomimetic drugs. Copyright © 2011 Elsevier B.V. All rights reserved.

Effects of age, adipose percent, and reproduction on PCB concentrations and profiles in an extreme fasting North Pacific marine mammal.

Directory of Open Access Journals (Sweden)

Sarah H Peterson

Full Text Available Persistent organic pollutants, including polychlorinated biphenyls (PCBs, are widely distributed and detectable far from anthropogenic sources. Northern elephant seals (Mirounga angustirostris biannually travel thousands of kilometers to forage in coastal and open-ocean regions of the northeast Pacific Ocean and then return to land where they fast while breeding and molting. Our study examined potential effects of age, adipose percent, and the difference between the breeding and molting fasts on PCB concentrations and congener profiles in blubber and serum of northern elephant seal females. Between 2005 and 2007, we sampled blubber and blood from 58 seals before and after a foraging trip, which were then analyzed for PCBs. Age did not significantly affect total PCB concentrations; however, the proportion of PCB congeners with different numbers of chlorine atoms was significantly affected by age, especially in the outer blubber. Younger adult females had a significantly greater proportion of low-chlorinated PCBs (tri-, tetra-, and penta-CBs than older females, with the opposite trend observed for hepta-CBs, indicating that an age-associated process such as parity (birth may significantly affect congener profiles. The percent of adipose tissue had a significant relationship with inner blubber PCB concentrations, with the highest mean concentrations observed at the end of the molting fast. These results highlight the importance of sampling across the entire blubber layer when assessing contaminant levels in phocid seals and taking into account the adipose stores and reproductive status of an animal when conducting contaminant research.

Assessing the utility of an anti-malarial pharmacokinetic-pharmacodynamic model for aiding drug clinical development

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Zaloumis Sophie

2012-08-01

Full Text Available Abstract Background Mechanistic within-host models relating blood anti-malarial drug concentrations with the parasite-time profile help in assessing dosing schedules and partner drugs for new anti-malarial treatments. A comprehensive simulation study to assess the utility of a stage-specific pharmacokinetic-pharmacodynamic (PK-PD model for predicting within-host parasite response was performed. Methods Three anti-malarial combination therapies were selected: artesunate-mefloquine, dihydroartemisinin-piperaquine, and artemether-lumefantrine. The PK-PD model included parameters to represent the concentration-time profiles of both drugs, the initial parasite burden and distribution across the parasite life cycle, and the parasite multiplication factor due to asexual reproduction. The model also included the maximal killing rate of each drug, and the blood drug concentration associated with half of that killing effect (in vivo EC50, derived from the in vitro IC50, the extent of binding to 0.5% Albumax present in the in vitro testing media, and the drugs plasma protein binding and whole blood to plasma partitioning ratio. All stochastic simulations were performed using a Latin-Hypercube-Sampling approach. Results The simulations demonstrated that the proportion of patients cured was highly sensitive to the in vivo EC50 and the maximal killing rate of the partner drug co-administered with the artemisinin derivative. The in vivo EC50 values that corresponded to on average 95% of patients cured were much higher than the adjusted values derived from the in vitro IC50. The proportion clinically cured was not strongly influenced by changes in the parameters defining the age distribution of the initial parasite burden (mean age of 4 to 16 hours and the parasite multiplication factor every life cycle (ranging from 8 to 12 fold/cycle. The median parasite clearance times, however, lengthened as the standard deviation of the initial parasite burden increased (i

Application of PAH concentration profiles in lake sediments as indicators for smelting activity.

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Warner, Wiebke; Ruppert, Hans; Licha, Tobias

2016-09-01

The ability of lake sediment cores to store long-term anthropogenic pollution establishes them as natural archives. In this study, we focus on the influence of copper shale mining and smelting in the Mansfeld area of Germany, using the depth profiles of two sediment cores from Lake Süßer See. The sediment cores provide a detailed chronological deposition history of polycyclic aromatic hydrocarbons (PAHs) and heavy metals in the studied area. Theisen sludge, a fine-grained residue from copper shale smelting, reaches the lake via deflation by wind or through riverine input; it is assumed to be the main source of pollution. To achieve the comparability of absolute contaminant concentrations, we calculated the influx of contaminants based on the sedimentation rate. Compared to the natural background concentrations, PAHs are significantly more enriched than heavy metals. They are therefore more sensitive and selective for source apportionment. We suggest two diagnostic ratios of PAHs to distinguish between Theisen sludge and its leachate: the ratio fluoranthene to pyrene ~2 and the ratio of PAH with logKOW5.7 converging to an even lower value than 2.3 (the characteristic of Theisen sludge) to identify the particulate input in lake environments. Copyright © 2016 Elsevier B.V. All rights reserved.

What’s normal? Oligosaccharide concentrations and profiles in milk produced by healthy women vary geographically12

Science.gov (United States)

Meehan, Courtney L; McGuire, Mark A; Foster, James; Sellen, Daniel W; Kamau-Mbuthia, Elizabeth W; Kamundia, Egidioh W; Mbugua, Samwel; Moore, Sophie E; Prentice, Andrew M; Kvist, Linda J; Otoo, Gloria E; Brooker, Sarah L; Price, William J; Shafii, Bahman; Placek, Caitlyn; Lackey, Kimberly A; Robertson, Bianca; Ruíz, Lorena; Pareja, Rossina G; Bode, Lars

2017-01-01

Background: Human milk is a complex fluid comprised of myriad substances, with one of the most abundant substances being a group of complex carbohydrates referred to as human milk oligosaccharides (HMOs). There has been some evidence that HMO profiles differ in populations, but few studies have rigorously explored this variability. Objectives: We tested the hypothesis that HMO profiles differ in diverse populations of healthy women. Next, we examined relations between HMO and maternal anthropometric and reproductive indexes and indirectly examined whether differences were likely related to genetic or environmental variations. Design: In this cross-sectional, observational study, milk was collected from a total of 410 healthy, breastfeeding women in 11 international cohorts and analyzed for HMOs by using high-performance liquid chromatography. Results: There was an effect of the cohort (P 4 times higher in milk collected in Sweden than in milk collected in rural Gambia (mean ± SEM: 473 ± 55 compared with 103 ± 16 nmol/mL, respectively; P < 0.05), and disialyllacto-N-tetraose (DSLNT) concentrations ranged from 216 ± 14 nmol/mL (in Sweden) to 870 ± 68 nmol/mL (in rural Gambia) (P < 0.05). Maternal age, time postpartum, weight, and body mass index were all correlated with several HMOs, and multiple differences in HMOs [e.g., lacto-N-neotetrose and DSLNT] were shown between ethnically similar (and likely genetically similar) populations who were living in different locations, which suggests that the environment may play a role in regulating the synthesis of HMOs. Conclusions: The results of this study support our hypothesis that normal HMO concentrations and profiles vary geographically, even in healthy women. Targeted genomic analyses are required to determine whether these differences are due at least in part to genetic variation. A careful examination of sociocultural, behavioral, and environmental factors is needed to determine their roles in this regard. This

Optimization of diclofenac sodium profile from halloysite nanotubules.

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Krejčová, Kateřina; Deasy, Patrick B; Rabišková, Miloslava

2013-04-01

Halloysite, aluminosilicate clay with the particle shape of multilayered hollow nanotubes, used in various non-medical applications, e.g. in ceramic industry, was discovered for pharmaceutical purposes in recent years. Several drugs of hydrophilic and lipophilic nature have been successfully encapsulated into halloysite tubules in order to modify their dissolution profile. The main goal of this experiment was to optimize the dissolution profile of diclofenac sodium - a drug with problematic solubility - from halloysite tubules using various polymers. Loading of the drug together with povidone or Eudragit® RS did not lead to drug burst effect reduction and its slower dissolution. In the case of povidone, drug improved wettability and solubilization rather than viscosity increasing expectations were observed. Eudragit® RS formed a solid dispersion with diclofenac sodium and thus the solvent/drug solution penetration through the polymer and not the drug solubility was the dissolution rate limiting factor. Reduction of the burst effect and further prolongation of drug release was achieved by coating the drug-loaded halloysite with chitosan. This formulation exhibited a diffusion-controlled prolonged release following Higuchi kinetic model.

Study on Chitosan-Polyvinyl Alcohol Inter polymeric ph-Responsive Hydrogels for Controlled Drug Delivery

International Nuclear Information System (INIS)

Abdel-Bary, E.M.; El-Sherbiny, I.M.; Abdelaal, M.Y.; Abdel-Razik, E.A.

2005-01-01

Two series of ph-responsive biodegradable interpenetrating polymeric (IPN) hydrogels composed of chitosan and poly(vinyl alcohol) (PVA) were prepared for controlled drug release investigations. The first series was chemically crosslinked with different concentrations of glutaraldehyde as a crosslinked and the second series was crosslinked by gamma-radiation. Degree of crosslinking has been controlled by the concentration of crosslinked as well as by gamma irradiation dose. The equilibrium swelling -reflecting the degree of crosslinks - were carried out for the gels at 37 degree C in buffer solutions of ph 2.1 and 7.4 (simulated gastric and intestinal fluids respectively). 5-fluorouracil (5- FU) was entrapped, as a model therapeutic agent, in the hydrogels and equilibrium-swelling studies were carried out for the drug-entrapped gels at 37 degree C. The in-vitro release profiles of the drug were established at 37 degree C in ph 2.1 and 7.4. FT-IR was employed to investigate the structural changes of the gels with different degrees of crosslinking

Effects of pathological conditions on ocular pharmacokinetics of antimicrobial drugs.

Science.gov (United States)

Ueda, Kayoko; Ohtori, Akira; Tojo, Kakuji

2010-10-01

A diffusion model of ocular pharmacokinetics was used to estimate the effects of pathological conditions on ocular pharmacokinetics. In vivo rabbit data after topical instillation of ciprofloxacin and ofloxacin were compared with the simulated concentrations in the aqueous and vitreous humors. The barrier capacity of the surrounding membranes such as the retina/choroid/sclera (RCS) membrane and the cornea was characterized by dimensionless Sherwood number derived by the pseudo-steady state approach (PSSA). We assumed the barrier capacity decreased by inflammation; when the barrier capacity of the RCS membrane and the cornea was assumed to be one-tenth for the RCS membrane and a half for the cornea respectively, the in vivo data agreed with the simulated profile without contradiction. The drug concentration gradient simulated in the vitreous body near the RCS membrane was more significant in the inflamed eyes than in the normal eyes, suggesting that the elimination of the drugs from the RCS membrane was enhanced by inflammation. The present diffusion model can better describe the ocular pharmacokinetics in both normal and diseased conditions.

Modeling Cl- concentration and δ37Cl profiles in pore water across a 250 m-thick indurated argillite at the Tournemire URL (France)

International Nuclear Information System (INIS)

Le Gal La Salle, Corinne; Rebeix, Romain; Lancelot, Joel; Matray, Jean-Michel; Bensenouci, Fethic; Michelot, Jean-Luc; Dauzeres, Alexandre; Wittebroodt, Charles; Frape, Shaun; ShouakarStash, Orphane

2013-01-01

Dissolved chloride in argillite pore water has been studied as a natural analogue for radionuclides potentially released from radioactive waste disposal. The Tournemire URL intersects impervious and compacted argillite. A previously obtained chloride concentration profile of intact rock is symmetric with a maximum concentration of 0.6±0.1 g/L, compared to 19 g/L for the original connate seawater. Dissolved chloride shows high δ 37 Cl values, ranging between +6 and +80/00 vs. SMOC. The modeled profile considers diffusive exchange between connate seawater and meteoric freshwater. Transport parameters were obtained by radial diffusion experiments. Numerical modeling was performed with the coupled reactive-transport code Hytec. Simulations suggest a diffusive-exchange time of 85±10 Ma for Cl, which correlates with a major erosional period. Simulated δ 37 Cl values between 1.002 and 1.003 agree with observed pore water δ 37 Cl. This study strongly suggests that the dissolved chloride profile in the argillites results from diffusive exchange and indicates that unfractured argillites can provide good confinement. (authors)

Radiometric dating of sediment core from waterwork reservoir Rozgrund and analysis of mercury concentration depth profile

International Nuclear Information System (INIS)

Vanek, M.

2005-01-01

Radioisotope dating of lake sediments combined with analysis of chemical properties of the sediment layers allow us to study the history of the human impact on nature. Undisturbed sediment layers in the core samples serve as chronicle database with information about lake ecosystem and surrounding environment in the time of deposition. A sediment core sample from the bottom of the water-work reservoir Rozgrund was collected and separated into 2 cm thick layers. Samples were analysed by HPGe spectrometry for anthropogenous Cs-137 activity. From identified peaks corresponding to nuclear tests and Chernobyl accident the sedimentation rate was calculated and the chronology of layers established. Sub-samples from each layer were prepared separately for the analysis of the Hg concentration by atomic absorption spectrometry. The results show very small variations in Hg concentrations and there is no significant trend present in the profile. (author)

Dynamic Analysis of the Temperature and the Concentration Profiles of an Industrial Rotary Kiln Used in Clinker Production

Directory of Open Access Journals (Sweden)

DIULIA C.Q. RODRIGUES

Full Text Available ABSTRACT Cement is one of the most used building materials in the world. The process of cement production involves numerous and complex reactions that occur under different temperatures. Thus, there is great interest in the optimization of cement manufacturing. Clinker production is one of the main steps of cement production and it occurs inside the kiln. In this paper, the dry process of clinker production is analysed in a rotary kiln that operates in counter flow. The main phenomena involved in clinker production is as follows: free residual water evaporation of raw material, decomposition of magnesium carbonate, decarbonation, formation of C3A and C4AF, formation of dicalcium silicate, and formation of tricalcium silicate. The main objective of this study was to propose a mathematical model that realistically describes the temperature profile and the concentration of clinker components in a real rotary kiln. In addition, the influence of different speeds of inlet gas and solids in the system was analysed. The mathematical model is composed of partial differential equations. The model was implemented in Mathcad (available at CCA/UFES and solved using industrial input data. The proposal model is satisfactory to describe the temperature and concentration profiles of a real rotary kiln.

Dynamic Analysis of the Temperature and the Concentration Profiles of an Industrial Rotary Kiln Used in Clinker Production.

Science.gov (United States)

Rodrigues, Diulia C Q; Soares, Atílio P; Costa, Esly F; Costa, Andréa O S

2017-01-01

Cement is one of the most used building materials in the world. The process of cement production involves numerous and complex reactions that occur under different temperatures. Thus, there is great interest in the optimization of cement manufacturing. Clinker production is one of the main steps of cement production and it occurs inside the kiln. In this paper, the dry process of clinker production is analysed in a rotary kiln that operates in counter flow. The main phenomena involved in clinker production is as follows: free residual water evaporation of raw material, decomposition of magnesium carbonate, decarbonation, formation of C3A and C4AF, formation of dicalcium silicate, and formation of tricalcium silicate. The main objective of this study was to propose a mathematical model that realistically describes the temperature profile and the concentration of clinker components in a real rotary kiln. In addition, the influence of different speeds of inlet gas and solids in the system was analysed. The mathematical model is composed of partial differential equations. The model was implemented in Mathcad (available at CCA/UFES) and solved using industrial input data. The proposal model is satisfactory to describe the temperature and concentration profiles of a real rotary kiln.

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.

Drugs and personality: comparison of drug users, nonusers, and other clinical groups on the 16PF.

Science.gov (United States)

Spotts, J V; Shontz, F C

1991-10-01

This article reviews published 16PF research on drug users. It also compares the 16PF scores of a new sample of nonusers with scores of matched groups of heavy, chronic users of cocaine, amphetamine, opiates, and barbiturates/sedative hypnotics, as well as combined groups of stimulant users, depressant users, and a combined group of users of all substances. No significant differences were found among drug user groups, but the profile of the nonuser group was distinctive. K-Means Cluster Analyses, as well as Cattell's Similarity and Pearson Product Moment Correlation Coefficients, were used to compare profiles of these new samples with the 19 groups described in an earlier meta-analysis of published 16PF studies. Data from the new samples did not cluster with data from other published research, although certain specific similarities appeared in more detailed correlational analyses. Methodological problems are discussed, and it is recommended that in future studies drug user groups be more carefully selected and defined, sample descriptions be more thorough and complete, complete profile information be routinely provided, and efforts be made to explore the utility of the Cattell CAQ in studies of drug users/misusers.

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.)

Dynamic SIMS utilizing SF{sub 5}{sup +} polyatomic primary ion beams for drug delivery applications

Energy Technology Data Exchange (ETDEWEB)

Mahoney, Christine M.; Roberson, Sonya; Gillen, Greg

2004-06-15

The behavior of various biodegradable polymer films (e.g. polylactic acid, polyglycolic acid and polycaprolactone) as well as some model drugs (theophylline and 4-acetamidophenol) under dynamic SF{sub 5}{sup +} primary ion bombardment is explored. A series of polylactic acid films containing varying concentrations of 4-acetamidophenol are also analyzed under similar conditions. The resultant molecular depth profiles obtained from these polymer films doped with drug show very little degradation in molecular signal as a function of SF{sub 5}{sup +} primary ion dose, and it was found that the molecular ion signals of both polymer and drug remained constant for ion doses up to {approx}5x10{sup 15} ions/cm{sup 2}. In addition, the polymer film/Si interface was well defined which may imply that sputter-induced topography formation was not a significant limitation. These results suggest that the structure of the biodegradable polymers studied here which all have the common main chain structural unit, R-CO-O-R, allows for a greater ability to depth profile due to ease of bond cleavage. Most importantly, however, these results indicate that in these particular polymer systems, the distribution of the drug as a function of depth can be monitored.

Evaluation of drug interaction microcomputer software: Dambro's Drug Interactions.

Science.gov (United States)

Poirier, T I; Giudici, R A

1990-01-01

Dambro's Drug Interactions was evaluated using general and specific criteria. The installation process, ease of learning and use were rated excellent. The user documentation and quality of the technical support were good. The scope of coverage, clinical documentation, frequency of updates, and overall clinical performance were fair. The primary advantages of the program are the quick searching and detection of drug interactions, and the attempt to provide useful interaction data, i.e., significance and reference. The disadvantages are the lack of current drug interaction information, outdated references, lack of evaluative drug interaction information, and the inability to save or print patient profiles. The program is not a good value for the pharmacist but has limited use as a quick screening tool.

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...

Determining clinical benefits of drug-eluting coronary stents according to the population risk profile: a meta-regression from 31 randomized trials.

Science.gov (United States)

Moreno, Raul; Martin-Reyes, Roberto; Jimenez-Valero, Santiago; Sanchez-Recalde, Angel; Galeote, Guillermo; Calvo, Luis; Plaza, Ignacio; Lopez-Sendon, Jose-Luis

2011-04-01

The use of drug-eluting stents (DES) in unfavourable patients has been associated with higher rates of clinical complications and stent thrombosis, and because of that concerns about the use of DES in high-risk settings have been raised. This study sought to demonstrate that the clinical benefit of DES increases as the risk profile of the patients increases. A meta-regression analysis from 31 randomized trials that compared DES and bare-metal stents, including overall 12,035 patients, was performed. The relationship between the clinical benefit of using DES (number of patients to treat [NNT] to prevent one episode of target lesion revascularization [TLR]), and the risk profile of the population (rate of TLR in patients allocated to bare-metal stents) in each trial was evaluated. The clinical benefit of DES increased as the risk profile of each study population increased: NNT for TLR=31.1-1.2 (TLR for bare-metal stents); prisk profile of each study population, since the effect of DES in mortality, myocardial infarction, and stent thrombosis, was not adversely affected by the risk profile of each study population (95% confidence interval for β value 0.09 to 0.11, -0.12 to 0.19, and -0.03 to-0.15 for mortality, myocardial infarction, and stent thrombosis, respectively). The clinical benefit of DES increases as the risk profile of the patients increases, without affecting safety. Copyright © 2009 Elsevier Ireland Ltd. All rights reserved.

Evaluation of optimized bronchoalveolar lavage sampling designs for characterization of pulmonary drug distribution.

Science.gov (United States)

Clewe, Oskar; Karlsson, Mats O; Simonsson, Ulrika S H

2015-12-01

Bronchoalveolar lavage (BAL) is a pulmonary sampling technique for characterization of drug concentrations in epithelial lining fluid and alveolar cells. Two hypothetical drugs with different pulmonary distribution rates (fast and slow) were considered. An optimized BAL sampling design was generated assuming no previous information regarding the pulmonary distribution (rate and extent) and with a maximum of two samples per subject. Simulations were performed to evaluate the impact of the number of samples per subject (1 or 2) and the sample size on the relative bias and relative root mean square error of the parameter estimates (rate and extent of pulmonary distribution). The optimized BAL sampling design depends on a characterized plasma concentration time profile, a population plasma pharmacokinetic model, the limit of quantification (LOQ) of the BAL method and involves only two BAL sample time points, one early and one late. The early sample should be taken as early as possible, where concentrations in the BAL fluid ≥ LOQ. The second sample should be taken at a time point in the declining part of the plasma curve, where the plasma concentration is equivalent to the plasma concentration in the early sample. Using a previously described general pulmonary distribution model linked to a plasma population pharmacokinetic model, simulated data using the final BAL sampling design enabled characterization of both the rate and extent of pulmonary distribution. The optimized BAL sampling design enables characterization of both the rate and extent of the pulmonary distribution for both fast and slowly equilibrating drugs.

Artificial intelligence in drug combination therapy.

Science.gov (United States)

Tsigelny, Igor F

2018-02-09

Currently, the development of medicines for complex diseases requires the development of combination drug therapies. It is necessary because in many cases, one drug cannot target all necessary points of intervention. For example, in cancer therapy, a physician often meets a patient having a genomic profile including more than five molecular aberrations. Drug combination therapy has been an area of interest for a while, for example the classical work of Loewe devoted to the synergism of drugs was published in 1928-and it is still used in calculations for optimal drug combinations. More recently, over the past several years, there has been an explosion in the available information related to the properties of drugs and the biomedical parameters of patients. For the drugs, hundreds of 2D and 3D molecular descriptors for medicines are now available, while for patients, large data sets related to genetic/proteomic and metabolomics profiles of the patients are now available, as well as the more traditional data relating to the histology, history of treatments, pretreatment state of the organism, etc. Moreover, during disease progression, the genetic profile can change. Thus, the ability to optimize drug combinations for each patient is rapidly moving beyond the comprehension and capabilities of an individual physician. This is the reason, that biomedical informatics methods have been developed and one of the more promising directions in this field is the application of artificial intelligence (AI). In this review, we discuss several AI methods that have been successfully implemented in several instances of combination drug therapy from HIV, hypertension, infectious diseases to cancer. The data clearly show that the combination of rule-based expert systems with machine learning algorithms may be promising direction in this field. © The Author(s) 2018. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Expression Profile of Genes Related to Drug Metabolism in Human Brain Tumors.

Directory of Open Access Journals (Sweden)

Pantelis Stavrinou

Full Text Available Endogenous and exogenous compounds as well as carcinogens are metabolized and detoxified by phase I and II enzymes, the activity of which could be crucial to the inactivation and hence susceptibility to carcinogenic factors. The expression of these enzymes in human brain tumor tissue has not been investigated sufficiently. We studied the association between tumor pathology and the expression profile of seven phase I and II drug metabolizing genes (CYP1A1, CYP1B1, ALDH3A1, AOX1, GSTP1, GSTT1 and GSTM3 and some of their proteins.Using qRT-PCR and western blotting analysis the gene and protein expression in a cohort of 77 tumors were investigated. The major tumor subtypes were meningioma, astrocytoma and brain metastases, -the later all adenocarcinomas from a lung primary.Meningeal tumors showed higher expression levels for AOX1, CYP1B1, GSTM3 and GSTP1. For AOX1, GSTM and GSTP1 this could be verified on a protein level as well. A negative correlation between the WHO degree of malignancy and the strength of expression was identified on both transcriptional and translational level for AOX1, GSTM3 and GSTP1, although the results could have been biased by the prevalence of meningiomas and glioblastomas in the inevitably bipolar distribution of the WHO grades. A correlation between the gene expression and the protein product was observed for AOX1, GSTP1 and GSTM3 in astrocytomas.The various CNS tumors show different patterns of drug metabolizing gene expression. Our results suggest that the most important factor governing the expression of these enzymes is the histological subtype and to a far lesser extent the degree of malignancy itself.

Herbs with anti-lipid effects and their interactions with statins as a chemical anti- hyperlipidemia group drugs: A systematic review

Directory of Open Access Journals (Sweden)

Hojjat Rouhi-Boroujeni

2015-08-01

Full Text Available BACKGROUND: The present systematic review aimed to express the clinical anti-lipid effects of different types of herbs, as well as described studied interactions between herbal remedies and prescribed drugs for hyperlipidemic patients which were based on in vitro experiments, animal studies, and empirical clinical experiences. METHODS: For this systematic review, we explored 2183 published papers about herbal drugs interactions from November 1967 to August 2014, fulfilling eligibility criteria by searching in some databases such as Web of Science, Medline, Scopus, Embase, Cinahl, and the Cochrane database. The main keywords used for searching included: herbal medicine, herbs, statin, lipid, and herb-drug interaction. RESULTS: Among published articles about herb-drug interactions, 185 papers met the initial search criteria and among them, 92 papers were potentially retrievable including a description of 17 herbs and medicinal plants. In first step and by reviewing all published manuscripts on beneficial effects of herbs on serum lipids level, 17 herbs were described to be effective on lipid profile as lowering serum triglyceride, total cholesterol, low-density lipoprotein cholesterol as well as increasing serum high-density lipoprotein level. Some herbs such as celery could even affect the hepatic triglyceride concentrations. The herbal reaction toward different types of statins is varied so that grapefruit or pomegranate was interacted with only some types of statins, but not with all statin types. In this context, administration of herbal materials can lead to decreased absorption of statins or decreased the plasma concentration of these drugs. CONCLUSION: Various types of herbs can potentially reduce serum lipid profile with the different pathways; however, the herb-drug interactions may decrease pharmacological therapeutic effects of anti-hyperlipidemic drugs that should be considered when approved herbs are prescribed. 

Rheological, mechanical and membrane penetration properties of novel dual drug systems for percutaneous delivery.

Science.gov (United States)

Woolfson, A D; Malcolm, R K; Campbell, K; Jones, D S; Russell, J A

2000-07-03

In this study it has been demonstrated that mixtures of two solid drugs, ibuprofen and methyl nicotinate, with different but complementary pharmacological activities and which exist as a single liquid phase over a wide composition range at skin temperature, can be formulated as o/w emulsions without the use of an additional hydrophobic carrier. These novel dual drug systems provided significantly enhanced in vitro penetration rates through a model lipophilic barrier membrane compared to conventional individual formulations of each active. Thus, for ibuprofen, drug penetration flux enhancements of three- and 10-fold were observed when compared to an aqueous ibuprofen suspension and a commercial alcohol-based ibuprofen formulation, respectively. Methyl nicotinate penetration rates were shown to be similar for aqueous gels and emulsified systems. Mechanisms explaining these observations are proposed. Novel dual drug formulations of ibuprofen and methyl nicotinate, formulated within the liquid range at skin temperature, were investigated by oscillatory rheology and texture profile analysis, demonstrating the effects of drug and viscosity enhancer concentrations, and disperse phase type upon the rheological, mechanical and drug penetration properties of these systems.

Intranasal administration of carbamazepine-loaded carboxymethyl chitosan nanoparticles for drug delivery to the brain

Directory of Open Access Journals (Sweden)

Shanshan Liu

2018-01-01

Full Text Available Epilepsy is considered as a common and diverse set of chronic neurological disorders and its symptoms can be controlled by antiepileptic drugs (AEDs. The presence of p-glycoprotein and multi-drug resistance transporters in the blood-brain barrier could prevent the entry of AEDs into the brain, causing drug resistant epilepsy. To overcome this problem, we propose using carboxymethyl chitosan nanoparticles as a carrier to deliver carbamazepine (CBZ intra-nasally with the purpose to bypass the blood-brain barrier thus to enhance the brain drug concentration and the treatment efficacy. Results so far indicate that the developed CBZ-NPs have small particle size (218.76 ± 2.41 nm with high drug loading (around 35% and high entrapment efficiency (around 80%. The in vitro release profiles of CBZ from the NPs are in accordance with the Korsmeyer-peppas model. The in vivo results show that both encapsulation of CBZ in nanoparticles and the nasal route determined the enhancement of the drug bioavailability and brain targeting characteristics.

Determination of the concentration profile and homogeneity of antioxidants and degradation products in a cross-linked polyethylene type A (PEXa) pipe

DEFF Research Database (Denmark)

Denberg, Martin; Mosbæk, Hans; Hassager, Ole

2009-01-01

, the concentration profile was measured at four different places on a 100 m PEXa pipe. A two-way ANOVA analysis showed that the composition of Irganox (R) 1076 was homogenous in the radial direction and heterogeneous in the longitudinal direction. Two degradation products of antioxidants were detected, 2,6-di...

Effects of forage type, forage to concentrate ratio, and crushed linseed supplementation on milk fatty acid profile in lactating dairy cows

NARCIS (Netherlands)

Sterk, A.R.; Johansson, B.E.O.; Taweel, H.Z.H.; Murphy, M.; Vuuren, van A.M.; Hendriks, W.H.; Dijkstra, J.

2011-01-01

The effects of an increasing proportion of crushed linseed (CL) in combination with varying forage type (grass or corn silage) and forage to concentrate ratio (F:C), and their interactions on milk fatty acid (FA) profile of high-producing dairy cows was studied using a 3-factor Box-Behnken design.

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.

An Excel®-based visualization tool of 2-D soil gas concentration profiles in petroleum vapor intrusion.

Science.gov (United States)

Verginelli, Iason; Yao, Yijun; Suuberg, Eric M

2016-01-01

In this study we present a petroleum vapor intrusion tool implemented in Microsoft ® Excel ® using Visual Basic for Applications (VBA) and integrated within a graphical interface. The latter helps users easily visualize two-dimensional soil gas concentration profiles and indoor concentrations as a function of site-specific conditions such as source strength and depth, biodegradation reaction rate constant, soil characteristics and building features. This tool is based on a two-dimensional explicit analytical model that combines steady-state diffusion-dominated vapor transport in a homogeneous soil with a piecewise first-order aerobic biodegradation model, in which rate is limited by oxygen availability. As recommended in the recently released United States Environmental Protection Agency's final Petroleum Vapor Intrusion guidance, a sensitivity analysis and a simplified Monte Carlo uncertainty analysis are also included in the spreadsheet.

Multi-analytical approach for profiling some essential medical drugs

International Nuclear Information System (INIS)

Abubakar, M.

2015-07-01

Counterfeit and substandard pharmaceutical drugs are chiefly rampant in developing countries due to inadequate analytical facilities and lack of regulatory oversight. The production of counterfeit or substandard drugs is broadly problematic. Underestimating it therefore leads to morbidity, mortality, drug resistance, introduction of toxic substances into the body and loss of confidence in health care systems. Medical drugs that are often counterfeited range from antimalarial drugs to antiretroviral drugs with antibiotics being counterfeited the most. This research work, therefore, aims at contributing towards the establishment of measures/processes for distinguishing between fake and genuine amoxicillin drugs. This was achieved by the identification and quantification of the Active Pharmaceutical Ingredient (API) and the excipients in the drug formulation. The major analytical techniques employed for this research work were Instrumental Neutron Activation Analysis (INAA), X-ray Powder Diffraction (XRD), High Performance Liquid Chromatography (HPLC) and in vitro Dissolution Test. The amoxicillin samples analyzed were the foreign generic amoxicillin purchased from Ernest Chemists pharmacy at East Legon, Accra, the National Health Insurance Scheme (NHIS) amoxicillin purchased at Fair Mile pharmacy at West Legon, Accra and the Suspected Fake amoxicillin purchased at Okaishi market. For the establishment of fingerprint for identification of substandard amoxicillin, INAA was used to qualitatively determine the short lived radionuclides (excipients) which then facilitated the correct identification of the API and the excipient phases in each of the amoxicillin groups. The phases identified were Amoxicillin Trihydrate as the excipient, Magnesium Stearate (hydrated) and Magnesium Stearate (anhydrous) as the excipients. For Quality control purposes, High Performance Liquid Chromatography approach and also, the in vitro Dissolution test were conducted on each of the groups of

10Be concentrations and the long-term fate of particle-reactive nuclides in five soil profiles from California

International Nuclear Information System (INIS)

Monaghan, M.C.; Krishnaswami, S.; Thomas, J.H.

1983-01-01

Concentration-depth profiles of cosmic-ray-produced 10 Be(tsub(1/2)=1.5 m.y.) have been measured by accelerator-mass spectrometry in five soil profiles. These measurements were made in an effort (1) to understand the retentivity of soil surfaces for particle-reactive tracers depositing from the atmosphere on time scales of 10 4 -10 6 years, and (2) to explore the application of 10 Be as a chronometer of geomorphic surface age. The profiles sampled are from two wave-cut terraces located near Mendocino, California, a table mountain top and an alluvial fan, both located near Friant, California. The ages of the Mendocino terraces are inferred to be (1-5) x 10 5 years based on amino-stratigraphic correlations and models of terrace evolution; those of the table mountain top and alluvial fan are 9.5 x 10 6 years and 6.0 x 10 5 years, respectively, based on K-Ar analyses. All the surfaces sampled are nearly flat and exhibit few erosional features. In addition to 10 Be we measured 210 Pb, sup(239,) 240 Pu and 7 Be to ascertain the retentivity of the soils for particle-reactive nuclides and to assess the present-day delivery rate of nuclides from the atmosphere. The 7 Be inventory is 4.0 dpm/cm 2 similar to those observed at nearby locations. The inventories of 210 Pb and Pu isotopes conform to those predicted from model calculations and suggest that the soil surfaces sampled retain the entire burden of particle-reactive nuclides delivered to them over short time scales, approx.= 100 years. The 10 Be concentrations in the sample range between (0.2 and 7) x 10 8 atoms/g soil and show strong correlations with leachable Fe and/or Al. (orig./WL)

Nano-enabled drug delivery: a research profile.

Science.gov (United States)

Zhou, Xiao; Porter, Alan L; Robinson, Douglas K R; Shim, Min Suk; Guo, Ying

2014-07-01

Nano-enabled drug delivery (NEDD) systems are rapidly emerging as a key area for nanotechnology application. Understanding the status and developmental prospects of this area around the world is important to determine research priorities, and to evaluate and direct progress. Global research publication and patent databases provide a reservoir of information that can be tapped to provide intelligence for such needs. Here, we present a process to allow for extraction of NEDD-related information from these databases by involving topical experts. This process incorporates in-depth analysis of NEDD literature review papers to identify key subsystems and major topics. We then use these to structure global analysis of NEDD research topical trends and collaborative patterns, inform future innovation directions. This paper describes the process of how to derive nano-enabled drug delivery-related information from global research and patent databases in an effort to perform comprehensive global analysis of research trends and directions, along with collaborative patterns. Copyright © 2014 Elsevier Inc. All rights reserved.

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

Direct observation of solid-phase adsorbate concentration profile in powdered activated carbon particle to elucidate mechanism of high adsorption capacity on super-powdered activated carbon.

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Ando, Naoya; Matsui, Yoshihiko; Matsushita, Taku; Ohno, Koichi

2011-01-01

Decreasing the particle size of powdered activated carbon (PAC) by pulverization increases its adsorption capacities for natural organic matter (NOM) and polystyrene sulfonate (PSS, which is used as a model adsorbate). A shell adsorption mechanism in which NOM and PSS molecules do not completely penetrate the adsorbent particle and instead preferentially adsorb near the outer surface of the particle has been proposed as an explanation for this adsorption capacity increase. In this report, we present direct evidence to support the shell adsorption mechanism. PAC particles containing adsorbed PSS were sectioned with a focused ion beam, and the solid-phase PSS concentration profiles of the particle cross-sections were directly observed by means of field emission-scanning electron microscopy/energy-dispersive X-ray spectrometry (FE-SEM/EDXS). X-ray emission from sulfur, an index of PSS concentration, was higher in the shell region than in the inner region of the particles. The X-ray emission profile observed by EDXS did not agree completely with the solid-phase PSS concentration profile predicted by shell adsorption model analysis of the PSS isotherm data, but the observed and predicted profiles were not inconsistent when the analytical errors were considered. These EDXS results provide the first direct evidence that PSS is adsorbed mainly in the vicinity of the external surface of the PAC particles, and thus the results support the proposition that the increase in NOM and PSS adsorption capacity with decreasing particle size is due to the increase in external surface area on which the molecules can be adsorbed. Copyright © 2010 Elsevier Ltd. All rights reserved.

[Research Progress on Forensic Toxicology of Z-drugs].

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Zhang, Yong-zhi; He, Hong-yuan; She, Cai-meng; Lian, Jie

2015-08-01

The Z-drugs (zolpidem, zopiclone, and zaleplon), as the innovative hypnotics, have an improvement over the traditional benzodiazepines in the management of insomnia. Z-drugs have significant hypnotic effects by reducing sleep latency and improving sleep quality, though duration of sleep may not be significantly increased. As benzodiazepines, Z-drugs exert their effects through increasing the transmission of γ-aminobutyric acid. Z-drugs overdose are less likely to be fatal, more likely would result in poisoning. Z-drugs can be detected in blood, urine, saliva, and other postmortem specimens through liquid chromatography-mass spectrometry techniques. Zolpidem and zaleplon exhibit significant postmortem redistribution. Z-drugs have improved pharmacokinetic profiles, but incidence of neuropsychiatric sequelae, poisoning, and death may prove to be similar to the other hypnotics. This review focuses on the pharmacology and toxicology of Z-drugs with respect to their adverse effect profile and toxicity and toxicology data in the field of forensic medicine.

Surface bioengineering of diatomite based nanovectors for efficient intracellular uptake and drug delivery.

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Terracciano, Monica; Shahbazi, Mohammad-Ali; Correia, Alexandra; Rea, Ilaria; Lamberti, Annalisa; De Stefano, Luca; Santos, Hélder A

2015-12-21

Diatomite is a natural porous silica material of sedimentary origin. Due to its peculiar properties, it can be considered as a valid surrogate of synthetic porous silica for nano-based drug delivery. In this work, we exploit the potential of diatomite nanoparticles (DNPs) for drug delivery with the aim of developing a successful dual-biofunctionalization method by polyethylene glycol (PEG) coverage and cell-penetrating peptide (CPP) bioconjugation, to improve the physicochemical and biological properties of the particles, to enhance the intracellular uptake in cancer cells, and to increase the biocompatibility of 3-aminopropyltriethoxysilane (APT) modified-DNPs. DNPs-APT-PEG-CPP showed hemocompatibility for up to 200 μg mL(-1) after 48 h of incubation with erythrocytes, with a hemolysis value of only 1.3%. The cytotoxicity of the modified-DNPs with a concentration up to 200 μg mL(-1) and incubation with MCF-7 and MDA-MB-231 breast cancer cells for 24 h, demonstrated that PEGylation and CPP-bioconjugation can strongly reduce the cytotoxicity of DNPs-APT. The cellular uptake of the modified-DNPs was also evaluated using the above mentioned cancer cell lines, showing that the CPP-bioconjugation can considerably increase the DNP cellular uptake. Moreover, the dual surface modification of DNPs improved both the loading of a poorly water-soluble anticancer drug, sorafenib, with a loading degree up to 22 wt%, and also enhanced the drug release profiles in aqueous solutions. Overall, this work demonstrates that the biofunctionalization of DNPs is a promising platform for drug delivery applications in cancer therapy as a result of its enhanced stability, biocompatibility, cellular uptake, and drug release profiles.

Adverse Drug Event Monitoring at the Food and Drug Administration: Your Report Can Make a Difference

OpenAIRE

Ahmad, Syed Rizwanuddin

2003-01-01

The Food and Drug Administration (FDA) is responsible not only for approving drugs but also for monitoring their safety after they reach the market. The complete adverse event profile of a drug is not known at the time of approval because of the small sample size, short duration, and limited generalizability of pre-approval clinical trials. This report describes the FDA's postmarketing surveillance system, to which many clinicians submit reports of adverse drug events encountered while treati...

DEVELOPMENT AND REGISTRATION OF CHIRAL DRUGS

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WITTE, DT; ENSING, K; FRANKE, JP; DEZEEUW, RA

1993-01-01

In this review we describe the impact of chirality on drug development and registration in the United States, Japan and the European Community. Enantiomers may have differences in their pharmacological profiles, and, therefore, chiral drugs ask for special analytical and pharmacological attention

Rural Indiana Profile: Alcohol, Tobacco & Other Drugs.

Science.gov (United States)

Drug Strategies, Washington, DC.

This report examines alcohol, tobacco, and other drug use in rural parts of Indiana, as well as public and private initiatives to reduce these problems. The report is based on epidemiological, health, and criminal justice indicators; focus groups; and in-depth interviews with local officials, researchers, service providers, and civic leaders.…

Characterization and drug resistance patterns of Ewing's sarcoma family tumor cell lines.

Directory of Open Access Journals (Sweden)

William A May

Full Text Available Despite intensive treatment with chemotherapy, radiotherapy and surgery, over 70% of patients with metastatic Ewing's Sarcoma Family of Tumors (EFT will die of their disease. We hypothesize that properly characterized laboratory models reflecting the drug resistance of clinical tumors will facilitate the application of new therapeutic agents to EFT. To determine resistance patterns, we studied newly established EFT cell lines derived from different points in therapy: two established at diagnosis (CHLA-9, CHLA-32, two after chemotherapy and progressive disease (CHLA-10, CHLA-25, and two at relapse after myeloablative therapy and autologous bone marrow transplantation (post-ABMT (CHLA-258, COG-E-352. The new lines were compared to widely studied EFT lines TC-71, TC-32, SK-N-MC, and A-673. These lines were extensively characterized with regard to identity (short tandem repeat (STR analysis, p53, p16/14 status, and EWS/ETS breakpoint and target gene expression profile. The DIMSCAN cytotoxicity assay was used to assess in vitro drug sensitivity to standard chemotherapy agents. No association was found between drug resistance and the expression of EWS/ETS regulated genes in the EFT cell lines. No consistent association was observed between drug sensitivity and p53 functionality or between drug sensitivity and p16/14 functionality across the cell lines. Exposure to chemotherapy prior to cell line initiation correlated with drug resistance of EFT cell lines in 5/8 tested agents at clinically achievable concentrations (CAC or the lower tested concentration (LTC: (cyclophosphamide (as 4-HC and doxorubicin at CAC, etoposide, irinotecan (as SN-38 and melphalan at LTC; P<0.1 for one agent, and P<0.05 for four agents. This panel of well-characterized drug-sensitive and drug-resistant cell lines will facilitate in vitro preclinical testing of new agents for EFT.

Soluble polymer conjugates for drug delivery.

Science.gov (United States)

Minko, Tamara

2005-01-01

The use of water-soluble polymeric conjugates as drug carriers offers several possible advantages. These advantages include: (1) improved drug pharmacokinetics; (2) decreased toxicity to healthy organs; (3) possible facilitation of accumulation and preferential uptake by targeted cells; (4) programmed profile of drug release. In this review, we will consider the main types of useful polymeric conjugates and their role and effectiveness as carriers in drug delivery systems.: © 2005 Elsevier Ltd . All rights reserved.

Warfarin: pharmacological profile and drug interactions with antidepressants

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Juliana Souto Teles

2012-03-01

Full Text Available Oral anticoagulants are among the drugs with the greatest numberof drug interactions. The concomitant use of several medications isa common practice in patients with cardiovascular problems, whooften also present with depression; therefore, the probability of aninteraction occurring between warfarin and the antidepressants ishigh, and may result in increased or decreased anticoagulant activity.Since the possible interactions between these two classes of drugshave been poorly explored in literature, with a risk to the patients who use them, we reviewed the pharmacology of warfarin and its possible interactions with antidepressants. Of the antidepressants analyzed, those that showed relevant effects on the interaction with warfarin were, in decreasing order: paroxetine, venlafaxine, fluoxetine, and duloxetine.

Bacterial microbiota profiling in gastritis without Helicobacter pylori infection or non-steroidal anti-inflammatory drug use.

Directory of Open Access Journals (Sweden)

Xiao-Xing Li

Full Text Available Recent 16S ribosomal RNA gene (rRNA molecular profiling of the stomach mucosa revealed a surprising complexity of microbiota. Helicobacter pylori infection and non-steroidal anti-inflammatory drug (NSAID use are two main contributors to gastritis and peptic ulcer. However, little is known about the association between other members of the stomach microbiota and gastric diseases. In this study, cloning and sequencing of the 16S rRNA was used to profile the stomach microbiota from normal and gastritis patients. One hundred and thirty three phylotypes from eight bacterial phyla were identified. The stomach microbiota was found to be closely adhered to the mucosa. Eleven Streptococcus phylotypes were successfully cultivated from the biopsies. One to two genera represented a majority of clones within any of the identified phyla. We further developed two real-time quantitative PCR assays to quantify the relative abundance of the Firmicutes phylum and the Streptococcus genus. Significantly higher abundance of the Firmicutes phylum and the Streptococcus genus within the Firmicutes phylum was observed in patients with antral gastritis, compared with normal controls. This study suggests that the genus taxon level can largely represent much higher taxa such as the phylum. The clinical relevance and the mechanism underlying the altered microbiota composition in gastritis require further functional studies.

HOW ADVERSE DRUG-REACTIONS CAN PLAY A ROLE IN INNOVATIVE DRUG RESEARCH - SIMILARITIES IN ADVERSE DRUG REACTION PROFILES OF CAPTOPRIL AND PENICILLAMINE

NARCIS (Netherlands)

RIKKEN, F; VOS, R

1995-01-01

We describe how adverse drug reactions (ADRs) can play an important role in pharmaceutical research and drug development. Not only do ADRs represent the risks and drawbacks associated with drugs but they can also be related to other knowledge available in pharmaceutical and medical research. We

Trust in the pharmaceutical sector : Analysis of drug safety controversies by means of drug life cycles

NARCIS (Netherlands)

Hernández, J.F.

2015-01-01

Before obtaining a marketing approval, the efficacy and safety profile of drugs is studied in specific populations and under well-controlled circumstances. After marketing approval, the drug is made available and used in ‘real world conditions’, which are known to deviate from the trial setting.

One year of Seaglider dissolved oxygen concentration profiles at the PAP site

Science.gov (United States)

Binetti, Umberto; Kaiser, Jan; Heywood, Karen; Damerell, Gillian; Rumyantseva, Anna

2015-04-01

Oxygen is one of the most important variables measured in oceanography, influenced both by physical and biological factors. During the OSMOSIS project, 7 Seagliders were used in 3 subsequent missions to measure a multidisciplinary suite of parameters at high frequency in the top 1000 m of the water column for one year, from September 2012 to September 2013. The gliders were deployed at the PAP time series station (nominally at 49° N 16.5° W) and surveyed the area following a butterfly-shaped path. Oxygen concentration was measured by Aanderaa optodes and calibrated using ship CTD O2 profiles during 5 deployment and recovery cruises, which were in turn calibrated by Winkler titration of discrete samples. The oxygen-rich mixed layer deepens in fall and winter and gets richer in oxygen when the temperature decreases. The spring bloom did not happen as expected, but instead the presence of a series of small blooms was measured throughout spring and early summer. During the summer the mixed layer become very shallow and oxygen concentrations decreased. A Deep Oxygen Maximum (DOM) developed along with a deep chlorophyll maximum during the summer and was located just below the mixed layer . At this depth, phytoplankton had favourable light and nutrient conditions to grow and produce oxygen, which was not subject to immediate outgassing. The oxygen concentration in the DOM was not constant, but decreased, then increased again until the end of the mission. Intrusions of oxygen rich water are also visible throughout the mission. These are probably due to mesoscale events through the horizontal transport of oxygen and/or nutrients that can enhance productivity, particularly at the edge of the fronts. We calculate net community production (NCP) by analysing the variation in oxygen with time. Two methods have been proposed. The classical oxygen budget method assumes that changes in oxygen are due to the sum of air-sea flux, isopycnal advection, diapycnal mixing and NCP. ERA

Controlling the Glycosylation Profile in mAbs Using Time-Dependent Media Supplementation

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Devesh Radhakrishnan

2017-12-01

Full Text Available In order to meet desired drug product quality targets, the glycosylation profile of biotherapeutics such as monoclonal antibodies (mAbs must be maintained consistently during manufacturing. Achieving consistent glycan distribution profiles requires identifying factors that influence glycosylation, and manipulating them appropriately via well-designed control strategies. Now, the cell culture media supplement, MnCl2, is known to alter the glycosylation profile in mAbs generally, but its effect, particularly when introduced at different stages during cell growth, has yet to be investigated and quantified. In this study, we evaluate the effect of time-dependent addition of MnCl2 on the glycan profile quantitatively, using factorial design experiments. Our results show that MnCl2 addition during the lag and exponential phases affects the glycan profile significantly more than stationary phase supplementation does. Also, using a novel computational technique, we identify various combinations of glycan species that are affected by this dynamic media supplementation scheme, and quantify the effects mathematically. Our experiments demonstrate the importance of taking into consideration the time of addition of these trace supplements, not just their concentrations, and our computational analysis provides insight into what supplements to add, when, and how much, in order to induce desired changes.

Profiling structured product labeling with NDF-RT and RxNorm

Science.gov (United States)

2012-01-01

Background Structured Product Labeling (SPL) is a document markup standard approved by Health Level Seven (HL7) and adopted by United States Food and Drug Administration (FDA) as a mechanism for exchanging drug product information. The SPL drug labels contain rich information about FDA approved clinical drugs. However, the lack of linkage to standard drug ontologies hinders their meaningful use. NDF-RT (National Drug File Reference Terminology) and NLM RxNorm as standard drug ontology were used to standardize and profile the product labels. Methods In this paper, we present a framework that intends to map SPL drug labels with existing drug ontologies: NDF-RT and RxNorm. We also applied existing categorical annotations from the drug ontologies to classify SPL drug labels into corresponding classes. We established the classification and relevant linkage for SPL drug labels using the following three approaches. First, we retrieved NDF-RT categorical information from the External Pharmacologic Class (EPC) indexing SPLs. Second, we used the RxNorm and NDF-RT mappings to classify and link SPLs with NDF-RT categories. Third, we profiled SPLs using RxNorm term type information. In the implementation process, we employed a Semantic Web technology framework, in which we stored the data sets from NDF-RT and SPLs into a RDF triple store, and executed SPARQL queries to retrieve data from customized SPARQL endpoints. Meanwhile, we imported RxNorm data into MySQL relational database. Results In total, 96.0% SPL drug labels were mapped with NDF-RT categories whereas 97.0% SPL drug labels are linked to RxNorm codes. We found that the majority of SPL drug labels are mapped to chemical ingredient concepts in both drug ontologies whereas a relatively small portion of SPL drug labels are mapped to clinical drug concepts. Conclusions The profiling outcomes produced by this study would provide useful insights on meaningful use of FDA SPL drug labels in clinical applications through

Profiling structured product labeling with NDF-RT and RxNorm

Directory of Open Access Journals (Sweden)

Zhu Qian

2012-12-01

Full Text Available Abstract Background Structured Product Labeling (SPL is a document markup standard approved by Health Level Seven (HL7 and adopted by United States Food and Drug Administration (FDA as a mechanism for exchanging drug product information. The SPL drug labels contain rich information about FDA approved clinical drugs. However, the lack of linkage to standard drug ontologies hinders their meaningful use. NDF-RT (National Drug File Reference Terminology and NLM RxNorm as standard drug ontology were used to standardize and profile the product labels. Methods In this paper, we present a framework that intends to map SPL drug labels with existing drug ontologies: NDF-RT and RxNorm. We also applied existing categorical annotations from the drug ontologies to classify SPL drug labels into corresponding classes. We established the classification and relevant linkage for SPL drug labels using the following three approaches. First, we retrieved NDF-RT categorical information from the External Pharmacologic Class (EPC indexing SPLs. Second, we used the RxNorm and NDF-RT mappings to classify and link SPLs with NDF-RT categories. Third, we profiled SPLs using RxNorm term type information. In the implementation process, we employed a Semantic Web technology framework, in which we stored the data sets from NDF-RT and SPLs into a RDF triple store, and executed SPARQL queries to retrieve data from customized SPARQL endpoints. Meanwhile, we imported RxNorm data into MySQL relational database. Results In total, 96.0% SPL drug labels were mapped with NDF-RT categories whereas 97.0% SPL drug labels are linked to RxNorm codes. We found that the majority of SPL drug labels are mapped to chemical ingredient concepts in both drug ontologies whereas a relatively small portion of SPL drug labels are mapped to clinical drug concepts. Conclusions The profiling outcomes produced by this study would provide useful insights on meaningful use of FDA SPL drug labels in clinical

Profiling structured product labeling with NDF-RT and RxNorm.

Science.gov (United States)

Zhu, Qian; Jiang, Guoqian; Chute, Christopher G

2012-12-20

Structured Product Labeling (SPL) is a document markup standard approved by Health Level Seven (HL7) and adopted by United States Food and Drug Administration (FDA) as a mechanism for exchanging drug product information. The SPL drug labels contain rich information about FDA approved clinical drugs. However, the lack of linkage to standard drug ontologies hinders their meaningful use. NDF-RT (National Drug File Reference Terminology) and NLM RxNorm as standard drug ontology were used to standardize and profile the product labels. In this paper, we present a framework that intends to map SPL drug labels with existing drug ontologies: NDF-RT and RxNorm. We also applied existing categorical annotations from the drug ontologies to classify SPL drug labels into corresponding classes. We established the classification and relevant linkage for SPL drug labels using the following three approaches. First, we retrieved NDF-RT categorical information from the External Pharmacologic Class (EPC) indexing SPLs. Second, we used the RxNorm and NDF-RT mappings to classify and link SPLs with NDF-RT categories. Third, we profiled SPLs using RxNorm term type information. In the implementation process, we employed a Semantic Web technology framework, in which we stored the data sets from NDF-RT and SPLs into a RDF triple store, and executed SPARQL queries to retrieve data from customized SPARQL endpoints. Meanwhile, we imported RxNorm data into MySQL relational database. In total, 96.0% SPL drug labels were mapped with NDF-RT categories whereas 97.0% SPL drug labels are linked to RxNorm codes. We found that the majority of SPL drug labels are mapped to chemical ingredient concepts in both drug ontologies whereas a relatively small portion of SPL drug labels are mapped to clinical drug concepts. The profiling outcomes produced by this study would provide useful insights on meaningful use of FDA SPL drug labels in clinical applications through standard drug ontologies such as NDF-RT and

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.

Serum concentrations and profiles of polychlorinated biphenyls in Taiwan Yu-cheng victims twenty years after the incident

Energy Technology Data Exchange (ETDEWEB)

Lung, S.-C. Candice [Research Center for Environmental Changes, Academia Sinica, Nankang, Taipei, Taiwan 115 (China); Guo, Y.-L.L. [Department of Environmental and Occupational Health, College of Medicine, National Cheng Kung University, 138 Sheng-Li Rd., Tainan, Taiwan 70428 (China); Chang, H.-Y.[Department of Environmental and Occupational Health, College of Medicine, National Cheng Kung University, 138 Sheng-Li Rd., Tainan, Taiwan 70428 (China)]. E-mail: h7154@mail.ncku.edu.tw

2005-07-15

In 1979, about 2000 people in central Taiwan were intoxicated via rice oil consumption that was contaminated with polychlorinated biphenyls (PCBs). This 'Yu-cheng' incident was one of the two known major human PCB intoxication episodes. Twenty years after the intoxication, serum samples of 435 Yu-cheng victims, 414 adults and 21 children, were collected. Sixteen PCB congeners were analyzed with a gas chromatograph-electron capture detector. We found the median concentration of total PCBs in the adult serum was 1500 ng/g lipid, still substantially higher than that of the general population in Taiwan (3.7-fold) and most seafood consumers in the world. Most of analyzed PCB congeners in children were below or around the detection limits. Congener no. 138, however, had the highest concentrations, approximately accounting for 55% and 29% in the child and adult groups, respectively. Given that PCBs are persistent organic pollutants and endocrine disruptors, the concentrations and congener-specific profiles regarding the Yu-cheng victims provide valuable information for the investigation of such chemicals in humans. - Total serum PCBs in the Yu-cheng adult victims twenty years after the incident were still higher than that of the general population in Taiwan.

Current manufacturing processes of drug-eluting sutures.

Science.gov (United States)

Champeau, Mathilde; Thomassin, Jean-Michel; Tassaing, Thierry; Jérôme, Christine

2017-11-01

Drug-eluting sutures represent the next generation of surgical sutures since they fulfill their mechanical functions but also deliver the drug in their vicinity after implantation. These implants are produced by a variety of manufacturing processes. Drug-eluting sutures represent the next generation of surgical sutures since they fulfill their mechanical functions but also deliver the drug in their vicinity after implantation. These implants are produced by a variety of manufacturing processes. Two general approaches can be followed: (i) the ones that add the API into the material during the manufacturing process of the suture and (ii) the ones that load the API to an already manufactured suture. Areas covered: This review provides an overview of the current manufacturing processes for drug-eluting suture production and discusses their benefits and drawbacks depending on the type of drugs. The mechanical properties and the drug delivery profile of drug-eluting sutures are highlighted since these implants must fulfill both criteria. Expert opinion: For limited drug contents, melt extrusion and electrospinning are the emerging processes since the drug is added during the suture manufacture process. Advantageously, the drug release profile can be tuned by controlling the processing parameters specific to each process and the composition of the drug-containing polymer. If high drug content is targeted, the coating or grafting of a drug layer on a pre-manufactured suture allows for preservation of the tensile strength requirements of the suture.

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.

Science.gov (United States)

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

Interactions between a poorly soluble cationic drug and sodium dodecyl sulfate in dissolution medium and their impact on in vitro dissolution behavior.

Science.gov (United States)

Huang, Zongyun; Parikh, Shuchi; Fish, William P

2018-01-15

In the pharmaceutical industry, in vitro dissolution testing ofsolid oral dosage forms is a very important tool for drug development and quality control. However, ion-pairing interaction between the ionic drugand surfactants in dissolution medium often occurs, resulting in inconsistent and incomplete drug release. The aim of this study is toevaluate the effects ofsodium dodecyl sulfate (SDS) mediated medium onthe dissolution behaviors of a poorly soluble cationic drug (Drug B). The study was carried out by measuring solubility of Drug B substance and dissolution rate of Drug B product in media containing SDS.Desolubilization of Drug B substance was observed at pH 4.5 in the presence of SDS at concentrations below critical micelle concentration (CMC) which is attributed to the formation of an insoluble di-dodecyl sulfate salt between SDS and Drug B. This ion-pairing effect is less significant with increasing medium pH where Drug B is less ionized and CMC of SDS is lower. In medium at pH 4.5, dissolution of Drug B product was found incomplete with SDS concentration below CMC due to the desolubilization of Drug B substance. In media with SDS level above CMC, the dissolution rate is rather slower with higher inter-vessel variations compared to that obtained in pH 4.5 medium without SDS. The dissolution results demonstrate that the presence of SDS in medium generates unexpected irregular dissolution profiles for Drug B which are attributed to incompatible dissolution medium for this particular drug. Therefore, non-ionic surfactant was selected for Drug B product dissolution method and ion-pairing effect in SDS mediated medium should be evaluated when developing a dissolution method for any poorly soluble cationic drugs. Copyright © 2017 Elsevier B.V. All rights reserved.

Modeling Cl{sup -} concentration and δ{sup 37}Cl profiles in pore water across a 250 m-thick indurated argillite at the Tournemire URL (France)

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Le Gal La Salle, Corinne; Rebeix, Romain; Lancelot, Joel [Universite de Nimes / Site GIS - 30035 Nimes cedex 01 (France); Aix-Marseille Universite, CEREGE UMR7330, 13545 Aix en Provence (France); Matray, Jean-Michel [IRSN, BP17 - 92262 Fontenay-aux-Roses Cedex (France); Bensenouci, Fethic [IRSN, BP17 - 92262 Fontenay-aux-Roses Cedex (France); IDES, UMR CNRS 8148 Universite Paris-Sud - 91405 Orsay Cedex (France); Michelot, Jean-Luc [IDES, UMR CNRS 8148 Universite Paris-Sud - 91405 Orsay Cedex (France); Dauzeres, Alexandre; Wittebroodt, Charles [IRSN, BP17 - 92262 Fontenay-aux-Roses Cedex (France); Frape, Shaun; ShouakarStash, Orphane [University of Waterloo, 200 University Avenue. West Waterloo, Ontario N2L 3G (Canada)

2013-07-01

Dissolved chloride in argillite pore water has been studied as a natural analogue for radionuclides potentially released from radioactive waste disposal. The Tournemire URL intersects impervious and compacted argillite. A previously obtained chloride concentration profile of intact rock is symmetric with a maximum concentration of 0.6±0.1 g/L, compared to 19 g/L for the original connate seawater. Dissolved chloride shows high δ{sup 37}Cl values, ranging between +6 and +80/00 vs. SMOC. The modeled profile considers diffusive exchange between connate seawater and meteoric freshwater. Transport parameters were obtained by radial diffusion experiments. Numerical modeling was performed with the coupled reactive-transport code Hytec. Simulations suggest a diffusive-exchange time of 85±10 Ma for Cl, which correlates with a major erosional period. Simulated δ{sup 37}Cl values between 1.002 and 1.003 agree with observed pore water δ{sup 37}Cl. This study strongly suggests that the dissolved chloride profile in the argillites results from diffusive exchange and indicates that unfractured argillites can provide good confinement. (authors)

A novel experimental design method to optimize hydrophilic matrix formulations with drug release profiles and mechanical properties.

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Choi, Du Hyung; Lim, Jun Yeul; Shin, Sangmun; Choi, Won Jun; Jeong, Seong Hoon; Lee, Sangkil

2014-10-01

To investigate the effects of hydrophilic polymers on the matrix system, an experimental design method was developed to integrate response surface methodology and the time series modeling. Moreover, the relationships among polymers on the matrix system were studied with the evaluation of physical properties including water uptake, mass loss, diffusion, and gelling index. A mixture simplex lattice design was proposed while considering eight input control factors: Polyethylene glycol 6000 (x1 ), polyethylene oxide (PEO) N-10 (x2 ), PEO 301 (x3 ), PEO coagulant (x4 ), PEO 303 (x5 ), hydroxypropyl methylcellulose (HPMC) 100SR (x6 ), HPMC 4000SR (x7 ), and HPMC 10(5) SR (x8 ). With the modeling, optimal formulations were obtained depending on the four types of targets. The optimal formulations showed the four significant factors (x1 , x2 , x3 , and x8 ) and other four input factors (x4 , x5 , x6 , and x7 ) were not significant based on drug release profiles. Moreover, the optimization results were analyzed with estimated values, targets values, absolute biases, and relative biases based on observed times for the drug release rates with four different targets. The result showed that optimal solutions and target values had consistent patterns with small biases. On the basis of the physical properties of the optimal solutions, the type and ratio of the hydrophilic polymer and the relationships between polymers significantly influenced the physical properties of the system and drug release. This experimental design method is very useful in formulating a matrix system with optimal drug release. Moreover, it can distinctly confirm the relationships between excipients and the effects on the system with extensive and intensive evaluations. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.

222Rn flux and soil air concentration profiles in West-Germany. Soil 222Rn as tracer for gas transport in the unsaturated soil zone

International Nuclear Information System (INIS)

Doerr, H.; Muennich, K.O.

1990-01-01

Measurements of the 222 Rn activity concentration profile in the soil and the 222 Rn flux in West-Germany are presented. The spatial pattern of the 222 Rn flux depends more on soil type than on the 226 Ra activity of the soil material. The average 222 Rn flux from sandy soils is 1000-2000 dpm m -2 h -1 and 4000-6000 dpm m -2 h -1 froam loamy and clayey soils. Weekly 222 Rn flux measurements during a period of 1 year at a sandy site show no significant temporal variations. At a clayey site, the 222 Rn flux tends to be higher in summer than in winter. The permeability coefficient P Rn , obtained from simultaneous 222 Rn flux and concentration profile measurements in various soils, can be expressed as a function of the soil parameters total porosity ε 0 , soil moisture F, tortuosity k and the molecular diffusion coefficient D 0 of 222 Rn in air: P = D 0 ((ε 0 -F)/k-const.). The flux of any other gas into or out of the soil can thus be calculated from its measured concentration profile in the soil and from the 222 Rn permeability coefficient, replacing the molecular diffusion coefficient of 222 Rn by that of the specific gas under consideration. As an example, this method of flux determination is demonstrated for the soil CO 2 flux to the atmosphere and for the flux of atmospheric CH 4 into the soil. (author) 14 refs

Impact of Drug Metabolism/Pharmacokinetics and Their Relevance upon Taxus-based Drug Development.

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Hao, Da-Cheng; Ge, Guang-Bo; Wang, Ping; Yang, Ling

2018-05-22

Drug metabolism and pharmacokinetic (DMPK) studies of Taxus natural products, their semi-synthetic derivatives and analogs are indispensable in the optimization of lead compounds and clinical therapy. These studies can lead to development of new drug entities with improved absorption, distribution, metabolism, excretion and toxicity (ADME/T) profiles. To date, there have been no comprehensive reviews of the DMPK features of Taxus derived medicinal compounds.Natural and semi-synthetic taxanes may cause and could be affected by drug-drug interaction (DDI). Hence ADME/T studies of various taxane-containing formulations are important; to date these studies indicate that the role of cytochrome p450s and drug transporters is more prominent than phase II drug metabolizing enzymes. Mechanisms of taxane DMPK mediated by nuclear receptors, microRNAs, and single nucleotide polymorphisms are being revealed. Herein we review the latest knowledge on these topics, as well as the gaps in knowledge of the DMPK issues of Taxus compounds. DDIs significantly impact the PK/pharmacodynamics performance of taxanes and co-administered chemicals, which may inspire researchers to develop novel formula. While the ADME/T profiles of some taxanes are well defined, DMPK studies should be extended to more Taxus compounds, species, and Taxus -involved formulations, which would be streamlined by versatile omics platforms and computational analyses. Further biopharmaceutical investigations will be beneficial tothe translation of bench findings to the clinical applications. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

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

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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.

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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.

Effect of ingested lipids on drug dissolution and release with concurrent digestion: a modeling approach

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Buyukozturk, Fulden; Di Maio, Selena; Budil, David E.; Carrier, Rebecca L.

2014-01-01

Purpose To mechanistically study and model the effect of lipids, either from food or self-emulsifying drug delivery systems (SEDDS), on drug transport in the intestinal lumen. Methods Simultaneous lipid digestion, dissolution/release, and drug partitioning were experimentally studied and modeled for two dosing scenarios: solid drug with a food-associated lipid (soybean oil) and drug solubilized in a model SEDDS (soybean oil and Tween 80 at 1:1 ratio). Rate constants for digestion, permeability of emulsion droplets, and partition coefficients in micellar and oil phases were measured, and used to numerically solve the developed model. Results Strong influence of lipid digestion on drug release from SEDDS and solid drug dissolution into food-associated lipid emulsion were observed and predicted by the developed model. 90 minutes after introduction of SEDDS, there was 9% and 70% drug release in the absence and presence of digestion, respectively. However, overall drug dissolution in the presence of food-associated lipids occurred over a longer period than without digestion. Conclusion A systems-based mechanistic model incorporating simultaneous dynamic processes occurring upon dosing of drug with lipids enabled prediction of aqueous drug concentration profile. This model, once incorporated with a pharmacokinetic model considering processes of drug absorption and drug lymphatic transport in the presence of lipids, could be highly useful for quantitative prediction of impact of lipids on bioavailability of drugs. PMID:24234918

Cardioprotective and Metabolomic Profiling of Selected Medicinal Plants against Oxidative Stress

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Nadia Afsheen

2018-01-01

Full Text Available In this research work, the antioxidant and metabolomic profiling of seven selected medicinally important herbs including Rauvolfia serpentina, Terminalia arjuna, Coriandrum sativum, Elettaria cardamom, Piper nigrum, Allium sativum, and Crataegus oxyacantha was performed. The in vivo cardioprotective potential of these medicinal plants was evaluated against surgically induced oxidative stress through left anterior descending coronary artery ligation (LADCA in dogs. The antioxidant profiling of these plants was done through DPPH and DNA protection assay. The C. oxyacantha and T. arjuna showed maximum antioxidant potential, while the E. cardamom showed poor antioxidative strength even at its high concentration. Different concentrations of extracts of the said plants exhibited the protection of plasmid DNA against H2O2 damage as compared to the plasmid DNA merely treated with H2O2. The metabolomic profiling through LC-MS analysis of these antioxidants revealed the presence of active secondary metabolites responsible for their antioxidant potential. During in vivo analysis, blood samples of all treatment groups were drawn at different time intervals to analyze the cardiac and hemodynamic parameters. The results depicted that the group pretreated with HC4 significantly sustained the level of CK-MB, SGOT, and LDH as well as hemodynamic parameters near to normal. The histopathological examination also confirmed the cardioprotective potential of HC4. Thus, the HC4 being safe and inexpensive cardioprotective herbal combination could be considered as an alternate of synthetic drugs.

Cardioprotective and Metabolomic Profiling of Selected Medicinal Plants against Oxidative Stress

Science.gov (United States)

Afsheen, Nadia; Jahan, Nazish; Ijaz, Misbah; Manzoor, Asad; Khan, Khalid Mahmood; Hina, Saman

2018-01-01

In this research work, the antioxidant and metabolomic profiling of seven selected medicinally important herbs including Rauvolfia serpentina, Terminalia arjuna, Coriandrum sativum, Elettaria cardamom, Piper nigrum, Allium sativum, and Crataegus oxyacantha was performed. The in vivo cardioprotective potential of these medicinal plants was evaluated against surgically induced oxidative stress through left anterior descending coronary artery ligation (LADCA) in dogs. The antioxidant profiling of these plants was done through DPPH and DNA protection assay. The C. oxyacantha and T. arjuna showed maximum antioxidant potential, while the E. cardamom showed poor antioxidative strength even at its high concentration. Different concentrations of extracts of the said plants exhibited the protection of plasmid DNA against H2O2 damage as compared to the plasmid DNA merely treated with H2O2. The metabolomic profiling through LC-MS analysis of these antioxidants revealed the presence of active secondary metabolites responsible for their antioxidant potential. During in vivo analysis, blood samples of all treatment groups were drawn at different time intervals to analyze the cardiac and hemodynamic parameters. The results depicted that the group pretreated with HC4 significantly sustained the level of CK-MB, SGOT, and LDH as well as hemodynamic parameters near to normal. The histopathological examination also confirmed the cardioprotective potential of HC4. Thus, the HC4 being safe and inexpensive cardioprotective herbal combination could be considered as an alternate of synthetic drugs. PMID:29576858

Ingestion of Milk Containing Very Low Concentration of Antimicrobials: Longitudinal Effect on Fecal Microbiota Composition in Preweaned Calves.

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Richard Van Vleck Pereira

Full Text Available Although antimicrobial drugs are central to combat disease in modern medicine, the use of these drugs can have undesired consequences for human and animal health. One consequence is the post-therapy excretion of pharmacological agents, such as the elimination of drug residues at very low concentrations in the milk of lactating mammals. Limited information is currently available on the impact from the exposure of the gut microbiota to drug residues using in vivo natural models. The objective of our study was to address this knowledge gap and evaluate the effect on the fecal microbiota composition from feeding preweaned dairy calves raw milk with residual concentrations of ampicillin, ceftiofur, penicillin, and oxytetracycline from birth to weaning. At birth, thirty calves were randomly assigned to a controlled feeding trial where: 15 calves were fed raw milk with no drug residues (NR, and 15 calves were fed raw milk with drug residues (DR by adding ceftiofur, penicillin, ampicillin, and oxytetracycline at final concentrations in the milk of 0.1, 0.005, 0.01, and 0.3 μg/ml, respectively. Fecal samples were rectally collected from each calf once a week starting at birth, prior to the first feeding in the trial (pre-treatment, until 6 weeks of age. Sequencing of the microbial 16S rRNA genes was conducted using the Illumina MiSeq, which provides a high resolution of the microbiota down to the genus level. Discriminant analysis showed that, except for pre-treatment samples, calves fed milk with drug residues and calves fed milk without drug residues easily discriminated at the genus level on their weekly microbial profile. However, analysis comparing the abundance of taxon between NR and DR showed significant differences only at the genus levels, and not at the phylum, class, order or family levels. These results suggest that although drug residues can result in clear discriminate gut microbial communities, they do not result in disruption of

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

A phase I trial to evaluate the safety and pharmacokinetics of low-dose methotrexate as an anti-malarial drug in Kenyan adult healthy volunteers

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Oyoo George O

2011-03-01

Full Text Available Abstract Background Previous investigations indicate that methotrexate, an old anticancer drug, could be used at low doses to treat malaria. A phase I evaluation was conducted to assess the safety and pharmacokinetic profile of this drug in healthy adult male Kenyan volunteers. Methods Twenty five healthy adult volunteers were recruited and admitted to receive a 5 mg dose of methotrexate/day/5 days. Pharmacokinetics blood sampling was carried out at 2, 4, 6, 12 and 24 hours following each dose. Nausea, vomiting, oral ulcers and other adverse events were solicited during follow up of 42 days. Results The mean age of participants was 23.9 ± 3.3 years. Adherence to protocol was 100%. No grade 3 solicited adverse events were observed. However, one case of transiently elevated liver enzymes, and one serious adverse event (not related to the product were reported. The maximum concentration (Cmax was 160-200 nM and after 6 hours, the effective concentration (Ceff was Conclusion Low-dose methotraxate had an acceptable safety profile. However, methotrexate blood levels did not reach the desirable Ceff of 250-400-nM required to clear malaria infection in vivo. Further dose finding and safety studies are necessary to confirm suitability of this drug as an anti-malarial agent.

Vaginal drug distribution modeling.

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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.

Laboratory markers in personalized drug therapy

NARCIS (Netherlands)

Geerts, A.F.J.

2012-01-01

During the last decade two major trends have influenced the thinking about the benefit-risk balance in drug therapy.The first trend showed that this balance is not only determined by the interaction of the pharmacological properties of the drug with the patient’s (patho)physiological profile, but is

Human abuse liability evaluation of CNS stimulant drugs.

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Romach, Myroslava K; Schoedel, Kerri A; Sellers, Edward M

2014-12-01

Psychoactive drugs that increase alertness, attention and concentration and energy, while also elevating mood, heart rate and blood pressure are referred to as stimulants. Despite some overlapping similarities, stimulants cannot be easily categorized by their chemical structure, mechanism of action, receptor binding profile, effects on monoamine uptake, behavioral pharmacology (e.g., effects on locomotion, temperature, and blood pressure), therapeutic indication or efficacy. Because of their abuse liability, a pre-market assessment of abuse potential is required for drugs that show stimulant properties; this review article focuses on the clinical aspects of this evaluation. This includes clinical trial adverse events, evidence of diversion or tampering, overdoses and the results of a human abuse potential study. While there are different types of human experimental studies that can be employed to evaluate stimulant abuse potential (e.g., drug discrimination, self-administration), only the human abuse potential study and clinical trial adverse event data are required for drug approval. The principal advances that have improved human abuse potential studies include using study enrichment strategies (pharmacologic qualification), larger sample sizes, better selection of endpoints and measurement strategies and more carefully considered interpretation of data. Because of the methodological advances, comparisons of newer studies with historical data is problematic and may contribute to a biased regulatory framework for the evaluation of newer stimulant-like drugs, such as A2 antagonists. This article is part of the Special Issue entitled 'CNS Stimulants'. Copyright © 2014 Elsevier Ltd. All rights reserved.

A Decade in the MIST: Learnings from Investigations of Drug Metabolites in Drug Development under the "Metabolites in Safety Testing" Regulatory Guidance.

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Schadt, Simone; Bister, Bojan; Chowdhury, Swapan K; Funk, Christoph; Hop, Cornelis E C A; Humphreys, W Griffith; Igarashi, Fumihiko; James, Alexander D; Kagan, Mark; Khojasteh, S Cyrus; Nedderman, Angus N R; Prakash, Chandra; Runge, Frank; Scheible, Holger; Spracklin, Douglas K; Swart, Piet; Tse, Susanna; Yuan, Josh; Obach, R Scott

2018-06-01

Since the introduction of metabolites in safety testing (MIST) guidance by the Food and Drug Administration in 2008, major changes have occurred in the experimental methods for the identification and quantification of metabolites, ways to evaluate coverage of metabolites, and the timing of critical clinical and nonclinical studies to generate this information. In this cross-industry review, we discuss how the increased focus on human drug metabolites and their potential contribution to safety and drug-drug interactions has influenced the approaches taken by industry for the identification and quantitation of human drug metabolites. Before the MIST guidance was issued, the method of choice for generating comprehensive metabolite profile was radio chromatography. The MIST guidance increased the focus on human drug metabolites and their potential contribution to safety and drug-drug interactions and led to changes in the practices of drug metabolism scientists. In addition, the guidance suggested that human metabolism studies should also be accelerated, which has led to more frequent determination of human metabolite profiles from multiple ascending-dose clinical studies. Generating a comprehensive and quantitative profile of human metabolites has become a more urgent task. Together with technological advances, these events have led to a general shift of focus toward earlier human metabolism studies using high-resolution mass spectrometry and to a reduction in animal radiolabel absorption/distribution/metabolism/excretion studies. The changes induced by the MIST guidance are highlighted by six case studies included herein, reflecting different stages of implementation of the MIST guidance within the pharmaceutical industry. Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics.