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Sample records for affect drug absorption

  1. Rationale for ibuprofen co-administration with antacids: potential interaction mechanisms affecting drug absorption.

    PubMed

    Parojcić, Jelena; Corrigan, Owen I

    2008-06-01

    Ibuprofen is a widely used NSAID which is often co-administered with antacids because of its gastro-irritant effects. Literature data suggest that antacid interactions may increase or decrease the drug's absorption rate and onset of action and that the interaction may be formulation specific. In the present study, literature data on ibuprofen absorption were evaluated in order to gain insight into the nature of the in vivo effect. Solubility determinations in reactive media containing magnesium or aluminium and dissolution studies in the presence of antacid suspension were performed in an attempt to simulate in vitro the effects observed in vivo. The results obtained indicate that magnesium hydroxide enhances ibuprofen solubility, dissolution and bioavailability, while aluminium hydroxide has a retarding effect. Solubility studies indicated formation of a soluble solid ibuprofen phase in the presence of Mg2+, in contrast, an insoluble ibuprofen salt was formed with Al3+. The introduction of magnesium based antacid suspension into the dissolution media resulted in a formulation specific increase in drug dissolution rate with the most pronounced effect observed for the slowest release tablet formulation. The results obtained indicate the potential for in vitro studies to predict physicochemical interactions that are likely to influence drug absorption rate in vivo.

  2. Compounds affecting cholesterol absorption

    NASA Technical Reports Server (NTRS)

    Hua, Duy H. (Inventor); Koo, Sung I. (Inventor); Noh, Sang K. (Inventor)

    2004-01-01

    A class of novel compounds is described for use in affecting lymphatic absorption of cholesterol. Compounds of particular interest are defined by Formula I: ##STR1## or a pharmaceutically acceptable salt thereof.

  3. A theoretical consideration of percutaneous drug absorption.

    PubMed

    Kubota, K; Ishizaki, T

    1985-02-01

    The percutaneous drug absorption process and its clinical significance are not fully known. In this article we propose a theoretical method to obtain two parameters (kd and kc) of percutaneous drug absorption from in vivo data. These parameters are related to diffusion of a drug through the skin and removal process at the skin-capillary boundary, respectively, characterizing several pharmacokinetic aspects of the drug applied to the skin. Moreover, by employing these two kinetic constants, a simulation of percutaneous drug absorption can be theoretically generated. On the basis of our theoretical considerations on the percutaneous drug absorption process described herein, we conclude that the percutaneous drug absorption process is better understood by employing two kinetic constants in a mathematical model and that its clinical application would be highly possible. PMID:4020622

  4. A Quantitative Review and Meta-models of the Variability and Factors Affecting Oral Drug Absorption-Part II: Gastrointestinal Transit Time.

    PubMed

    Abuhelwa, Ahmad Y; Foster, David J R; Upton, Richard N

    2016-09-01

    This study aimed to conduct a quantitative meta-analysis for the values of, and variability in, gastrointestinal (GI) transit times of non-disintegrating single-unit ("tablet") and multiple-unit ("pellets/multi-unit tablet") solid dosage forms, characterize the effect of food on the values and variability in these parameters and present quantitative meta-models of the distributions of GI transit times in the respective GI regions to help inform models of oral drug absorption. The literature was systemically reviewed for the values of, and the variability in, gastric, small intestinal and colonic transit times under fed and fasted conditions. Meta-analysis used the "metafor" package of the R language. Meta-models of GI transit were assumed to be log-normally distributed between the studied populations. Twenty-nine studies including 125 reported means and standard deviations were used in the meta-analysis. Caloric content of administered food increased variability and delayed the gastric transit of both pellets and tablets. Conversely, food caloric content reduced the variability but had no significant influence on the mean small intestinal transit time (SITT). Food had no significant effect on the transit time through the colon. The transit of pellets through the colon was significantly slower than that of single-unit tablets which is most likely related to their smaller size. GI transit times may influence the dissolution and absorption of oral drugs. The meta-models of GI transit times may be used as part of semi-physiological absorption models to characterize the influence of transit time on the dissolution, absorption and in vivo pharmacokinetic profiles of oral drugs.

  5. A Quantitative Review and Meta-models of the Variability and Factors Affecting Oral Drug Absorption-Part II: Gastrointestinal Transit Time.

    PubMed

    Abuhelwa, Ahmad Y; Foster, David J R; Upton, Richard N

    2016-09-01

    This study aimed to conduct a quantitative meta-analysis for the values of, and variability in, gastrointestinal (GI) transit times of non-disintegrating single-unit ("tablet") and multiple-unit ("pellets/multi-unit tablet") solid dosage forms, characterize the effect of food on the values and variability in these parameters and present quantitative meta-models of the distributions of GI transit times in the respective GI regions to help inform models of oral drug absorption. The literature was systemically reviewed for the values of, and the variability in, gastric, small intestinal and colonic transit times under fed and fasted conditions. Meta-analysis used the "metafor" package of the R language. Meta-models of GI transit were assumed to be log-normally distributed between the studied populations. Twenty-nine studies including 125 reported means and standard deviations were used in the meta-analysis. Caloric content of administered food increased variability and delayed the gastric transit of both pellets and tablets. Conversely, food caloric content reduced the variability but had no significant influence on the mean small intestinal transit time (SITT). Food had no significant effect on the transit time through the colon. The transit of pellets through the colon was significantly slower than that of single-unit tablets which is most likely related to their smaller size. GI transit times may influence the dissolution and absorption of oral drugs. The meta-models of GI transit times may be used as part of semi-physiological absorption models to characterize the influence of transit time on the dissolution, absorption and in vivo pharmacokinetic profiles of oral drugs. PMID:27439620

  6. A Quantitative Review and Meta-Models of the Variability and Factors Affecting Oral Drug Absorption-Part I: Gastrointestinal pH.

    PubMed

    Abuhelwa, Ahmad Y; Foster, David J R; Upton, Richard N

    2016-09-01

    This study aimed to conduct a quantitative meta-analysis for the values of, and variability in, gastrointestinal (GI) pH in the different GI segments; characterize the effect of food on the values and variability in these parameters; and present quantitative meta-models of distributions of GI pH to help inform models of oral drug absorption. The literature was systemically reviewed for the values of, and the variability in, GI pH under fed and fasted conditions. The GI tract was categorized into the following 10 distinct regions: stomach (proximal, mid-distal), duodenum (proximal, mid-distal), jejunum and ileum (proximal, mid, and distal small intestine), and colon (ascending, transverse, and descending colon). Meta-analysis used the "metafor" package of the R language. The time course of postprandial stomach pH was modeled using NONMEM. Food significantly influenced the estimated meta-mean stomach and duodenal pH but had no significant influence on small intestinal and colonic pH. The time course of postprandial pH was described using an exponential model. Increased meal caloric content increased the extent and duration of postprandial gastric pH buffering. The different parts of the small intestine had significantly different pH. Colonic pH was significantly different for descending but not for ascending and transverse colon. Knowledge of GI pH is important for the formulation design of the pH-dependent dosage forms and in understanding the dissolution and absorption of orally administered drugs. The meta-models of GI pH may also be used as part of semi-physiological pharmacokinetic models to characterize the effect of GI pH on the in vivo drug release and pharmacokinetics. PMID:27495120

  7. A Quantitative Review and Meta-Models of the Variability and Factors Affecting Oral Drug Absorption-Part I: Gastrointestinal pH.

    PubMed

    Abuhelwa, Ahmad Y; Foster, David J R; Upton, Richard N

    2016-09-01

    This study aimed to conduct a quantitative meta-analysis for the values of, and variability in, gastrointestinal (GI) pH in the different GI segments; characterize the effect of food on the values and variability in these parameters; and present quantitative meta-models of distributions of GI pH to help inform models of oral drug absorption. The literature was systemically reviewed for the values of, and the variability in, GI pH under fed and fasted conditions. The GI tract was categorized into the following 10 distinct regions: stomach (proximal, mid-distal), duodenum (proximal, mid-distal), jejunum and ileum (proximal, mid, and distal small intestine), and colon (ascending, transverse, and descending colon). Meta-analysis used the "metafor" package of the R language. The time course of postprandial stomach pH was modeled using NONMEM. Food significantly influenced the estimated meta-mean stomach and duodenal pH but had no significant influence on small intestinal and colonic pH. The time course of postprandial pH was described using an exponential model. Increased meal caloric content increased the extent and duration of postprandial gastric pH buffering. The different parts of the small intestine had significantly different pH. Colonic pH was significantly different for descending but not for ascending and transverse colon. Knowledge of GI pH is important for the formulation design of the pH-dependent dosage forms and in understanding the dissolution and absorption of orally administered drugs. The meta-models of GI pH may also be used as part of semi-physiological pharmacokinetic models to characterize the effect of GI pH on the in vivo drug release and pharmacokinetics.

  8. Factors affecting gallbladder motility: drugs.

    PubMed

    Marzio, L

    2003-07-01

    Various drugs and medications that inhibit or stimulate gallbladder contraction and basal tone in humans are described. Active gallbladder contraction may be achieved using synthetic hormones such as cholecystokinin, caerulein and motilin, cholinomimetic drugs such as bethanecol, prostigmine, and erythromycin due to its motilin-like effect. Furthermore, cisapride and cholestyramine, may have some excitatory activity on the gallbladder muscle. Intravenous amino acids also induce gallbladder contraction through the release of cholecystokinin. Inhibition of gallbladder contraction induced by a meal, or reduction of the basal fasting tone may be achieved by using atropine and other cholinergics, and by inhibitory hormones such as somatostatin, the nitric acid releaser arginine, the calcium channel antagonist nifedipine, and progesterone. Other drugs such as trimebutine, loperamide and ondansetron may negatively affect gallbladder contraction. PMID:12974504

  9. Solvent drag effect in drug intestinal absorption. II. Studies on drug absorption clearance and water influx.

    PubMed

    Karino, A; Hayashi, M; Awazu, S; Hanano, M

    1982-09-01

    In order to study the solvent drag effect, it was shown that back flux of absorbed drug from blood to intestinal lumen can be ignored but the back flux of water cannot. Then, apparent water influx was calculated as a new measure of solvent drag based on the model in which the back flux of D2O from blood to lumen was considered during absorption. Consequently, the correlation between drug absorption clearance (CLdrug) and apparent water influx was highly significant for benzoic acid, salicylic acid, p-hydroxybenzoic acid, antipyrine, cephalexin (CEX) and cefroxadine (CXD), resulting the high solvent drag effects were detected. The mean values of the slopes in the regression lines of CLdrug versus apparent water influx, i.e., sieving coefficients, were smaller than one for benzoic acid and salicylic acid, but the values were not significantly different from one. The sieving coefficients of the other drugs were significantly smaller than one. From these results, the molecular size dependence in the reflection from the intestinal membrane during absorption was clearly shown. And the intercepts of the regression lines including diffusive permeabilities were found to be significantly different from zero in CEX and CXD. On the basis of the sieving coefficients and intercept values obtained in such ways, the appropriateness of this model was discussed.

  10. PREDICTING DRUG DISPOSITION, ABSORPTION / ELIMINATION / TRANSPORTER INTERPLAY AND THE ROLE OF FOOD ON DRUG ABSORPTION

    PubMed Central

    Custodio, Joseph M.; Wu, Chi-Yuan; Benet, Leslie Z.

    2008-01-01

    The ability to predict drug disposition involves concurrent consideration of many chemical and physiological variables and the effect of food on the rate and extent of availability adds further complexity due to postprandial changes in the gastrointestinal (GI) tract. A system that allows for the assessment of the multivariate interplay occurring following administration of an oral dose, in the presence or absence of meal, would greatly benefit the early stages of drug development. This is particularly true in an era when the majority of new molecular entities are highly permeable, poorly soluble, extensively metabolized compounds (BDDCS Class 2), which present the most complicated relationship in defining the impact of transporters due to the marked effects of transporter-enzyme interplay. This review evaluates the GI luminal environment by taking into account the absorption / transport / elimination interplay and evaluates the physiochemical property issues by taking into account the importance of solubility, permeability and metabolism. We concentrate on the BDDCS and its utility in predicting drug disposition. Furthermore, we focus on the effect of food on the extent of drug availability (F), which appears to follow closely what might be expected if a significant effect of high fat meals is inhibition of transporters. That is, high fat meals and lipidic excipients would be expected to have little effect on F for Class 1 drugs; they would increase F of Class 2 drugs, while decreasing F for Class 3 drugs. PMID:18199522

  11. Drug absorption in gastrointestinal disease and surgery. Clinical pharmacokinetic and therapeutic implications.

    PubMed

    Gubbins, P O; Bertch, K E

    1991-12-01

    Drug absorption from the gastrointestinal (GI) tract and the impact of GI surgery and disease on drug absorption are discussed. Recommendations are made to manage problems of drug malabsorption. Absorption from the GI tract is a first-order process described by its rate and extent. GI surgery changes the anatomy of the GI tract and alters important variables in the absorption process. In the wake of procedures which diminish small bowel surface area, the extent of absorption of phenytoin, digoxin, cyclosporin, aciclovir, hydrochlorothiazide and certain oral contraceptives is reported to be reduced. The underlying cause of the reduction is unknown. When gastric emptying time or pH are altered by surgery, the rate of drug absorption appears to be reduced. However, it is not clear which variable is more important in determining therapeutic effects. The effects of coeliac and inflammatory bowel diseases on the distribution and clearance of drugs must be considered before attributing abnormal serum concentrations of drugs to malabsorption. GI disease may slow gastric emptying and delay the complete absorption of drugs when their rate of absorption depends on gastric emptying time. Other inflammatory GI diseases such as graft-versus-host disease (GVHD) of the gut, Behçet's syndrome and scleroderma involving the GI tract may directly reduce absorption of drugs such as cyclosporin, amitriptyline, benzodiazepines, anticonvulsants, paracetamol (acetaminophen) and penicillamine. GI diseases which alter gut pH affect the absorption only of drugs with limited water solubility and pH-dependent dissolution such as ketoconazole. Clinicians should be aware of the variable absorption seen after GI disease and surgery and monitor their patients accordingly. PMID:1782738

  12. On the absorption of drugs using chronic dog ileal loop method.

    PubMed

    Kukan, M; Bezek, S; Trnovec, T; Gabauer, I; Styk, J

    1994-01-01

    The absorption rate of three model drugs, i.e., pentacaine (highly lipophilic), stobadine (moderately lipophilic) and acetylsalicylic acid (hydrophilic), was studied using the chronic dog ileal loop method. The drugs were dissolved either in 0.9% unbuffered solution of NaCl or in antacid mixture. When using 0.9% NaCl, the half-lives of absorption (t1/2 (dis)) of pentacaine and stobadine were (mean +/- SD) 23.2 +/- 7.8 min and 20.8 +/- 7.2 min, respectively. For stobadine a good agreement was found between its t1/2 (dis) from the ileum and its absorption half-life determined from blood concentrations after oral administration to dogs. The absorption of acetylsalicylic acid accounted for only 10-20% of the dose introduced into the loop over 45 min; thus, a reliable value of t1/2 (dis) could not be determined. The administration of unbuffered solution of NaCl into the loop was accompanied by rapid increase of pH from acidic to basic value. The antacid mixture failed to affect the absorption rate of the drugs studied. Sampling from the ileum was limited to 35-55 min due to rapid absorption of water. These results suggest that: 1) measurement of the absorption rate of some drugs, e.g., stobadine, by using the chronic dog ileal loop method may adequately predict their absorption rate after peroral administration to the dog, 2) interactions of antacids with drug absorption in the ileum may not play a significant role because of the strong buffering capacity of the ileum, and 3) rapid absorption of water from the ileum does not allow to reliably determine the value of t1/2 (dis) for slowly absorbed drugs. PMID:7837833

  13. A new physiologically based pharmacokinetic model for the prediction of gastrointestinal drug absorption: translocation model.

    PubMed

    Ando, Hirotaka; Hisaka, Akihiro; Suzuki, Hiroshi

    2015-04-01

    This study aimed to construct a new local pharmacokinetic model of gastrointestinal absorption, the translocation model (TLM), using an anatomically relevant, minimally segmented structure to explain linear and nonlinear intestinal absorption, metabolism, and transport. The TLM was based on the concept of a single absorption site that flexibly moves, expands, and shrinks along with the length of the gastrointestinal tract after the intake of an oral dose. The structure of the small intestine is continuous, and various time- and location-dependent issues are freely incorporated in the analysis. Since the model has only one absorption site, understanding and modification of factors affecting absorption are simple. The absorption site is composed of four compartments: solid drug in the lumen, solution drug in the lumen, concentration in the enterocytes, and concentration in the lamina propria. The lamina propria includes the blood capillaries. Blood flow in the absorption site of the lamina propria appropriately accounts for the absorption. In the TLM, the permeability of the apical membrane and that of the basolateral membrane are distinct. By considering plicate, villi, and microvilli expansions of the surface area, the apparent permeability measured in Caco-2 experiments was converted to the effective permeability in vivo. The intestinal availability, bioavailability, and dose product of intestinal availability and absorption rate relationship of the model drugs were well explained using the TLM. The TLM would be a useful tool for the consideration of local pharmacokinetics in the gastrointestinal tract in various situations.

  14. Drug gastrointestinal absorption in rat: Strain and gender differences.

    PubMed

    Oltra-Noguera, Davinia; Mangas-Sanjuan, Victor; González-Álvarez, Isabel; Colon-Useche, Sarin; González-Álvarez, Marta; Bermejo, Marival

    2015-10-12

    Predictive animal models of intestinal drug absorption are essential tools in drug development to identify compounds with promising biopharmaceutical properties. In situ perfusion absorption studies are routinely used in the preclinical setting to screen drug candidates. The objective of this work is to explore the differences in magnitude and variability on intestinal absorption associated with rat strain and gender. Metoprolol and Verapamil absorption rate coefficients were determined using the in situ closed loop perfusion model in four strains of rats and in both genders. Strains used were Sprague-Dawley, Wistar-Han, Wistar-Unilever, Long-Evans and CD∗IGS. In the case of Metoprolol only CD∗IGS and Wistar Unilever showed differences between males and females. For Verapamil, Wistar Han and Sprague-Dawley strains do not show differences between male and female rats. That means that in these strains permeability data from male and female could be combined. In male rats, which are commonly used for permeability estimation, there were differences for Metoprolol permeability between Sprague-Dawley (with lower permeability values) and the other strains, while for Verapamil Sprague-Dawley and Wistar-Han showed the lower permeability values. In conclusion, the selection of rat's strain and gender for intestinal absorption experiments is a relevant element during study design and data from different strains may not be always comparable.

  15. Influence of drug physicochemical characteristics on in vitro transdermal absorption of hydrophobic drug nanosuspensions.

    PubMed

    Shen, Cheng-Ying; Li, Rui-Sheng; Shen, Bao-de; Shen, Gang; Wang, Li-Qiang; Zheng, Juan; Li, Xiao-Rong; Min, Hong-Yan; Han, Jin; Yuan, Hai-Long

    2015-01-01

    The purpose of this paper was to study the influence of drug physicochemical characteristics on in vitro transdermal absorption of hydrophobic drug nanosuspensions. Four drug nanosuspensions were produced by high-pressure homogenization technique, which were the same in stabilizer and similar in particle size. Differential scanning calorimetry and powder X-ray diffraction analysis showed that the crystalline state of the nanocrystals did not change. In vitro permeation study demonstrated that the drug nanosuspensions have a higher rate of permeation that ranged from 1.69- to 3.74-fold compared to drug microsuspensions. Correlation analysis between drug physicochemical properties and Jss revealed that log P and pKa were factors that influenced the in vitro transdermal absorption of hydrophobic drug nanosuspensions, and drugs with a log P value around 3 and a higher pKa value (when pKa < pH+2) would gain higher Jss in this paper.

  16. Assessment of absorption potential of poorly water-soluble drugs by using the dissolution/permeation system.

    PubMed

    Kataoka, Makoto; Yano, Koji; Hamatsu, Yoriko; Masaoka, Yoshie; Sakuma, Shinji; Yamashita, Shinji

    2013-11-01

    This study aims to assess the absorption potential of oral absorption of poorly water-soluble drugs by using the dissolution/permeation system (D/P system). The D/P system can be used to perform analysis of drug permeation under dissolution process and can predict the fraction of absorbed dose in humans. When celecoxib at 1/100 of a clinical dose was applied to the D/P system, percentage of dose dissolved and permeated significantly decreased with an increase in the applied amount, resulting in the oral absorption being predicted to be 22-55%. Whereas similar dissolution and permeation profiles of montelukast sodium were observed, estimated absorption (69-85%) was slightly affected. Zafirlukast absorption (33-36%) was not significantly affected by the dose, although zafirlukast did not show complete dissolution. The relationship between clinical dose and predicted oral absorption of drugs corresponded well to clinical observations. The limiting step of the oral absorption of celecoxib and montelukast sodium was solubility, while that of zafirlukast was dissolution rate. However, due to high permeability of montelukast, oral absorption was not affected by dose. Therefore, the D/P system is a useful tool to assess the absorption potential of poorly water-soluble drugs for oral use.

  17. Assessment of absorption potential of poorly water-soluble drugs by using the dissolution/permeation system.

    PubMed

    Kataoka, Makoto; Yano, Koji; Hamatsu, Yoriko; Masaoka, Yoshie; Sakuma, Shinji; Yamashita, Shinji

    2013-11-01

    This study aims to assess the absorption potential of oral absorption of poorly water-soluble drugs by using the dissolution/permeation system (D/P system). The D/P system can be used to perform analysis of drug permeation under dissolution process and can predict the fraction of absorbed dose in humans. When celecoxib at 1/100 of a clinical dose was applied to the D/P system, percentage of dose dissolved and permeated significantly decreased with an increase in the applied amount, resulting in the oral absorption being predicted to be 22-55%. Whereas similar dissolution and permeation profiles of montelukast sodium were observed, estimated absorption (69-85%) was slightly affected. Zafirlukast absorption (33-36%) was not significantly affected by the dose, although zafirlukast did not show complete dissolution. The relationship between clinical dose and predicted oral absorption of drugs corresponded well to clinical observations. The limiting step of the oral absorption of celecoxib and montelukast sodium was solubility, while that of zafirlukast was dissolution rate. However, due to high permeability of montelukast, oral absorption was not affected by dose. Therefore, the D/P system is a useful tool to assess the absorption potential of poorly water-soluble drugs for oral use. PMID:23811221

  18. In Silico Modeling of Gastrointestinal Drug Absorption: Predictive Performance of Three Physiologically Based Absorption Models.

    PubMed

    Sjögren, Erik; Thörn, Helena; Tannergren, Christer

    2016-06-01

    Gastrointestinal (GI) drug absorption is a complex process determined by formulation, physicochemical and biopharmaceutical factors, and GI physiology. Physiologically based in silico absorption models have emerged as a widely used and promising supplement to traditional in vitro assays and preclinical in vivo studies. However, there remains a lack of comparative studies between different models. The aim of this study was to explore the strengths and limitations of the in silico absorption models Simcyp 13.1, GastroPlus 8.0, and GI-Sim 4.1, with respect to their performance in predicting human intestinal drug absorption. This was achieved by adopting an a priori modeling approach and using well-defined input data for 12 drugs associated with incomplete GI absorption and related challenges in predicting the extent of absorption. This approach better mimics the real situation during formulation development where predictive in silico models would be beneficial. Plasma concentration-time profiles for 44 oral drug administrations were calculated by convolution of model-predicted absorption-time profiles and reported pharmacokinetic parameters. Model performance was evaluated by comparing the predicted plasma concentration-time profiles, Cmax, tmax, and exposure (AUC) with observations from clinical studies. The overall prediction accuracies for AUC, given as the absolute average fold error (AAFE) values, were 2.2, 1.6, and 1.3 for Simcyp, GastroPlus, and GI-Sim, respectively. The corresponding AAFE values for Cmax were 2.2, 1.6, and 1.3, respectively, and those for tmax were 1.7, 1.5, and 1.4, respectively. Simcyp was associated with underprediction of AUC and Cmax; the accuracy decreased with decreasing predicted fabs. A tendency for underprediction was also observed for GastroPlus, but there was no correlation with predicted fabs. There were no obvious trends for over- or underprediction for GI-Sim. The models performed similarly in capturing dependencies on dose and

  19. Vitamin, Mineral, and Drug Absorption Following Bariatric Surgery

    PubMed Central

    Sawaya, Ronald Andari; Jaffe, Jane; Friedenberg, Lindsay; Friedenberg, Frank K.

    2013-01-01

    The prevalence of obesity continues to rise throughout the world. Increasingly, bariatric surgery is used for those with morbid obesity as a pivotal approach to achieve weight loss. Along with substantial weight loss, malabsorption of essential vitamins, minerals, and drugs also occurs. Therefore, more than ever, a better understanding of the physiology and mechanisms by which these deficiencies occur is essential. We review the normal physiology of vitamin, mineral, and drug absorption. This is followed by a description of currently performed bariatric surgeries in the United States. A detailed review of specific nutrient and mineral deficiency states is presented, based on the most significant studies published in the last two decades. Of note, screening and supplementation recommendations have been included. Drug absorption data after these procedures is presented and discussed. Studies were identified by searching the Cochrane Registry and MEDLINE using relevant search terms, as well as through review of the reference section of included manuscripts. Conclusions Bariatric surgery can be effectively used to achieve sustainable weight-loss in morbidly obese patients. It simultaneously brings forth important functional consequences on nutrient deficiencies and drug absorption that clinician’s must be aware of. Further prospective, randomized research on specific procedures and deficiencies is required. PMID:22746302

  20. Microemulsion formulation for enhanced absorption of poorly soluble drugs. II. In vivo study.

    PubMed

    Kawakami, Kohsaku; Yoshikawa, Takayoshi; Hayashi, Takashi; Nishihara, Yoshitaka; Masuda, Kazuyoshi

    2002-05-17

    Oral administration study of microemulsion formulations, which are known to improve the bioavailability of poorly soluble drugs, was performed using rats. Nitrendipine was used as a poorly soluble model drug, and its absorption was enhanced significantly by employing the microemulsion formulations compared to a suspension or an oil solution. The effect of the fed state on the oral absorption of nitrendipine became insignificant with the microemulsion formulations, although it affected the absorption from the suspension formulation significantly. The absorption behavior also varied with the type of surfactant. The absorption from Tween 80-based formulation was very rapid, while HCO-60-based formulation showed prolonged plasma concentration profile. However, the absorption from BL-9EX (polyoxyethylene alkyl ether)-based formulation was hardly observed. Damage to the gastrointestinal mucosa, which seems to be a serious problem of surfactant-based formulations, also differed with the type of surfactant employed. HCO-60 and Tween 80-based formulations were mild to the organs, while BL-9EX-based formulation caused serious damage. The behavior and absorption mechanism of the microemulsion formulations are discussed.

  1. Evaluation of Factors Affecting Powdered Drug Reconstitution in Microgravity

    NASA Technical Reports Server (NTRS)

    Schaffner, Grant; Johnston, Smith; Marshburn, Tom

    1999-01-01

    Owing to the high cost of transporting mass into space, and the small volume available for equipment in the Space Shuttle Orbiter and the International Space Station, refrigeration space is extremely limited. For this reason, there exists strong motivation for transporting certain drugs in powdered form so that they do not require refrigeration. When needed, the powdered drug will be mixed with saline to obtain a liquid form that may be injected intravenously. While this is a relatively simple task in a 1-G environment, there are some difficulties that may be encountered in 0-G. In non-accelerated spaceflight, gravitational and inertial forces are eliminated allowing other smaller forces, such as capillary forces and surface tension, to dominate the behavior of fluids. For instance, water slowly ejected from a straw will tend to form a sphere, while fluid in a container will tend to wet the inside surface forming a highly rounded meniscus. Initial attempts at mixing powdered drugs with saline in microgravity have shown a tendency toward forming foamy emulsions instead of the desired homogeneous solution. The predominance of adhesive forces between the drug particles and the interface tensions at the gas/liquid and solid/liquid interfaces drastically reduce the rate of deaggregation of the drug powder and also reduce the rate of absorption of saline by the powder mass. In addition, the capillary forces cause the saline to wet the inside of the container, thus trapping air bubbles within the liquid. The rate of dissolution of a powder drug is directly proportional to the amount of surface area of the solid that is exposed to liquid solvent. The surface area of drug that is in contact with the liquid is greatly reduced in microgravity and, as a result, the dissolution rate is reduced as well. The KC-135 research described here was aimed at evaluating the extent to which it is possible to perform drug reconstitution in the weightlessness of parabolic flight using

  2. Canine gastrointestinal physiology: Breeds variations that can influence drug absorption.

    PubMed

    Oswald, Hayley; Sharkey, Michele; Pade, Devendra; Martinez, Marilyn N

    2015-11-01

    Although all dogs belong to Canis lupus familiaris, the physiological diversity resulting from selective breeding can lead to wide interbreed variability in drug pharmacokinetics (PK) or in oral drug product performance. It is important to understand this diversity in order to predict the impact of drug product formulation attributes on in vivo dissolution and absorption characteristics across the canine population when the dog represents the targeted patient population. Based upon published information, this review addresses breed differences in gastrointestinal (GI) physiology and discusses the in vivo implications of these differences. In addition to the importance of such information for understanding the variability that may exist in the performance of oral dosage forms in dogs for the purpose of developing canine therapeutics, an appreciation of breed differences in GI physiology can improve our prediction of oral drug formulation performance when we extrapolate bioavailability results from the dog to the humans, and vice versa. In this literature review, we examine reports of breed associated diversity in GI anatomy and morphology, gastric emptying time (GET), oro-cecal transit time (OCTT), small intestinal transit time (SITT), large intestinal transit time (LITT), intestinal permeability, sodium/potassium fecal concentrations, intestinal flora, and fecal moisture content.

  3. Canine gastrointestinal physiology: Breeds variations that can influence drug absorption.

    PubMed

    Oswald, Hayley; Sharkey, Michele; Pade, Devendra; Martinez, Marilyn N

    2015-11-01

    Although all dogs belong to Canis lupus familiaris, the physiological diversity resulting from selective breeding can lead to wide interbreed variability in drug pharmacokinetics (PK) or in oral drug product performance. It is important to understand this diversity in order to predict the impact of drug product formulation attributes on in vivo dissolution and absorption characteristics across the canine population when the dog represents the targeted patient population. Based upon published information, this review addresses breed differences in gastrointestinal (GI) physiology and discusses the in vivo implications of these differences. In addition to the importance of such information for understanding the variability that may exist in the performance of oral dosage forms in dogs for the purpose of developing canine therapeutics, an appreciation of breed differences in GI physiology can improve our prediction of oral drug formulation performance when we extrapolate bioavailability results from the dog to the humans, and vice versa. In this literature review, we examine reports of breed associated diversity in GI anatomy and morphology, gastric emptying time (GET), oro-cecal transit time (OCTT), small intestinal transit time (SITT), large intestinal transit time (LITT), intestinal permeability, sodium/potassium fecal concentrations, intestinal flora, and fecal moisture content. PMID:26409436

  4. Water vapor absorption into amorphous hydrophobic drug/poly(vinylpyrrolidone) dispersions.

    PubMed

    Crowley, Kieran J; Zografi, George

    2002-10-01

    Water vapor absorption isotherms were measured for three amorphous hydrophobic drug/poly(vinylpyrrolidone) (PVP) dispersions in the concentration range 10-90% w/w PVP. Experimental isotherms were compared to predicted isotherms calculated using each individual component isotherm multiplied by its weight fraction. Indomethacin (IMC)/PVP, ursodeoxycholic acid (UDCA)/PVP and indapamide (IDP)/PVP amorphous dispersions all exhibited experimental isotherms reduced relative to predicted isotherms indicating that dispersion formation altered the water vapor absorption properties of the individual components. For all three drug/PVP systems, deviation from predicted water uptake was greatest close to the 1:1 drug:PVP monomer composition, indicating that intermolecular interaction in amorphous dispersions affects the water uptake properties of the individual components. Using dry glass transition temperature (T(g)) data, the extent of drug/PVP interaction was shown to be greatest in the IDP/PVP system, which could explain why the largest reduction in water vapor absorption was found in this system. The plasticizing effect of absorbed water varied according to dry dispersion PVP content in all systems and the resulting nonideal changes in free volume, calculated using the Vrentas model, were greatest close to the 1:1 drug:PVP monomer composition. A three-component Flory-Huggins model successfully predicted isotherms for IMC/PVP compositions from 60 to 90% w/w PVP and identified an IMC-PVP interaction parameter chi in the range 1.27-1.49, values that suggest poor homogeneity of mixing in the dry system. These data indicate that amorphous dispersion formation causes both chemical and physical changes in the individual amorphous components that can have a significant effect on their water vapor absorption properties.

  5. Drug Convictions May Affect Your Student Aid.

    ERIC Educational Resources Information Center

    Department of Education, Washington, DC.

    This booklet explains problems posed by prior drug convictions to college-bound students seeking federal financial aid. Under a new law which takes effect on July 1, 2000, some students who have drug convictions may be ineligible for federal student aid. For possession of illegal drugs, students are ineligible from the date of conviction for one…

  6. Intestinal bile secretion promotes drug absorption from lipid colloidal phases via induction of supersaturation.

    PubMed

    Yeap, Yan Yan; Trevaskis, Natalie L; Quach, Tim; Tso, Patrick; Charman, William N; Porter, Christopher J H

    2013-05-01

    The oral bioavailability of poorly water-soluble drugs (PWSD) is often significantly enhanced by coadministration with lipids in food or lipid-based oral formulations. Coadministration with lipids promotes drug solubilization in intestinal mixed micelles and vesicles, however, the mechanism(s) by which PWSD are absorbed from these dispersed phases remain poorly understood. Classically, drug absorption is believed to be a product of the drug concentration in free solution and the apparent permeability across the absorptive membrane. Solubilization in colloidal phases such as mixed micelles increases dissolution rate and total solubilized drug concentrations, but does not directly enhance (and may reduce) the free drug concentration. In the absence of changes to cellular permeability (which is often high for lipophilic, PWSD), significant changes to membrane flux are therefore unexpected. Realizing that increases in effective dissolution rate may be a significant driver of increases in drug absorption for PWSD, we explore here two alternate mechanisms by which membrane flux might also be enhanced: (1) collisional drug absorption where drug is directly transferred from lipid colloidal phases to the absorptive membrane, and (2) supersaturation-enhanced drug absorption where bile mediated dilution of lipid colloidal phases leads to a transient increase in supersaturation, thermodynamic activity and absorption. In the current study, collisional uptake mechanisms did not play a significant role in the absorption of a model PWSD, cinnarizine, from lipid colloidal phases. In contrast, bile-mediated dilution of model intestinal mixed micelles and vesicles led to drug supersaturation. For colloids that were principally micellar, supersaturation was maintained for a period sufficient to promote absorption. In contrast, for primarily vesicular systems, supersaturation resulted in rapid drug precipitation and no increase in drug absorption. This work suggests that ongoing

  7. Clinical significance of organic anion transporting polypeptides (OATPs) in drug disposition: their roles in hepatic clearance and intestinal absorption.

    PubMed

    Shitara, Yoshihisa; Maeda, Kazuya; Ikejiri, Kazuaki; Yoshida, Kenta; Horie, Toshiharu; Sugiyama, Yuichi

    2013-01-01

    Organic anion transporting polypeptide (OATP) family transporters accept a number of drugs and are increasingly being recognized as important factors in governing drug and metabolite pharmacokinetics. OATP1B1 and OATP1B3 play an important role in hepatic drug uptake while OATP2B1 and OATP1A2 might be key players in intestinal absorption and transport across blood-brain barrier of drugs, respectively. To understand the importance of OATPs in the hepatic clearance of drugs, the rate-determining process for elimination should be considered; for some drugs, hepatic uptake clearance rather than metabolic intrinsic clearance is the more important determinant of hepatic clearances. The importance of the unbound concentration ratio (liver/blood), K(p,uu) , of drugs, which is partly governed by OATPs, is exemplified in interpreting the difference in the IC(50) of statins between the hepatocyte and microsome systems for the inhibition of HMG-CoA reductase activity. The intrinsic activity and/or expression level of OATPs are affected by genetic polymorphisms and drug-drug interactions. Their effects on the elimination rate or intestinal absorption rate of drugs may sometimes depend on the substrate drug. This is partly because of the different contribution of OATP isoforms to clearance or intestinal absorption. When the contribution of the OATP-mediated pathway is substantial, the pharmacokinetics of substrate drugs should be greatly affected. This review describes the estimation of the contribution of OATP1B1 to the total hepatic uptake of drugs from the data of fold-increases in the plasma concentration of substrate drugs by the genetic polymorphism of this transporter. To understand the importance of the OATP family transporters, modeling and simulation with a physiologically based pharmacokinetic model are helpful.

  8. Analysis of Intra- and Intersubject Variability in Oral Drug Absorption in Human Bioequivalence Studies of 113 Generic Products.

    PubMed

    Sugihara, Masahisa; Takeuchi, Susumu; Sugita, Masaru; Higaki, Kazutaka; Kataoka, Makoto; Yamashita, Shinji

    2015-12-01

    In this study, the data of 113 human bioequivalence (BE) studies of immediate release (IR) formulations of 74 active pharmaceutical ingredients (APIs) conducted at Sawai Pharmaceutical Co., Ltd., was analyzed to understand the factors affecting intra- and intersubject variabilities in oral drug absorption. The ANOVA CV (%) calculated from area under the time-concentration curve (AUC) in each BE study was used as an index of intrasubject variability (Vintra), and the relative standard deviation (%) in AUC was used as that of intersubject variability (Vinter). Although no significant correlation was observed between Vintra and Vinter of all drugs, Vintra of class 3 drugs was found to increase in association with a decrease in drug permeability (P(eff)). Since the absorption of class 3 drugs was rate-limited by the permeability, it was suggested that, for such drugs, the low P(eff) might be a risk factor to cause a large intrasubject variability. To consider the impact of poor water solubility on the variability in BE study, a parameter of P(eff)/Do (Do; dose number) was defined to discriminate the solubility-limited and dissolution-rate-limited absorption of class 2 drugs. It was found that the class 2 drugs with a solubility-limited absorption (P(eff)/Do < 0.149 × 10(-4) cm/s) showed high intrasubject variability. Furthermore, as a reason for high intra- or intersubject variability in AUC for class 1 drugs, effects of drug metabolizing enzymes were investigated. It was demonstrated that intrasubject variability was high for drugs metabolized by CYP3A4 while intersubject variability was high for drugs metabolized by CYP2D6. For CYP3A4 substrate drugs, the Km value showed the significant relation with Vintra, indicating that the affinity to the enzyme can be a parameter to predict the risk of high intrasubject variability. In conclusion, by analyzing the in house data of human BE study, low permeability, solubility-limited absorption, and high affinity to CYP3A4 are

  9. Two-photon absorption induced drug delivery from polymeric intraocular lenses

    NASA Astrophysics Data System (ADS)

    Hampp, Norbert A.; Kim, Hee-Cheol; Kreiling, Stefan; Hesse, Lutz; Greiner, Andreas

    2003-10-01

    Secondary cataracts are quite often observed after implantation of polymeric intraocular lenses. The reason for this complication is that lens epithelial cells remain in the capsular bag when the natural lens is removed. They begin proliferation and cause secondary cataracts. It is not desireable to add cell toxic agents at the time of the implantation because wound healing is negatively affected. We have developed polymeric intraocular lenses which are equipped with a drug depot which may be released non-invasively through photochemical treatment. In the example presented the drug is 5-fluoruracil (5FU) which is covalently bound to the polymer. Deliberation of 5FU from the polymer is done photochemically. Since light is transmitted permanently through the artificial intraocular lens and wearing of special glasses by the patient should be omitted conventional photochemistry is not a suitable tool for the drug release. The polymer-5FU linkage is designed in a way that it has a high two-photon absorption cross-section. Two-photon absorption is used to selectively release 5FU from the lens. The one-photon reaction is blocked since the cornea does absorb UV light. The principle shown here is not limited to 5FU but may be applied to other drugs also.

  10. Constant optimization of oral drug absorption kinetics in the compartment absorption and transit models using particle swarm optimization algorithm

    NASA Astrophysics Data System (ADS)

    Prabowo, K.; Sumaryada, T.; Kartono, A.

    2016-01-01

    Simulation of predictive modeling oral drug namely Compartment Absorption and Transit (CAT) using Particle Swarm Optimization (PSO) algorithm has been performed. This research will be carried out optimization of kinetic constant value oral drug use PSO algorithm to obtain the best global transport constant values for CAT equation that can predict drug concentration in plasma. The value of drug absorption rate constant for drug atenolol 25 mg is k10, k12, k21, k13 and k31 with each value is 0.8562, 0.3736, 0.2191, 0.4334 and 1.000 have been obtained thus raising the value of the coefficient of determination of a model CAT. From the experimental data plasma drug concentrations used are Atenolol, the coefficient of determination (R2) obtained from simulations atenolol 25 mg (PSO) was 81.72% and 99.46%. Better correlation between the dependent variable as the drug concentration and explanatory variables such as mass medication, plasma volume, and rate of absorption of the drug has increased in CAT models using PSO algorithm. Based on the results of CAT models fit charts can predict drug concentration in plasma.

  11. Against Their Wills: Children Born Affected by Drugs.

    ERIC Educational Resources Information Center

    Hodgkinson, Harold L.; Outtz, Janice Hamilton

    There is no national policy on assisting drug-using pregnant mothers nor on the children they produce. This paper looks at the issue of "crack-cocaine" and mothers who give birth to children after using drugs during pregnancy. It attempts to lay out what is known, and it puts forth "best guesses" regarding helping children born affected by drugs.…

  12. Dissolution and absorption modeling: model expansion to simulate the effects of precipitation, water absorption, longitudinally changing intestinal permeability, and controlled release on drug absorption.

    PubMed

    Johnson, Kevin C

    2003-09-01

    A previously described model for simulating drug dissolution, absorption, and pharmacokinetics has been expanded beyond the original application of simulating immediate-release dosage forms to include simulation of drug precipitation, water absorption from the gastrointestinal tract, changing gastrointestinal permeability, disintegration, and controlled-release and dissolution from a GITS-type dosage form. A mathematical description of the model is presented as well as a retrospective analysis of nifedipine to demonstrate the utility of the model. The fourth-order Runge-Kutta numerical method was used to solve the series of coupled differential equations used to simulate the process of dissolution, absorption, and drug disposition. The model was able to simulate the clinically demonstrated effect for drug particle size on nifedipine plasma concentrations for an immediate-release dosage form. Further simulations indicated that drug particle size was less important for a GITS-type dosage form at a release rate of 1.7 mg/hr compared to rate of 17 mg/hr. Hypothetical calculations simulated the potential effect of drug precipitation, water absorption, and changing permeability on drug plasma concentrations. The expanded model increases the utility of a previously described model in providing guidance in drug development and selection.

  13. Oral exposure to polystyrene nanoparticles affects iron absorption

    NASA Astrophysics Data System (ADS)

    Mahler, Gretchen J.; Esch, Mandy B.; Tako, Elad; Southard, Teresa L.; Archer, Shivaun D.; Glahn, Raymond P.; Shuler, Michael L.

    2012-04-01

    The use of engineered nanoparticles in food and pharmaceuticals is expected to increase, but the impact of chronic oral exposure to nanoparticles on human health remains unknown. Here, we show that chronic and acute oral exposure to polystyrene nanoparticles can influence iron uptake and iron transport in an in vitro model of the intestinal epithelium and an in vivo chicken intestinal loop model. Intestinal cells that are exposed to high doses of nanoparticles showed increased iron transport due to nanoparticle disruption of the cell membrane. Chickens acutely exposed to carboxylated particles (50 nm in diameter) had a lower iron absorption than unexposed or chronically exposed birds. Chronic exposure caused remodelling of the intestinal villi, which increased the surface area available for iron absorption. The agreement between the in vitro and in vivo results suggests that our in vitro intestinal epithelium model is potentially useful for toxicology studies.

  14. How Do Beta Blocker Drugs Affect Exercise?

    MedlinePlus

    ... American Heart area Search by State SELECT YOUR LANGUAGE Español (Spanish) 简体中文 (Traditional Chinese) 繁体中文 (Simplified Chinese) ... used because beta blockers affect everyone differently. The second way to monitor your intensity is simpler: making ...

  15. In situ perfusion in rodents to explore intestinal drug absorption: challenges and opportunities.

    PubMed

    Stappaerts, Jef; Brouwers, Joachim; Annaert, Pieter; Augustijns, Patrick

    2015-01-30

    The in situ intestinal perfusion technique in rodents is a very important absorption model, not only because of its predictive value, but it is also very suitable to unravel the mechanisms underlying intestinal drug absorption. This literature overview covers a number of specific applications for which the in situ intestinal perfusion set-up can be applied in favor of established in vitro absorption tools, such as the Caco-2 cell model. Qualities including the expression of drug transporters and metabolizing enzymes relevant for human intestinal absorption and compatibility with complex solvent systems render the in situ technique the most designated absorption model to perform transporter-metabolism studies or to evaluate the intestinal absorption from biorelevant media. Over the years, the in situ intestinal perfusion model has exhibited an exceptional ability to adapt to the latest challenges in drug absorption profiling. For instance, the introduction of the mesenteric vein cannulation allows determining the appearance of compounds in the blood and is of great use, especially when evaluating the absorption of compounds undergoing intestinal metabolism. Moreover, the use of the closed loop intestinal perfusion set-up is interesting when compounds or perfusion media are scarce. Compatibility with emerging trends in pharmaceutical profiling, such as the use of knockout or transgenic animals, generates unparalleled possibilities to gain mechanistic insight into specific absorption processes. Notwithstanding the fact that the in situ experiments are technically challenging and relatively time-consuming, the model offers great opportunities to gain insight into the processes determining intestinal drug absorption.

  16. Factors That Affect Adolescent Drug Users' Suicide Attempts.

    PubMed

    Park, Subin; Song, Hokwang

    2016-05-01

    Drug abuse has been widely linked to suicide risk. We examined the factors that affect adolescent drug users' suicide attempts in South Korea. This study analyzed the data of 311 adolescents who had used drugs such as inhalants, psychotropic drugs, and marijuana (195 males and 116 females). Among 311 subjects, 109 (35.0%) had attempted suicide during the last 12 months. After adjusting for other variables, depressive mood (OR=19.79) and poly-drug use (OR=2.79), and low/middle levels of academic achievement compared with a high level (OR=3.72 and 4.38) were independently associated with increased odds of a suicide attempt, while better perceived health (OR=0.32) was independently associated with reduced odds of a suicide attempt. For adolescent drug users, preventive work should be directed toward the active treatment of drug use, depression, and physical health and reinforcing proper coping strategies for academic and other stress. PMID:27247604

  17. Factors That Affect Adolescent Drug Users' Suicide Attempts

    PubMed Central

    Song, Hokwang

    2016-01-01

    Drug abuse has been widely linked to suicide risk. We examined the factors that affect adolescent drug users' suicide attempts in South Korea. This study analyzed the data of 311 adolescents who had used drugs such as inhalants, psychotropic drugs, and marijuana (195 males and 116 females). Among 311 subjects, 109 (35.0%) had attempted suicide during the last 12 months. After adjusting for other variables, depressive mood (OR=19.79) and poly-drug use (OR=2.79), and low/middle levels of academic achievement compared with a high level (OR=3.72 and 4.38) were independently associated with increased odds of a suicide attempt, while better perceived health (OR=0.32) was independently associated with reduced odds of a suicide attempt. For adolescent drug users, preventive work should be directed toward the active treatment of drug use, depression, and physical health and reinforcing proper coping strategies for academic and other stress. PMID:27247604

  18. Food properties affecting the digestion and absorption of carbohydrates.

    PubMed

    Björck, I; Granfeldt, Y; Liljeberg, H; Tovar, J; Asp, N G

    1994-03-01

    Carbohydrate foods differ considerably in their effects on postprandial glucose and insulin responses. Qualitative differences among starchy foods are particularly intriguing because of the dominance of starch in human diets. This paper focuses on food properties in cereal (eg, pasta, bread, Arepas, and porridge) and legume products (eg, red kidney beans and lentils) that affect metabolic responses to starch. Studies in healthy subjects have found that postprandial blood glucose and insulin responses are greatly affected by food structure. Any process that disrupts the physical or botanical structure of food ingredients will increase the plasma glucose and insulin responses. The glycemic responses to bread products were reduced by the use of ingredients with an intact botanical or physical structure or a high amylose content or by enrichment with viscous dietary fiber. However, the important of a moderate increase in the amylose-amylopectin ratio and the naturally occurring levels of viscous cereal fiber is less clear. The rate of starch digestion in vitro was shown to be a key determinant of metabolic responses to most products. Assuming the sample preparation mimics chewing, in vitro enzymic procedures can be used to facilitate ranking. One such procedure, based on chewed rather than artificially disintegrated products, was recently developed and correlates well with glycemic and insulinemic indices for several starchy foods. PMID:8116553

  19. Meals and dephytinization affect calcium and zinc absorption in Nigerian children with rickets.

    PubMed

    Thacher, Tom D; Aliu, Oluseyi; Griffin, Ian J; Pam, Sunday D; O'Brien, Kimberly O; Imade, Godwin E; Abrams, Steven A

    2009-05-01

    Nutritional rickets resulting from calcium insufficiency is common in Nigeria and high dietary phytate is thought to inhibit calcium and zinc absorption. We compared the effects of a high-phytate meal and enzymatic dephytinization on calcium and zinc absorption in Nigerian children with and without rickets. Nineteen children with rickets and 15 age-matched control children, aged 2-10 y, were given calcium (600 mg/d) and ergocalciferol (1250 microg/wk). After 6 wk, calcium and zinc absorption were measured in both groups with and without maize porridge using stable isotopes. One week later, absorption measurements were repeated to assess the effects of enzymatic dephytinization and fermentation of the maize porridge. The phytate concentration of maize porridge (3.87 +/- 0.38 g/kg wet weight) was reduced by enzymatic dephytinization (2.83 +/- 0.41 g/kg; P < 0.001) but not by fermentation (3.35 +/- 0.27 g/kg; P = 0.08). Calcium and zinc absorption were unaffected by the presence of rickets or by fermentation of maize porridge. Calcium absorption was greater with a meal (61.3 +/- 25.1%) than without (27.8 +/- 14.6%; P < 0.001). Zinc absorption was lower with a meal (16.2 +/- 8.0%) than without (63.4 +/- 23.9%; P < 0.001). Enzymatic dephytinization increased relative zinc absorption from a meal by 101 +/- 81% (P < 0.001) but did not affect calcium absorption. Rickets was not associated with impaired calcium or zinc absorption. Calcium absorption was enhanced by maize porridge, but zinc absorption was reduced. Enzymatic dephytinization increased zinc absorption. Multiple strategies may be required to optimize calcium and zinc absorption in deficient populations.

  20. Comparison of activated charcoal and ipecac syrup in prevention of drug absorption.

    PubMed

    Neuvonen, P J; Vartiainen, M; Tokola, O

    1983-01-01

    The efficacy of activated charcoal and ipecac syrup in the prevention of drug absorption was studied in 6 healthy adult volunteers, using a randomized, cross-over design. Paracetamol 1000 mg, tetracycline 500 mg and aminophylline 350 mg were ingested on an empty stomach with 100 ml water. Then, after 5 or 30 min, the subjects ingested, either activated charcoal suspension (50 g charcoal), syrup of ipecac, or, only after 5 min, water 300 ml. Activated charcoal, given either after 5 or 30 min, significantly (p less than 0.01 or less 0.05) reduced the absorption of these 3 drugs measured, for example as AUC0-24 h. Syrup of ipecac caused emesis on each occasion, with a mean delay of 15 min. When ipecac was given 5 min after the drugs, its effect on absorption was significant, but when it was given after 30 min only the absorption of tetracycline was reduced. Activated charcoal was significantly (p less than 0.05) more effective than ipecac in reducing drug absorption when given at the same time points. In cases of acute intoxication, depending on the quality and quantity of the drugs ingested, the relative efficacy of charcoal and ipecac may be somewhat different from that observed in the present study. Despite its emetic action, however, ipecac syrup is not very effective in preventing drug absorption and, in general, activated charcoal should also be given after induced emesis or gastric lavage. PMID:6134626

  1. Developments in Methods for Measuring the Intestinal Absorption of Nanoparticle-Bound Drugs

    PubMed Central

    Liu, Wei; Pan, Hao; Zhang, Caiyun; Zhao, Liling; Zhao, Ruixia; Zhu, Yongtao; Pan, Weisan

    2016-01-01

    With the rapid development of nanotechnology, novel drug delivery systems comprising orally administered nanoparticles (NPs) have been paid increasing attention in recent years. The bioavailability of orally administered drugs has significant influence on drug efficacy and therapeutic dosage, and it is therefore imperative that the intestinal absorption of oral NPs be investigated. This review examines the various literature on the oral absorption of polymeric NPs, and provides an overview of the intestinal absorption models that have been developed for the study of oral nanoparticles. Three major categories of models including a total of eight measurement methods are described in detail (in vitro: dialysis bag, rat gut sac, Ussing chamber, cell culture model; in situ: intestinal perfusion, intestinal loops, intestinal vascular cannulation; in vivo: the blood/urine drug concentration method), and the advantages and disadvantages of each method are contrasted and elucidated. In general, in vitro and in situ methods are relatively convenient but lack accuracy, while the in vivo method is troublesome but can provide a true reflection of drug absorption in vivo. This review summarizes the development of intestinal absorption experiments in recent years and provides a reference for the systematic study of the intestinal absorption of nanoparticle-bound drugs. PMID:27455239

  2. Modeling the influence of cyclodextrins on oral absorption of low-solubility drugs: I. Model development.

    PubMed

    Gamsiz, Ece Dilber; Miller, Lee; Thombre, Avinash G; Ahmed, Imran; Carrier, Rebecca Lyn

    2010-02-01

    The ability to quantitatively predict the influence of a solubilization technology on oral absorption would be highly beneficial in rational selection of drug delivery technology and formulation design. Cyclodextrins (CDs) are cyclic oligosaccharides which form inclusion complexes with a large variety of compounds including drugs. There are many studies in the literature showing that complexation between CD and drug enhances oral bioavailability and some demonstrating failure of CD in bioavailability enhancement, but relatively little guidance regarding when CD can be used to enhance bioavailability. A model was developed based upon mass transport expressions for drug dissolution and absorption and a pseudo-equilibrium assumption for the complexation reaction with CD. The model considers neutral compound delivered as a physical mixture with CD in both immediate release (IR) and controlled release (CR) formulations. Simulation results demonstrated that cyclodextrins can enhance, have no effect, or hurt drug absorption when delivered as a physical mixture with drug. The predicted influence depends on interacting parameter values, including solubility, drug absorption constant, binding constant, CD:drug molar ratio, dose, and assumed volume of the intestinal lumen. In general, the predicted positive influence of dosing as a physical mixture with CD was minimal, alluding to the significance of dosing as a preformed complex. The model developed enabled examination of which physical and chemical properties result in oral absorption enhancement for neutral drug administered as a physical mixture with CD, demonstrating the utility of modeling the influence of a drug delivery agent (e.g., CD) on absorption for rational dosage form design.

  3. Contribution of interstitial diffusion in drug absorption from perfused rabbit muscle: effect of hyaluronidase on absorption.

    PubMed

    Nara, E; Saikawa, A; Masegi, M; Hashida, M; Sezaki, H

    1992-03-01

    [3H]Water and [14C]inulin were injected into perfused rabbit muscle with or without hyaluronidase (300 units/ml) and their absorption into venous effluent from muscle was determined. Hyaluronidase accelerated the absorption of both compounds but the enhancement of [14C]inulin was much larger than that for [3H]water. The pharmacokinetic analysis of venous appearance curves based on a physiological diffusion model elucidated that interstitial diffusion of [14C]inulin was remarkably increased by hyaluronidase treatment, suggesting the existence of steric hindrance for it by the polysaccharide network under normal conditions. Enhancement of [3H]water diffusion was also detected although enhancement ratio was about one-half of that of [14C]inulin. Mean time necessary for each process was calculated using the statistical moment concepts. The results suggested predominant contribution of the interstitial diffusion process and secondary and little contribution of local perfusion flow and permeation process across the capillary wall, respectively, in total absorption of [14C]inulin. Effect of hyaluronidase on transcapillary movement of [14C]inulin was studied using an in vitro diffusion experiment with cultured endothelial cell monolayer and no enhancing effect was shown on [14C]inulin transport across the cell monolayer. The contribution of the local perfusion flow, on the other hand, was shown to be almost equivalent to that of the diffusion process in the total absorption of [3H]water.

  4. Absorption, distribution, metabolism and excretion pharmacogenomics of drugs of abuse.

    PubMed

    Meyer, Markus R; Maurer, Hans H

    2011-02-01

    Pharmacologic and toxic effects of xenobiotics, such as drugs of abuse, depend on the genotype and phenotype of an individual, and conversely on the isoenzymes involved in their metabolism and transport. The current knowledge of such isoenzymes of frequently abused therapeutics such as opioids (oxycodone, hydrocodone, methadone, fentanyl, buprenorphine, tramadol, heroin, morphine and codeine), anesthetics (γ-hydroxybutyric acid, propofol, ketamine and phencyclidine) and cognitive enhancers (methylphenidate and modafinil), and some important plant-derived hallucinogens (lysergide, salvinorin A, psilocybin and psilocin), as well as of nicotine in humans are summarized in this article. The isoenzymes (e.g., cytochrome P450, glucuronyltransferases, esterases and reductases) involved in the metabolism of drugs and some pharmacokinetic data are discussed. The relevance of such data is discussed for predicting possible interactions with other xenobiotics, understanding pharmacokinetic behavior and pharmacogenomic variations, assessing toxic risks, developing suitable toxicological analysis procedures, and finally for interpretating drug testing results.

  5. Drug-drug interactions related to altered absorption and plasma protein binding: theoretical and regulatory considerations, and an industry perspective.

    PubMed

    Hochman, Jerome; Tang, Cuyue; Prueksaritanont, Thomayant

    2015-03-01

    Drug-drug interactions (DDIs) related to altered drug absorption and plasma protein binding have received much less attention from regulatory agencies relative to DDIs mediated via drug metabolizing enzymes and transporters. In this review, a number of theoretical bases and regulatory framework are presented for these DDI aspects. Also presented is an industry perspective on how to approach these issues in support of drug development. Overall, with the exception of highly permeable and highly soluble (BCS 1) drugs, DDIs related to drug-induced changes in gastrointestinal (GI) physiology can be substantial, thus warranting more attentions. For a better understanding of absorption-associated DDI potential in a clinical setting, mechanistic studies should be conducted based on holistic integration of the pharmaceutical profiles (e.g., pH-dependent solubility) and pharmacological properties (e.g., GI physiology and therapeutic margin) of drug candidates. Although majority of DDI events related to altered plasma protein binding are not expected to be of clinical significance, exceptions exist for a subset of compounds with certain pharmacokinetic and pharmacological properties. Knowledge of the identity of binding proteins and the binding extent in various clinical setting (including disease states) can be valuable in aiding clinical DDI data interpretations, and ensuring safe and effective use of new drugs.

  6. Drug salts and solubilization: modeling the influence of cyclodextrins on oral absorption.

    PubMed

    Gamsiz, Ece Dilber; Thombre, Avinash G; Ahmed, Imran; Carrier, Rebecca Lyn

    2011-01-01

    Substantial effort and resources are spent for the oral delivery of low solubility compounds using drug delivery technologies. Complexation using cyclodextrins (CDs) is one popular strategy used to enhance drug dissolution kinetics and solubility. In addition to delivery technologies, another common method of improving dissolution kinetics of a low solubility compound is to dose it as a salt. It is not often possible to anticipate how effective a technology such as CD will be in a certain formulation in improving drug absorption, leading to a trial-and-error based formulation process; simultaneous use of salt and complexation technologies increases the complexity of the system. A simple dynamic, systems-based model was developed for predicting the influence of CDs on oral absorption of a salt form of low solubility drug administered as a physical mixture with CD, and validated by in vitro experiments. Model predictions indicate that while CD is generally considered a solubilization technology, CD can enhance overall absorption of salt form drug mainly by decreasing the driving force for precipitation through binding free drug in solution. Modeling enabled examination of which physical and chemical properties result in oral absorption enhancement or decrement for drug salt administered as a physical mixture with CD.

  7. Prodrug/Enzyme based acceleration of absorption of hydrophobic drugs: an in vitro study.

    PubMed

    Kapoor, Mamta; Siegel, Ronald A

    2013-09-01

    Poor water solubility of APIs is a key challenge in drug discovery and development as it results in low drug bioavailability upon local or systemic administration. The prodrug approach is commonly utilized to enhance solubility of hydrophobic drugs. However, for accelerated drug absorption, supersaturated solutions need to be employed. In this work, a novel prodrug/enzyme based system was developed wherein prodrug and enzyme are coadministered at the point of absorption (e.g., nasal cavity) to form in situ supersaturated drug solutions for enhanced bioavailability. A combination of fosphenytoin/alkaline phosphatase was used as a model system. Prodrug conversion kinetics were evaluated with various prodrug/enzyme ratios at pH 7.4 and 32 °C. Phenytoin permeation rates were determined at various degrees of supersaturation (S = 0.8-6.1), across confluent Madin Darby canine kidney II-wild type monolayers (a nasal epithelium model), with prodrug and enzyme spiked into the apical chamber. Membrane intactness was confirmed by measuring transepithelial electrical resistance and inulin permeability. Fosphenytoin and phenytoin concentrations were analyzed using HPLC. Results indicated that a supersaturated solution could be formed using such prodrug/enzyme systems. Drug absorption increased proportionately with increasing degrees of supersaturation; this flux was 1.5-6 fold greater than that for the saturated phenytoin solution. The experimental data fitted reasonably well to a two compartment pharmacokinetic (PK) model with first order conversion of prodrug to drug. This prodrug/enzyme system markedly enhances drug transport across the model membrane. Applied in vivo, this strategy could be used to facilitate drug absorption through mucosal membranes when absorption is limited by solubility.

  8. [Improvement of intestinal absorption of poorly absorbable drugs by various sugar esters].

    PubMed

    Yamamoto, Akira; Katsumi, Hidemasa; Kusamori, Kosuke; Sakane, Toshiyasu

    2014-01-01

    Effects of sucrose fatty acid esters (sugar esters) on the intestinal absorption of poorly absorbable drugs were examined by an in situ closed loop method in rats. 5(6)-Carboxyfluorescein (CF) and fluorescein isothiocyanate-dextrans (FDs) with various molecular weights were used as model drugs of poorly absorbable drugs. The absorption of CF from the rat small intestine was significantly enhanced in the presence of various sugar esters and a maximal absorption enhancing effect was observed in the presence of 0.5%(w/v) S-1670. The absorption enhancing effect of S-1670 in the small intestine decreased as the molecular weights of drugs increased. Moreover, we evaluated the intestinal membrane damage with or without various sugar esters. These sugar esters (0.5%(w/v)) did not increase the activities of lactate dehydrogenase (LDH), suggesting that these sugar esters did not cause serious membrane damage to the intestinal epithelium. Furthermore, these sugar esters increased membrane fluidity of lipid layers of the intestinal brush border membranes and decreased the transepithelial electrical resistance (TEER) of Caco-2 cells. Therefore, these findings suggested that these sugar esters might improve the intestinal absorption of poorly absorbable drugs via a transcellular and a paracellular pathways.

  9. Enhancing drugs absorption through third-degree burn wound eschar.

    PubMed

    Manafi, Ali; Hashemlou, Azadeh; Momeni, Parisa; Moghimi, Hamid R

    2008-08-01

    Antimicrobial therapy remains the most important method of wound infection treatment. Systemically administered antimicrobials may not achieve therapeutic levels in wound. On the other hand, some topically applied antimicrobials cannot penetrate eschar well enough. Therefore, an attempt has been made here to increase permeation of topically applied drugs through eschar using the so-called skin penetration enhancers. To perform this investigation, effects of different potential penetration enhancers on permeation of chlorhexidine, silver sulfadiazine and nitroglycerin through human third-degree burn eschar was evaluated. Results showed that water, glycerin, saline, sodium lauryl sulphate (SDS) and ethanol tend to reduce permeation of chlorhexidine through burn eschar. But, water, glycerin, hexane:ethanol and ethyl acetate:ethanol were able to increase permeation of silver sulfadiazine significantly by about 1.2-1.8 times, while saline, SDS and dimethyl sulfoxide were not able to change its permeation. Glycine showed 2.7 times enhancement toward permeation of nitroglycerin, followed by water, hexane:ethanol mixture, saline and SDS with enhancement ratios of 1.8-2.3. Urea, ethanol and citral were not able to increase permeation of nitroglycerin through eschar. This study shows that permeation of drugs through burn eschar can be improved by penetration enhancement including hydration; the effect depends on the nature of the penetrant.

  10. Ophthalmic drug delivery utilizing two-photon absorption: a novel approach to treat posterior capsule opacification

    NASA Astrophysics Data System (ADS)

    Kim, H.-C.; Träger, J.; Zorn, M.; Haberkorn, N.; Hampp, N.

    2007-07-01

    Intraocular lens (IOL) implantation is the standard technique to treat cataract. Despite recent progress in surgical procedures, posterior capsule opacification is one of the sill remaining postoperative complications of cataract surgery. We present a novel strategy to reduce the incidence of posterior capsule opacification. A drug delivery polymer suitable for manufacturing intraocular lenses has been developed which enables repeated drug release in a non-invasive and controlled manner. The therapeutic molecules are attached through a UV light sensitive linkage to the polymer backbone which is mainly responsible for the optical properties of the intraocular lenses. However, UV light can not trigger the release of drug from the polymer due to the high absorption of the cornea. We developed linkers which enable drug release by two-photon absorption induced cleavage of the linker structure. Since the two-photon absorption requires high photon densities, this does not occur in ambient light conditions in daily life, but is easily triggered by focused laser beams from a pulsed laser. In this proof-of-principle study we have employed a cyclobutane type linker and investigated the properties of the therapeutic system with the approved drugs 5-fluorouracil and chlorambucil. The controlled drug delivery was successfully demonstrated in vitro and additional cell tests confirmed that the device itself shows no cytotoxicity until photochemical activation. This presented concept can provide a powerful method in ophthalmic drug delivery.

  11. Molecular Aspects of Mucoadhesive Carrier Development for Drug Delivery and Improved Absorption

    PubMed Central

    Peppas, Nicholas A; Thomas, J. Brock; McGinity, James

    2011-01-01

    Although the oral route remains the most favored route of drug administration, major scientific obstacles prevent the effective and efficient delivery of low-molecular-mass drugs, peptides and proteins that exhibit poor solubility and permeability. Mucoadhesive dosage forms and the associated drug carriers have the ability to interact at a molecular level with the mucus gel layer that lines the epithelial surfaces of the major absorptive regions of the body. This interaction provides an increased residence time of the therapeutic formulation while localizing the drug at the site of administration. Such local, non-specific targeting leads to an increase in both oral absorption and bioavailability. Fundamental understanding of the biological processes encountered along the gastrointestinal tract can provide a sufficient engineer of carriers that are capable to provide this increase in residence time. Here we discuss the theoretical framework for achieving mucoadhesive systems as related to biomaterials science and the structure of the biomaterials used. PMID:19105897

  12. True manganese absorption in chicks as affected by dietary excesses of calcium and phosphorus

    SciTech Connect

    Wedekind, K.J.; Titgemeyer, E.C.; Twardock, A.R.; Baker, D.H. )

    1991-03-15

    Two balance studies with growing chicks were conducted to evaluate the effects of excess calcium (Ca) or excess phosphorus (P) on endogenous fecal manganese (Mn) excretion and true Mn absorption determined using an isotope-dilution technique. Supplements were added to a corn-soybean meal diet containing 1% Ca, 0.7% P and 37 mg/kg Mn. In Exp. 1, supplemental Ca levels of 0, 0.5 and 1.0% from feedgrade limestone were compared. True absorption of Mn was not affected by Ca level and averaged 2.8% for birds fed the Mn-unsupplemented diet. In Exp. 2, a 2 x 3 factorial arrangement of treatments included: 100 and 1,000 mg/kg supplemental Mn and 0, 0.4 and 0.8% added P supplied by dicalcium phosphate. Excess P decreased true absorption of Mn. In birds fed 100 mg/kg supplemental Mn, absorption of Mn decreased 22% as excess P increased from 0 to 0.8%, whereas in birds fed 1,000 mg/kg supplemental Mn, Mn absorption decreased 58% as a result of 0.8% P supplementation. These results confirm that excess Ca has little effect while excess P has a marked effect on gut absorption of Mn.

  13. [CH4 absorption and its affecting factors in a wheat field with conservation tillage].

    PubMed

    Zhao, Jian-bo; Li, Zeng-jia; Chi, Shu-jun; Ning, Tang-yuan; Gu, Shu-bo; Qiu, Li-qun; Wang, Yun; Jiang, Xiao-dong

    2008-11-01

    In order to understand the relationships between CH4 fluxes and its affecting factors in a wheat field with conservation tillage, the CH4 fluxes in two wheat fields, one with conservation tillage and the another with conventional tillage, were measured in situ by static chamber-GC method, with soil temperature and soil moisture and inorganic nitrogen contents determined at the same time. The results showed that these two fields had an obvious and similar seasonal variation pattern of CH4 fluxes, but the average and seasonal CH4 absorption fluxes differed significantly. In the growth period of wheat, the fields were the sink of CH4, and the CH4 absorption fluxes was in the order of conventional tillage with no straw returning (CN) > conventional tillage with straw returning (CS) > subsoiling with straw returning (PS) > harrowing with straw returning (HS) > rotary tillage with straw returning (RS) > no tillage with straw covered (NS). Comparing with conventional tillage, conservation tillage reduced the CH4 absorption fluxes. In conservation tillage, the CH4 absorption fluxes was positively correlated with soil temperature but negatively correlated with soil moisture content; while in conventional tillage, the CH4 absorption fluxes had no significant correlations with the two factors. In all treatments, there was a significant negative correlation between CH4 absorption fluxes and soil NH4+ -N content.

  14. Concomitant intake of alcohol may increase the absorption of poorly soluble drugs.

    PubMed

    Fagerberg, Jonas H; Sjögren, Erik; Bergström, Christel A S

    2015-01-25

    Ethanol can increase the solubility of poorly soluble and hence present a higher drug concentration in the gastrointestinal tract. This may produce a faster and more effective absorption resulting in variable and/or high drug plasma concentrations, both of which can lead to adverse drug reactions. In this work we therefore studied the solubility and absorption effects of nine diverse compounds when ethanol was present. The apparent solubility was measured using the μDiss Profiler Plus (pION, MA) in four media representing gastric conditions with and without ethanol. The solubility results were combined with in-house data on solubility in intestinal fluids (with and without ethanol) and pharmacokinetic parameters extracted from the literature and used as input in compartmental absorption simulations using the software GI-Sim. Apparent solubility increased more than 7-fold for non-ionized compounds in simulated gastric fluid containing 20% ethanol. Compounds with weak base functions (cinnarizine, dipyridamole and terfenadine) were completely ionized at the studied gastric pH and their solubility was therefore unaffected by ethanol. Compounds with low solubility in intestinal media and a pronounced solubility increase due to ethanol in the upper gastric compartments showed an increased absorption in the simulations. The rate of absorption of the acidic compounds indomethacin and indoprofen was slightly increased but the extent of absorption was unaffected as the complete doses were readily absorbed even without ethanol. This was likely due to a high apparent solubility in the intestinal compartment where the weak acids are ionized. The absorption of the studied non-ionizable compounds increased when ethanol was present in the gastric and intestinal media. These results indicate that concomitant intake of alcohol may significantly increase the solubility and hence, the plasma concentration for non-ionizable, lipophilic compounds with the potential of adverse drug

  15. Influence of acute uraemia on percutaneous absorption of nonsteroidal anti-inflammatory drugs.

    PubMed

    Príborský, J; Takayama, K; Nagai, T

    1998-01-01

    The influence of uraemia on percutaneous absorption of three model drugs (diclofenac, ibuprofen and indomethacin) which are eliminated entirely via nonrenal route was investigated in the rats. Following day after bilateral nephrectomy (BUN levels were between 30-50 mmol/l), gel ointment containing drugs under test was applied on the abdominal site of the skin. Comparing with the sham operated controls the percutaneous absorption significantly decreased in all three challenged substances. Influence on percutaneous absorption of indomethacin was investigated more in depth as this compound can serve as a model for other nonsteroid anti-inflammatory drugs. The 50 mmol/l concentration of urea (equal to uraemia) added to the gel ointment did not influence percutaneous absorption while 10% concentration of urea decreased percutaneous absorption of indomethacin approximately 5 times. Solubility of indomethacin increased in the presence of 10% urea in the gel more than two times. Elimination ratios Q0 were estimated to find if there is any effect on pharmacokinetics linked directly to the renal elimination. None of such changes were observed.

  16. Rate- and Extent-Limiting Factors of Oral Drug Absorption: Theory and Applications.

    PubMed

    Sugano, Kiyohiko; Terada, Katsuhide

    2015-09-01

    The oral absorption of drugs has been represented by various concepts such as the absorption potential, the maximum absorbable dose, the biopharmaceutics classification system, and in vitro-in vivo correlation. The aim of this article is to provide an overview of the theoretical relationships between these concepts. It shows how a simple analytical solution for the fraction of a dose absorbed (Fa equation) can offer a theoretical base to tie together the various concepts, and discusses how this solution relates to the rate-limiting cases of oral drug absorption. The article introduces the Fa classification system as a framework in which all the above concepts were included, and discusses its applications for food effect prediction, active pharmaceutical ingredient form selection, formulation design, and biowaiver strategy.

  17. Factors affecting the development of adverse drug reactions (Review article)

    PubMed Central

    Alomar, Muaed Jamal

    2013-01-01

    Objectives To discuss the effect of certain factors on the occurrence of Adverse Drug Reactions (ADRs). Data Sources A systematic review of the literature in the period between 1991 and 2012 was made based on PubMed, the Cochrane database of systematic reviews, EMBASE and IDIS. Key words used were: medication error, adverse drug reaction, iatrogenic disease factors, ambulatory care, primary health care, side effects and treatment hazards. Summary Many factors play a crucial role in the occurrence of ADRs, some of these are patient related, drug related or socially related factors. Age for instance has a very critical impact on the occurrence of ADRs, both very young and very old patients are more vulnerable to these reactions than other age groups. Alcohol intake also has a crucial impact on ADRs. Other factors are gender, race, pregnancy, breast feeding, kidney problems, liver function, drug dose and frequency and many other factors. The effect of these factors on ADRs is well documented in the medical literature. Taking these factors into consideration during medical evaluation enables medical practitioners to choose the best drug regimen. Conclusion Many factors affect the occurrence of ADRs. Some of these factors can be changed like smoking or alcohol intake others cannot be changed like age, presence of other diseases or genetic factors. Understanding the different effects of these factors on ADRs enables healthcare professionals to choose the most appropriate medication for that particular patient. It also helps the healthcare professionals to give the best advice to patients. Pharmacogenomics is the most recent science which emphasizes the genetic predisposition of ADRs. This innovative science provides a new perspective in dealing with the decision making process of drug selection. PMID:24648818

  18. Seismic signatures of carbonate caves affected by near-surface absorptions

    NASA Astrophysics Data System (ADS)

    Rao, Ying; Wang, Yanghua

    2015-12-01

    The near-surface absorption within a low-velocity zone generally has an exponential attenuation effect on seismic waves. But how does this absorption affect seismic signatures of karstic caves in deep carbonate reservoirs? Seismic simulation and analysis reveals that, although this near-surface absorption attenuates the wave energy of a continuous reflection, it does not alter the basic kinematic shape of bead-string reflections, a special seismic characteristic associated with carbonate caves in the Tarim Basin, China. Therefore, the bead-strings in seismic profiles can be utilized, with a great certainty, for interpreting the existence of caves within the deep carbonate reservoirs and for evaluating their pore spaces. Nevertheless, the difference between the central frequency and the peak frequency is increased along with the increment in the absorption. While the wave energy of bead-string reflections remains strong, due to the interference of seismic multiples generated by big impedance contrast between the infill materials of a cave and the surrounding carbonate rocks, the central frequency is shifted linearly with respect to the near-surface absorption. These two features can be exploited simultaneously, for a stable attenuation analysis of field seismic data.

  19. Mechanisms of membrane transport of poorly soluble drugs: role of micelles in oral absorption processes.

    PubMed

    Yano, Koji; Masaoka, Yoshie; Kataoka, Makoto; Sakuma, Shinji; Yamashita, Shinji

    2010-03-01

    Micelles formed in the GI tract by bile acid and lecithin play an important role in oral absorption of poorly soluble drugs. In this situation, the drug molecules are present in equilibrium between the free and micellar states. In this study, the relationship between the free drug concentration and the membrane permeability of poorly soluble drugs was examined. Permeability across a Caco-2 monolayer and a dialysis membrane were measured in a side-by-side chamber system. The concentrations of sodium taurocholate (NaTC) and lecithin were varied to allow measurement of membrane permeability at different concentrations of free drugs. For troglitazone, hexylparaben, and heptylparaben, an increase in the NaTC and lecithin concentrations caused the permeability across the Caco-2 monolayer to decrease slightly, whereas the permeability across the dialysis membrane decreased markedly. In contrast, the changes in permeability of griseofulvin with an increased micelle concentration were similar for the Caco-2 monolayer and the dialysis membrane. Assuming that the permeability for the dialysis membrane reflects the free drug concentration in the medium, these results suggest that troglitazone and alkylparabens, but not griseofulvin, can partition directly from micelles to Caco-2 monolayers. This mechanism may contribute to oral absorption of drugs that are poorly soluble in water. PMID:19743502

  20. An analytical solution for the model of drug distribution and absorption in small intestine

    NASA Astrophysics Data System (ADS)

    Mingyu, Xu

    1990-11-01

    According to the physiological and anatomical characteristics of small intestine, neglecting the effect of its motility on the distribution and absorption of drug and nutrient, Y. Miyamoto et al.[1] proposed a model of two-dimensional laminar flow in a circular porous tube with permeable wall and calculated the concentration profile of drug by numerical analysis. In this paper, we give a steady state analytical solution of the above model including deactivation term. The obtained results are in agreement with the results of their numerical analysis. Moreover the analytical solution presented in this paper reveals the relation among the physiological parameters of the model and describes the basic absorption rule of drug and nutrient through the intestinal wall and hence provides a theoretical basis for determining the permeability and reflection coefficient through in situ experiments.

  1. Terahertz absorption and reflection imaging of carcinoma-affected colon tissues embedded in paraffin

    NASA Astrophysics Data System (ADS)

    Wahaia, Faustino; Kasalynas, Irmantas; Venckevicius, Rimvydas; Seliuta, Dalius; Valusis, Gintaras; Urbanowicz, Andrzej; Molis, Gediminas; Carneiro, Fatima; Carvalho Silva, Catia D.; Granja, Pedro L.

    2016-03-01

    In the present study, dehydrated human colon tissues embedded in paraffin were studied at THz frequency. A compact THz imaging system with high numerical aperture optics was developed for the analysis of adenocarcinoma-affected colon sections, in transmission and reflection geometry. A comprehensive analysis of the THz images revealed a contrast up to 23% between the neoplastic and control tissues. Absorption and reflection THz images demonstrated the possibility to distinguish adenocarcinoma-affected areas even without water in the tissue, as the main contrast mechanism in THz measurements has been observed to be water absorption in in vivo or freshly excised tissues. The present results corroborate with previous histologic findings in the same tissues, and confirm that the contrast prevails even in dehydrated tissues.

  2. A microdialysis model to examine nasal drug delivery and olfactory absorption in rats using lidocaine hydrochloride as a model drug.

    PubMed

    Bagger, Morten; Bechgaard, Erik

    2004-01-28

    Targeting of the central nervous system by direct drug transport from the nose to the brain has gained increased attention through the last decade. In the present study, a model for olfactory drug absorption has been investigated using intravenous and unilateral nasal administration of lidocaine hydrochloride in rats. To investigate the possible drug delivery aspects of this route of transport to a central part of the brain a microdialysis model using in vivo recovery by calibrator was applied to the systemic blood and to right and left striatum. The integrity of the blood-brain barrier was evaluated following microdialysis probe implantation. The in vivo experiments were carried out as a cross-over study in rats. The drainage from the nasal cavity was not restricted by occlusion. It was found that true unbound lidocaine concentrations could be calculated from in vivo recovery measurements of retrodialysis of prilocaine hydrochloride. The relative in vivo recoveries in striatum (11.3%) and blood (24.0%) were significantly lower than in vitro (31.3 and 44.9%). The blood-brain barrier was found to retain its physical integrity when evaluated one hour after probe implantation. From pharmacokinetic modelling of the time-concentration curves it was found that the absorption rates and area under the curve (AUC) values of lidocaine in left and right striatum were not statistically different following nasal and intravenous administration, respectively. The average nasal bioavailabilities of lidocaine in blood, left and right striatum were 85, 103 and 129%, respectively. It was concluded that no significant olfactory absorption to striatum was evident in the present study. However, the method should be applicable to studies of drug delivery to blood and brain following nasal administration of other drugs.

  3. Nano-based drug delivery system enhances the oral absorption of lipophilic drugs with extensive presystemic metabolism.

    PubMed

    Zhang, Zhiwen; Gao, Fang; Jiang, Shijun; Ma, Li; Li, Yaping

    2012-10-01

    Oral administration remains the most preferred route for the treatment of many diseases due to its convenience and adaptability. However, the presystemic metabolism may be an important barrier that prevents lipophilic drugs from achieving their pharmacological effects following oral delivery. Nano-based drug delivery system provides an effective strategy to reduce the presystemic metabolism and increase the systemic exposure of lipophilic drugs. In this review, we described the physiological factors affecting the presystemic metabolism of lipophilic drugs, intestinal transport of nanosystems, strategy of nanosystems to avoid the presystemic metabolism, and the current application of various oral nanosystems including lipid and polymeric nanocarriers. The nano-based drug delivery system has a lot of potential for reducing the presystemic metabolism and enhancing the bioavailability of orally administrated lipophilic drugs.

  4. Application of Absorption Modeling in Rational Design of Drug Product Under Quality-by-Design Paradigm.

    PubMed

    Kesisoglou, Filippos; Mitra, Amitava

    2015-09-01

    Physiologically based absorption models can be an important tool in understanding product performance and hence implementation of Quality by Design (QbD) in drug product development. In this report, we show several case studies to demonstrate the potential application of absorption modeling in rational design of drug product under the QbD paradigm. The examples include application of absorption modeling—(1) prior to first-in-human studies to guide development of a formulation with minimal sensitivity to higher gastric pH and hence reduced interaction when co-administered with PPIs and/or H2RAs, (2) design of a controlled release formulation with optimal release rate to meet trough plasma concentrations and enable QD dosing, (3) understanding the impact of API particle size distribution on tablet bioavailability and guide formulation design in late-stage development, (4) assess impact of API phase change on product performance to guide specification setting, and (5) investigate the effect of dissolution rate changes on formulation bioperformance and enable appropriate specification setting. These case studies are meant to highlight the utility of physiologically based absorption modeling in gaining a thorough understanding of the product performance and the critical factors impacting performance to drive design of a robust drug product that would deliver the optimal benefit to the patients.

  5. In vitro percutaneous absorption enhancement of a lipophilic drug tamoxifen by terpenes.

    PubMed

    Gao, S; Singh, J

    1998-02-12

    Tamoxifen is a highly lipophilic drug that is widely used in breast malignancies and also as a prophylactic therapy in women at high risk for the development of this disease. Recently, the terpenes have been reported to show an enhancement effect on percutaneous drug absorption. The effect of terpenes (e.g. carvone, 1,8-cineole, menthol, and thymol) was studied on the in vitro percutaneous absorption of tamoxifen through porcine epidermis. The above terpenes (5% w/v) in combination with 50% ethanol significantly (P < 0.01) increased the permeability coefficient of tamoxifen in comparison to the control (50% ethanol). The solubility of tamoxifen was determined in the control and enhancer solutions to correct the permeability enhancement by way of fractional solubility adjustment. Binding of tamoxifen to powdered stratum corneum from control and enhancer solutions was also determined. Binding studies reveal that the enhancement in the permeability coefficient of tamoxifen by menthol and thymol is due at least in part, to improvement in the partitioning of the drug to the stratum corneum. In conclusion, terpenes in combination with ethanol can be used to enhance the percutaneous absorption of the highly lipophilic drug tamoxifen. PMID:9685917

  6. Drug marker absorption in relation to pellet size, gastric motility and viscous meals in humans

    NASA Technical Reports Server (NTRS)

    Rhie, J. K.; Hayashi, Y.; Welage, L. S.; Frens, J.; Wald, R. J.; Barnett, J. L.; Amidon, G. E.; Putcha, L.; Amidon, G. L.

    1998-01-01

    PURPOSE: The objective of this study was to evaluate drug marker absorption in relation to the gastric emptying (GE) of 0.7 mm and 3.6 mm enteric coated pellets as a function of viscosity and the underlying gastric motility. METHODS: Twelve subjects were evaluated in a 3-way crossover study. 0.7 mm caffeine and 3.6 mm acetaminophen enteric coated pellets were concurrently administered with a viscous caloric meal at the levels of 4000, 6000 and 8000 cP. Gastric motility was simultaneously measured with antral manometry and compared to time events in the plasma profiles of the drug markers. RESULTS: Caffeine, from the 0.7 mm pellets, was observed significantly earlier in the plasma than acetaminophen, from the 3.6 mm pellets, at all levels of viscosity. Motility related size differentiated GE was consistently observed at all viscosity levels, however, less variability was observed with the 4000 cP meal. Specifically, the onset of absorption from the of 3.6 mm pellets correlated with the onset of Phase II fasted state contractions (r = 0.929, p < 0.01). CONCLUSIONS: The timeframe of drug marker absorption and the onset of motility events were not altered within the range of viscosities evaluated. Rather, the differences in drug marker profiles from the non-digestible solids were most likely the result of the interaction between viscosity and motility influencing antral flow dynamics. The administration of the two sizes of pellets and a viscous caloric meal with subsequent monitoring of drug marker profiles is useful as a reference to assess the influence of motility patterns on the absorption profile of orally administered agents.

  7. Gene duplication and divergence affecting drug content in Cannabis sativa.

    PubMed

    Weiblen, George D; Wenger, Jonathan P; Craft, Kathleen J; ElSohly, Mahmoud A; Mehmedic, Zlatko; Treiber, Erin L; Marks, M David

    2015-12-01

    Cannabis sativa is an economically important source of durable fibers, nutritious seeds, and psychoactive drugs but few economic plants are so poorly understood genetically. Marijuana and hemp were crossed to evaluate competing models of cannabinoid inheritance and to explain the predominance of tetrahydrocannabinolic acid (THCA) in marijuana compared with cannabidiolic acid (CBDA) in hemp. Individuals in the resulting F2 population were assessed for differential expression of cannabinoid synthase genes and were used in linkage mapping. Genetic markers associated with divergent cannabinoid phenotypes were identified. Although phenotypic segregation and a major quantitative trait locus (QTL) for the THCA/CBDA ratio were consistent with a simple model of codominant alleles at a single locus, the diversity of THCA and CBDA synthase sequences observed in the mapping population, the position of enzyme coding loci on the map, and patterns of expression suggest multiple linked loci. Phylogenetic analysis further suggests a history of duplication and divergence affecting drug content. Marijuana is distinguished from hemp by a nonfunctional CBDA synthase that appears to have been positively selected to enhance psychoactivity. An unlinked QTL for cannabinoid quantity may also have played a role in the recent escalation of drug potency. PMID:26189495

  8. Gene duplication and divergence affecting drug content in Cannabis sativa.

    PubMed

    Weiblen, George D; Wenger, Jonathan P; Craft, Kathleen J; ElSohly, Mahmoud A; Mehmedic, Zlatko; Treiber, Erin L; Marks, M David

    2015-12-01

    Cannabis sativa is an economically important source of durable fibers, nutritious seeds, and psychoactive drugs but few economic plants are so poorly understood genetically. Marijuana and hemp were crossed to evaluate competing models of cannabinoid inheritance and to explain the predominance of tetrahydrocannabinolic acid (THCA) in marijuana compared with cannabidiolic acid (CBDA) in hemp. Individuals in the resulting F2 population were assessed for differential expression of cannabinoid synthase genes and were used in linkage mapping. Genetic markers associated with divergent cannabinoid phenotypes were identified. Although phenotypic segregation and a major quantitative trait locus (QTL) for the THCA/CBDA ratio were consistent with a simple model of codominant alleles at a single locus, the diversity of THCA and CBDA synthase sequences observed in the mapping population, the position of enzyme coding loci on the map, and patterns of expression suggest multiple linked loci. Phylogenetic analysis further suggests a history of duplication and divergence affecting drug content. Marijuana is distinguished from hemp by a nonfunctional CBDA synthase that appears to have been positively selected to enhance psychoactivity. An unlinked QTL for cannabinoid quantity may also have played a role in the recent escalation of drug potency.

  9. The antiepileptic drug phenytoin affects sodium transport in toad epithelium.

    PubMed

    Suwalsky, Mario; Mennickent, Sigrid; Norris, Beryl; Cárdenas, Hernan

    2006-01-01

    The effects of phenytoin on isolated Pleurodema thaul toad skin were investigated. Low (micromolar) concentrations of the antiepileptic agent applied to the outside surface of the toad epithelium increased the electrical parameters (short-circuit current and potential difference) by over 40%, reflecting stimulation of Na(+) transport, whereas higher (millimolar concentrations, outside and inside surface) decreased both electric parameters, the effect being greater at the inside surface (40% and 80% decrease, respectively). The amiloride test showed that the stimulatory effect was accompanied by an increase and the inhibitory effect by a decrease in the sodium electromotive force (ENa). It is concluded that the drug interaction with membrane lipid bilayers might result in a distortion of the lipid-protein interface contributing to disturbance of Na(+) epithelial channel activity. After applying the Na(+)-K(+)-ATPase blocker ouabain and replacing the Na(+) ions in the outer Ringer's solution by choline, it was concluded that both active and passive transport are involved in sodium absorption, although active transport predominates. PMID:16314149

  10. Positively charged polyethylenimines enhance nasal absorption of the negatively charged drug, low molecular weight heparin.

    PubMed

    Yang, Tianzhi; Hussain, Alamdar; Bai, Shuhua; Khalil, Ikramy A; Harashima, Hideyoshi; Ahsan, Fakhrul

    2006-10-27

    This study tests the hypothesis that positively charged polyethylenimines (PEIs) enhance nasal absorption of low molecular weight heparin (LMWH) by reducing the negative surface charge of the drug molecule. Physical interactions between PEIs and LMWH were studied by Fourier transform infrared (FTIR) spectroscopy, particle size analysis, conductivity measurements, zeta potential analysis, and azure A assay. The efficacy of PEIs in enhancing nasal absorption of LMWH was studied by administering LMWH formulated with PEI into the nose of anesthetized rats and monitoring drug absorption by measuring plasma anti-factor Xa activity. The metabolic stability of LMWH was evaluated by incubating the drug in rat nasal mucosal homogenates. FTIR spectra of the LMWH-PEI formulation showed a shift in peak position compared to LMWH or PEI alone. Decreases in conductivity, zeta potential and the amount of free LMWH in the PEI-LMWH formulation, as revealed by azure A assay, suggest that PEIs possibly neutralize the negative surface charge of LMWH. The efficacy of PEI in enhancing the bioavailability of nasally administered LMWH can be ranked as PEI-1000 kDa>or=PEI-750 kDa>PEI-25 kDa. When PEI-1000 kDa was used at a concentration of 0.25%, there was a 4-fold increase in both the absolute and relative bioavailabilities of LMWH compared to the control formulation. Overall, these results indicate that polyethylenimines can be used as potential carriers for nasally administered LMWHs. PMID:17023085

  11. Probabilistic modeling of percutaneous absorption for risk-based exposure assessments and transdermal drug delivery.

    SciTech Connect

    Ho, Clifford Kuofei

    2004-06-01

    Chemical transport through human skin can play a significant role in human exposure to toxic chemicals in the workplace, as well as to chemical/biological warfare agents in the battlefield. The viability of transdermal drug delivery also relies on chemical transport processes through the skin. Models of percutaneous absorption are needed for risk-based exposure assessments and drug-delivery analyses, but previous mechanistic models have been largely deterministic. A probabilistic, transient, three-phase model of percutaneous absorption of chemicals has been developed to assess the relative importance of uncertain parameters and processes that may be important to risk-based assessments. Penetration routes through the skin that were modeled include the following: (1) intercellular diffusion through the multiphase stratum corneum; (2) aqueous-phase diffusion through sweat ducts; and (3) oil-phase diffusion through hair follicles. Uncertainty distributions were developed for the model parameters, and a Monte Carlo analysis was performed to simulate probability distributions of mass fluxes through each of the routes. Sensitivity analyses using stepwise linear regression were also performed to identify model parameters that were most important to the simulated mass fluxes at different times. This probabilistic analysis of percutaneous absorption (PAPA) method has been developed to improve risk-based exposure assessments and transdermal drug-delivery analyses, where parameters and processes can be highly uncertain.

  12. Two-photon absorption-induced drug delivery from polymers for medical applications

    NASA Astrophysics Data System (ADS)

    Kim, Hee-Cheol; Kreiling, Stefan; Haertner, Sebastian; Hesse, Lutz; Greiner, Andreas; Hampp, Norbert A.

    2004-06-01

    Novel polymeric materials carrying a drug depot have been developed which are suitable for fabrication of photochemically modulated drug delivery devices. In order to avoid uncontrolled drug release the drug is covalently attached to the polymer backbone using a photo-active linker. Controlled drug release from the polymer can be accomplished either via single-photon excitation or by two-photon absorption (TPA). In particular the second possibility is of interest for applications where exposure to day light or UV light may not be omitted. One example are polymeric intraocular lenses (IOL), which are implanted instead of the opaque natural lens during cataract surgery. Secondary cataract formation is quite often observed after implantation of polymeric IOLs. In this study the well known cell toxic agent 5-fluorouracil (5FU) attached to a methylmethacrylate-based polymer was investigated as an IOL which can upon photochemical excitation release 5FU in order to treat or to prevent secondary cataract formation. The photochemical cleavage of the linker molecule was analyzed with single- and two-photon excitation. UV/VIS spectroscopy and HPLC analysis confirmed the release of 5FU form the polymer backbone. The diffusion of the drug precursor out from the polymer as well as the hydrolysis of the drug precursor which leads to 5FU formation were investigated in vitro.

  13. Modeling the influence of cyclodextrins on oral absorption of low solubility drugs: II. Experimental validation.

    PubMed

    Gamsiz, Ece Dilber; Miller, Lee; Thombre, Avinash G; Ahmed, Imran; Carrier, Rebecca Lyn

    2010-02-01

    A model was developed for predicting the influence of cyclodextrins (CDs) delivered as a physical mixture with drug on oral absorption. CDs are cyclic oligosaccharides which form inclusion complexes with many drugs and are often used as solubilizing agents. The purpose of this work is to compare the simulation predictions with in vitro as well as in vivo experimental results to test the model's ability to capture the influence of CD on key processes in the gastrointestinal (GI) tract environment. Dissolution and absorption kinetics of low solubility drugs (Naproxen and Nifedipine) were tested in the presence and absence of CD in a simulated gastrointestinal environment. Model predictions were also compared with in vivo experimental results (Glibenclamide and Carbamazepine) from the literature to demonstrate the model's ability to predict oral bioavailability. Comparisons of simulation and experimental results indicate that a model incorporating the influence of CD (delivered as a physical mixture) on dissolution kinetics and binding of neutral drug can predict trends in the influence of CD on bioavailability. Overall, a minimal effect of CD dosed as a physical mixture was observed and predicted. Modeling may aid in enabling rational design of CD containing formulations.

  14. Toward an increased understanding of the barriers to colonic drug absorption in humans: implications for early controlled release candidate assessment.

    PubMed

    Tannergren, Christer; Bergendal, Anna; Lennernäs, Hans; Abrahamsson, Bertil

    2009-01-01

    The purpose of this study was to increase the understanding of in vivo colonic drug absorption in humans by summarizing and evaluating all regional in vivo human absorption data with focus on the interpretation of the colonic absorption data in relation to intestinal permeability and solubility. In addition, the usefulness of the Biopharmaceutics Classification System (BCS) in early assessment of the in vivo colonic absorption potential of controlled release drug candidates was investigated. Clinical regional absorption data (Cmax, Tmax, and AUC) of 42 drugs were collected from journal articles, abstracts, and internal reports, and the relative bioavailability in the colon (Frel(colon)) was obtained directly or calculated. Bioavailability, fraction dose absorbed, and information if the compounds were substrates for P-glycoprotein (P-gp) or cytochrome P450 3A (CYP3A) were also obtained. The BCS I drugs were well absorbed in the colon (Frel(colon) > 70%), although some drugs had lower values due to bacterial degradation in the colon. The low permeability drugs (BCS III/IV) had a lower degree of absorption in the colon (Frel(colon) < 50%). There was a clear correlation between in vitro Caco-2 permeability and Frel(colon), and atenolol and metoprolol may function as permeability markers for low and high colonic absorption, respectively. No obvious effect of P-gp on the colonic absorption of the drugs in this study was detected. There was insufficient data available to fully assess the impact of low solubility and slow dissolution rate. The estimated in vivo fractions dissolved of the only two compounds administered to the colon as both a solution and as solid particles were 55% and 92%, respectively. In conclusion, permeability and solubility are important barriers to colonic absorption in humans, and in vitro testing of these properties is recommended in early assessment of colonic absorption potential.

  15. Enhancement of oral absorption of curcumin by self-microemulsifying drug delivery systems.

    PubMed

    Cui, Jing; Yu, Bo; Zhao, Yu; Zhu, Weiwei; Li, Houli; Lou, Hongxiang; Zhai, Guangxi

    2009-04-17

    Curcumin is a poorly water-soluble drug and its oral bioavailability is very low. A new self-microemulsifying drug delivery system (SMEDDS) has been successfully developed to improve the solubility and oral absorption of curcumin. Suitable compositions of SMEDDS formulation were screened via solubility studies of curcumin and compatibility tests. The formulation of curcumin-loaded SMEDDS was optimized by a simplex lattice experiment design. The optimal formulation of SMEDDS was comprised of 57.5% surfactant (emulsifier OP:Cremorphor EL = 1:1), 30.0% co-surfactant (PEG 400) and 12.5% oil (ethyl oleate). The solubility of curcumin (21 mg/g) significantly increased in SMEDDS. The average particle size of SMEDDS-containing curcumin was about 21 nm when diluted in water. No significant variations in particle size and curcumin content in SMEDDS were observed over a period of 3 months at 4 degrees C. The spherical shape of microemulsion droplet was observed under TEM. The dissolution study in vitro showed that more than 95% of curcumin in SMEDDS could be dissolved in pH 1.2 or pH 6.8 buffer solutions in 20 min, however, less than 2% for crude curcumin in 60 min.The in situ absorption property of curcumin-loaded SMEDDS was evaluated in intestines of rats. The results showed the absorption of curcumin in SMEDDS was via passive transfer by diffusion across the lipid membranes. The results of oral absorption experiment in mice showed that SMEDDS could significantly increase the oral absorption of curcumin compared with its suspension. Our study illustrated that the developed SMEDDS formulation held great potential as a possible alternative to traditional oral formulations of curcumin.

  16. Influence of Food on Paediatric Gastrointestinal Drug Absorption Following Oral Administration: A Review

    PubMed Central

    Batchelor, Hannah K.

    2015-01-01

    The objective of this paper was to review existing information regarding food effects on drug absorption within paediatric populations. Mechanisms that underpin food–drug interactions were examined to consider potential differences between adult and paediatric populations, to provide insights into how this may alter the pharmacokinetic profile in a child. Relevant literature was searched to retrieve information on food–drug interaction studies undertaken on: (i) paediatric oral drug formulations; and (ii) within paediatric populations. The applicability of existing methodology to predict food effects in adult populations was evaluated with respect to paediatric populations where clinical data was available. Several differences in physiology, anatomy and the composition of food consumed within a paediatric population are likely to lead to food–drug interactions that cannot be predicted based on adult studies. Existing methods to predict food effects cannot be directly extrapolated to allow predictions within paediatric populations. Development of systematic methods and guidelines is needed to address the general lack of information on examining food–drug interactions within paediatric populations. PMID:27417362

  17. High-performance dispersive Raman and absorption spectroscopy as tools for drug identification

    NASA Astrophysics Data System (ADS)

    Pawluczyk, Olga; Andrey, Sam; Nogas, Paul; Roy, Andrew; Pawluczyk, Romuald

    2009-02-01

    Due to increasing availability of pharmaceuticals from many sources, a need is growing to quickly and efficiently analyze substances in terms of the consistency and accuracy of their chemical composition. Differences in chemical composition occur at very low concentrations, so that highly sensitive analytical methods become crucial. Recent progress in dispersive spectroscopy with the use of 2-dimensional detector arrays, permits for signal integration along a long (up to 12 mm long) entrance slit of a spectrometer, thereby increasing signal to noise ratio and improving the ability to detect small concentration changes. This is achieved with a non-scanning, non-destructive system. Two different methods using P&P Optica high performance spectrometers were used. High performance optical dispersion Raman and high performance optical absorption spectroscopy were employed to differentiate various acetaminophen-containing drugs, such as Tylenol and other generic brands, which differ in their ingredients. A 785 nm excitation wavelength was used in Raman measurements and strong Raman signals were observed in the spectral range 300-1800 cm-1. Measurements with the absorption spectrometer were performed in the wavelength range 620-1020 nm. Both Raman and absorption techniques used transmission light spectrometers with volume phase holographic gratings and provided sufficient spectral differences, often structural, allowing for drug differentiation.

  18. Enhanced dissolution and oral absorption of tacrolimus by supersaturable self-emulsifying drug delivery system

    PubMed Central

    Lee, Dae Ro; Ho, Myoung Jin; Jung, Hyuck Jun; Cho, Ha Ra; Park, Jun Seo; Yoon, Suk-Hyun; Choi, Yong Seok; Choi, Young Wook; Oh, Chung-Hun; Kang, Myung Joo

    2016-01-01

    A new Soluplus (polyvinyl caprolactam–polyvinyl acetate–polyethylene glycol graft copolymer)-based supersaturable self-emulsifying drug delivery system (S-SEDDS) was formulated to enhance oral absorption of tacrolimus (FK506) with minimal use of oil, surfactant, and cosurfactant. A high payload supersaturable system (S-SEDDS) was prepared by incorporating Soluplus, as a precipitation inhibitor, to SEDDS consisting of Capmul MCM, Cremophor EL, and Transcutol (FK506:vehicle:Soluplus =1:15:1). In vitro dissolution profile and in vitro pharmacokinetic aspect of S-SEDDS in rats were comparatively evaluated with those of conventional SEDDS formulas containing four times greater content of vehicle components (FK506:vehicle =1:60). Both formulations formed spherical drug-loaded microemulsion <70 nm in size when in contact with aqueous medium. In an in vitro dissolution test in a nonsink condition, the amphiphilic polymer noticeably retarded drug precipitation and maintained >80% of accumulated dissolution rate for 24 hours, analogous to that from conventional SEDDS. Moreover, pharmacokinetic parameters of the maximum blood concentration and area under the curve from S-SEDDS formula in rats were not statistically different (P>0.05) than those of conventional SEDDS. The results suggest that the Soluplus-based supersaturable system can be an alternative to achieve a comparable in vitro dissolution profile and in vivo oral absorption with conventional SEDDS, with minimal use of vehicle ingredients. PMID:27051286

  19. Enhanced dissolution and oral absorption of tacrolimus by supersaturable self-emulsifying drug delivery system.

    PubMed

    Lee, Dae Ro; Ho, Myoung Jin; Jung, Hyuck Jun; Cho, Ha Ra; Park, Jun Seo; Yoon, Suk-Hyun; Choi, Yong Seok; Choi, Young Wook; Oh, Chung-Hun; Kang, Myung Joo

    2016-01-01

    A new Soluplus (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer)-based supersaturable self-emulsifying drug delivery system (S-SEDDS) was formulated to enhance oral absorption of tacrolimus (FK506) with minimal use of oil, surfactant, and cosurfactant. A high payload supersaturable system (S-SEDDS) was prepared by incorporating Soluplus, as a precipitation inhibitor, to SEDDS consisting of Capmul MCM, Cremophor EL, and Transcutol (FK506:vehicle:Soluplus =1:15:1). In vitro dissolution profile and in vitro pharmacokinetic aspect of S-SEDDS in rats were comparatively evaluated with those of conventional SEDDS formulas containing four times greater content of vehicle components (FK506:vehicle =1:60). Both formulations formed spherical drug-loaded microemulsion <70 nm in size when in contact with aqueous medium. In an in vitro dissolution test in a nonsink condition, the amphiphilic polymer noticeably retarded drug precipitation and maintained >80% of accumulated dissolution rate for 24 hours, analogous to that from conventional SEDDS. Moreover, pharmacokinetic parameters of the maximum blood concentration and area under the curve from S-SEDDS formula in rats were not statistically different (P>0.05) than those of conventional SEDDS. The results suggest that the Soluplus-based supersaturable system can be an alternative to achieve a comparable in vitro dissolution profile and in vivo oral absorption with conventional SEDDS, with minimal use of vehicle ingredients. PMID:27051286

  20. Abuse of Prescription (Rx) Drugs Affects Young Adults Most

    MedlinePlus

    ... Trends and Alerts Alcohol Club Drugs Cocaine Hallucinogens Heroin Inhalants Marijuana MDMA (Ecstasy/Molly) Methamphetamine Opioids Prescription ... died from overdoses of any other drug, including heroin and cocaine combined—and many more needed emergency ...

  1. Influence of pH on Drug Absorption from the Gastrointestinal Tract: A Simple Chemical Model

    NASA Astrophysics Data System (ADS)

    Hickman, Raymond J. S.; Neill, Jane

    1997-07-01

    A simple model of the gastrointestinal tract is obtained by placing ethyl acetate in contact with water at pH 2 and pH 8 in separate test tubes. The ethyl acetate corresponds to the lipid material lining the tract while the water corresponds to the aqueous contents of the stomach (pH 2) and intestine (pH 8). The compounds aspirin, paracetamol and 3-aminophenol are used as exemplars of acidic, neutral and basic drugs respectively to illustrate the influence which pH has on the distribution of each class of drug between the aqueous and organic phases of the model. The relative concentration of drug in the ethyl acetate is judged by applying microlitre-sized samples of ethyl acetate to a layer of fluorescent silica which, after evaporation of the ethyl acetate, is viewed under an ultraviolet lamp. Each of the three drugs, if present in the ethyl acetate, becomes visible as a dark spot on the silica layer. The observations made in the model system correspond well to the patterns of drug absorption from the gastrointestinal tract described in pharmacology texts and these observations are convincingly explained in terms of simple acid-base chemistry.

  2. The rule of unity for human intestinal absorption 2: application to pharmaceutical drugs that are marketed as salts.

    PubMed

    Patel, Raj B; Admire, Brittany; Yalkowsky, Samuel H

    2015-01-01

    The efficiency of the human intestinal absorption (HIA) of the 59 drugs which are marketed as salts is predicted using the rule of unity. Intrinsic aqueous solubilities and partition coefficients along with the drug dose are used to calculate modified absorption potential (MAP) values. These values are shown to be related to the fraction of the dose that is absorbed upon oral administration in humans (FA). It is shown that the MAP value can distinguish between drugs that are poorly absorbed (FA <0.5) and those that are well absorbed (FA ≥ 0.5). Inspection of the data as well as a receiver operative characteristic (ROC) plot shows that a single critical MAP value can be used for predicting efficient human absorption of drugs. This forms the basis of a simple rule of unity based solely on in vitro data for predicting whether or not a drug will be well absorbed at a given dose.

  3. Factors Affecting the Absorption, Metabolism, and Excretion of Cocoa Flavanols in Humans.

    PubMed

    Cifuentes-Gomez, Tania; Rodriguez-Mateos, Ana; Gonzalez-Salvador, Isidro; Alañon, María Elena; Spencer, Jeremy P E

    2015-09-01

    Cocoa is rich in a subclass of flavonoids known as flavanols, the cardiovascular health benefits of which have been extensively reported. The appearance of flavanol metabolites in the systemic circulation after flavanol-rich food consumption is likely to mediate the physiological effects on the vascular system, and these levels are influenced by numerous factors, including food matrix, processing, intake, age, gender, or genetic polymorphisms, among others. This review will focus on our current understanding of factors affecting the absorption, metabolism, and excretion of cocoa flavanols in humans. Second, it will identify gaps in these contributing factors that need to be addressed to conclusively translate our collective knowledge into the context of public health, dietary guidelines, and evidence-based dietary recommendations.

  4. Human in vivo regional intestinal permeability: quantitation using site-specific drug absorption data.

    PubMed

    Sjögren, Erik; Dahlgren, David; Roos, Carl; Lennernäs, Hans

    2015-06-01

    Application of information on regional intestinal permeability has been identified as a key aspect of successful pharmaceutical product development. This study presents the results and evaluation of an approach for the indirect estimation of site-specific in vivo intestinal effective permeability (Peff) in humans. Plasma concentration-time profiles from 15 clinical studies that administered drug solutions to specific intestinal regions were collected and analyzed. The intestinal absorption rate for each drug was acquired by deconvolution, using historical intravenous data as reference, and used with the intestinal surface area and the dose remaining in the lumen to estimate the Peff. Forty-three new Peff values were estimated (15 from the proximal small intestine, 11 from the distal small intestine, and 17 from the large intestine) for 14 active pharmaceutical ingredients representing a wide range of biopharmaceutical properties. A good correlation (r(2) = 0.96, slope = 1.24, intercept = 0.030) was established between these indirect jejunal Peff estimates and jejunal Peff measurements determined directly using the single-pass perfusion double balloon technique. On average, Peff estimates from the distal small intestine and large intestine were 90% and 40%, respectively, of those from the proximal small intestine. These results support the use of the evaluated deconvolution method for indirectly estimating regional intestinal Peff in humans. This study presents the first comprehensive data set of estimated human regional intestinal permeability values for a range of drugs. These biopharmaceutical data can be used to improve the accuracy of gastrointestinal absorption predictions used in drug development decision-making.

  5. The effects of microRNA on the absorption, distribution, metabolism and excretion of drugs

    PubMed Central

    He, Y; Chevillet, J R; Liu, G; Kim, T K; Wang, K

    2015-01-01

    The importance of genetic factors (e.g. sequence variation) in the absorption, distribution, metabolism, excretion (ADME) and overall efficacy of therapeutic agents is well established. Our ability to identify, interpret and utilize these factors is the subject of much clinical investigation and therapeutic development. However, drug ADME and efficacy are also heavily influenced by epigenetic factors such as DNA/histone methylation and non-coding RNAs [especially microRNAs (miRNAs)]. Results from studies using tools, such as in silico miRNA target prediction, in vitro functional assays, nucleic acid profiling/sequencing and high-throughput proteomics, are rapidly expanding our knowledge of these factors and their effects on drug metabolism. Although these studies reveal a complex regulation of drug ADME, an increased understanding of the molecular interplay between the genome, epigenome and transcriptome has the potential to provide practically useful strategies to facilitate drug development, optimize therapeutic efficacy, circumvent adverse effects, yield novel diagnostics and ultimately become an integral component of personalized medicine. PMID:25296724

  6. Aspergillus nidulans galactofuranose biosynthesis affects antifungal drug sensitivity.

    PubMed

    Alam, Md Kausar; El-Ganiny, Amira M; Afroz, Sharmin; Sanders, David A R; Liu, Juxin; Kaminskyj, Susan G W

    2012-12-01

    The cell wall is essential for fungal survival in natural environments. Many fungal wall carbohydrates are absent from humans, so they are a promising source of antifungal drug targets. Galactofuranose (Galf) is a sugar that decorates certain carbohydrates and lipids. It comprises about 5% of the Aspergillus fumigatus cell wall, and may play a role in systemic aspergillosis. We are studying Aspergillus wall formation in the tractable model system, A. nidulans. Previously we showed single-gene deletions of three sequential A. nidulans Galf biosynthesis proteins each caused similar hyphal morphogenesis defects and 500-fold reduced colony growth and sporulation. Here, we generated ugeA, ugmA and ugtA strains controlled by the alcA(p) or niiA(p) regulatable promoters. For repression and expression, alcA(p)-regulated strains were grown on complete medium with glucose or threonine, whereas niiA(p)-regulated strains were grown on minimal medium with ammonium or nitrate. Expression was assessed by qPCR and colony phenotype. The alcA(p) and niiA(p) strains produced similar effects: colonies resembling wild type for gene expression, and resembling deletion strains for gene repression. Galf immunolocalization using the L10 monoclonal antibody showed that ugmA deletion and repression phenotypes correlated with loss of hyphal wall Galf. None of the gene manipulations affected itraconazole sensitivity, as expected. Deletion of any of ugmA, ugeA, ugtA, their repression by alcA(p) or niiA(p), OR, ugmA overexpression by alcA(p), increased sensitivity to Caspofungin. Strains with alcA(p)-mediated overexpression of ugeA and ugtA had lower caspofungin sensitivity. Galf appears to play an important role in A. nidulans growth and vigor.

  7. Determination of platinum originated from antitumoral drugs in human urine by atomic absorption spectrometric methods.

    PubMed

    da Costa, Anilton Coelho; Vieira, Mariana Antunes; Luna, Aderval Severino; de Campos, Reinaldo Calixto

    2010-10-15

    Cisplatin and carboplatin are the most common platinum-based drugs used in cancer treatment. Pharmacokinetic investigations, the evaluation of the body burden during the treatment, as well as baseline levels of platinum in humans have attracted great interest. Thus, accurate analytical methods for fast and easy Pt monitoring in clinical samples become necessary. In the present study atomic absorption spectrometric methods for the determination of platinum in the forms of cisplatin and carboplatin in human urine were investigated. Platinum, in these different forms, could be determined in urine, after simple sample dilution. Regarding electrothermal atomic absorption spectrometry, the optimum parameters were defined by a central composite design optimization. Multiplicative matrix effects were overcome by using a mixture of HCl and NaCl as modifier. The limit of detection (LOD) was 0.004 mgL(-1) of platinum in the original sample. For the analysis of more concentrated samples, high resolution continuous source flame atomic absorption spectrometry was also investigated. Flame conditions were optimized by a multivariate D-optimal design, using as response the sum of the analyte addition calibration slopes and their standard deviations. Matrix matched external calibration with PtCl(2) calibration solutions, was possible, and the LOD was 0.06 mgL(-1) in the original sample. The results obtained by the proposed procedures were also in good agreement with those obtained by an independent comparative procedure.

  8. Lipid nanoparticles with no surfactant improve oral absorption rate of poorly water-soluble drug.

    PubMed

    Funakoshi, Yuka; Iwao, Yasunori; Noguchi, Shuji; Itai, Shigeru

    2013-07-15

    A pharmacokinetic study was performed in rats to evaluate the oral absorption ratios of nanoparticle suspensions containing the poorly water-soluble compound nifedipine (NI) and two different types of lipids, including hydrogenated soybean phosphatidylcholine and dipalmitoylphosphatidylglycerol. NI-lipid nanoparticle (LN) suspensions with a mean particle size of 48.0 nm and a zeta potential of -57.2 mV were prepared by co-grinding combined with a high-pressure homogenization process. The oral administration of NI-LN suspensions to rats led to a significant increase in the NI plasma concentration, and the area under the curve (AUC) value was found to be 108 min μg mL⁻¹, indicating a 4-fold increase relative to the NI suspensions. A comparison of the pharmacokinetic parameters of the NI-LN suspensions with those of the NI solution prepared using only the surfactant polysorbate 80 revealed that although the AUC and bioavailability (59%) values were almost identical, a rapid absorption rate was still observed in the NI-LN suspensions. These results therefore indicated that lipid nanoparticles prepared using only two types of phospholipid with a mean particle size of less than 50 nm could improve the absorption of the poorly water-soluble drug.

  9. Major diet-drug interactions affecting the kinetic characteristics and hypolipidaemic properties of statins.

    PubMed

    Vaquero, M P; Sánchez Muniz, F J; Jiménez Redondo, S; Prats Oliván, P; Higueras, F J; Bastida, S

    2010-01-01

    Concomitant administration of statins with food may alter statin pharmacokinetics or pharmacodynamics, increasing the risk of adverse reactions such as myopathy or rhabdomyolysis or reducing their pharmacological action. This paper reviews major interactions between statins and dietary compounds. Consumption of pectin or oat bran together with Lovastatin reduces absorption of the drug, while alcohol intake does not appear to affect the efficacy and safety of Fluvastatin treatment. Grapefruit juice components inhibit cytochrome P-4503A4, reducing the presystemic metabolism of drugs such as Simvastatin, Lovastatin and Atorvastatin. Follow-up studies on the therapeutic effect of statins in patients consuming a Mediterranean-style diet are necessary to assure the correct prescription because the oil-statin and minor oil compound-statin possible interactions have been only briefly studied. Preliminary study suggests that olive oil can increase the hypolipaemiant effect of Simvastatin with respect sunflower oil. The consumption of polyunsaturated rich oils, throughout the cytochrome P- 450 activation could decrease the half-life of some statins and therefore their hypolipaemic effects. The statins and n-3 fatty acids combined therapy gives rise to pharmacodinamic interaction that improves the lipid profile and leads greater cardioprotection. Although statins are more effective in high endogenous cholesterol production subjects and plant sterols are more effective in high cholesterol absorption efficacy subjects, plant esterols-statins combined therapy generates very positive complementary effects. This review ends suggesting possible diet-stain interactions that require further investigations (e.g. types of olive oils, fruit juices other than grapefruit, fibre or consumption of alcoholic beverages rich in polyphenols or ethanol).

  10. Major diet-drug interactions affecting the kinetic characteristics and hypolipidaemic properties of statins.

    PubMed

    Vaquero, M P; Sánchez Muniz, F J; Jiménez Redondo, S; Prats Oliván, P; Higueras, F J; Bastida, S

    2010-01-01

    Concomitant administration of statins with food may alter statin pharmacokinetics or pharmacodynamics, increasing the risk of adverse reactions such as myopathy or rhabdomyolysis or reducing their pharmacological action. This paper reviews major interactions between statins and dietary compounds. Consumption of pectin or oat bran together with Lovastatin reduces absorption of the drug, while alcohol intake does not appear to affect the efficacy and safety of Fluvastatin treatment. Grapefruit juice components inhibit cytochrome P-4503A4, reducing the presystemic metabolism of drugs such as Simvastatin, Lovastatin and Atorvastatin. Follow-up studies on the therapeutic effect of statins in patients consuming a Mediterranean-style diet are necessary to assure the correct prescription because the oil-statin and minor oil compound-statin possible interactions have been only briefly studied. Preliminary study suggests that olive oil can increase the hypolipaemiant effect of Simvastatin with respect sunflower oil. The consumption of polyunsaturated rich oils, throughout the cytochrome P- 450 activation could decrease the half-life of some statins and therefore their hypolipaemic effects. The statins and n-3 fatty acids combined therapy gives rise to pharmacodinamic interaction that improves the lipid profile and leads greater cardioprotection. Although statins are more effective in high endogenous cholesterol production subjects and plant sterols are more effective in high cholesterol absorption efficacy subjects, plant esterols-statins combined therapy generates very positive complementary effects. This review ends suggesting possible diet-stain interactions that require further investigations (e.g. types of olive oils, fruit juices other than grapefruit, fibre or consumption of alcoholic beverages rich in polyphenols or ethanol). PMID:20449528

  11. [Disposition behavior and absorption mechanism of trientine, an orphan drug for Wilson's disease].

    PubMed

    Tanabe, R

    1996-03-01

    The disposition behavior of trientine, a selective copper-chelating drug for Wilson's disease, and its metabolites in normal patients with Wilson's disease and rats were studied. A high concentration of metabolites appeared in blood samples of patients and rats in the early stage after administration of trientine. Furthermore, large amount of trientine metabolites were excreted into the urine of patients. These results suggest that trientine is remarkably subjected to a first-pass effect. The drug concentration area under the curve (AUC) of the unchanged form and the metabolites of trientine in patients was not dependent on the administered dosage. It seems that the absorption process is an important factor for the disposition behavior of trientine, we have also investigated the uptake characteristics of trientine by rat intestinal brush-border membrane vesicles. The uptake characteristics of trientine were similar to the physiological polyamines, spermine and spermidine. The uptake rate of trientine was dose-dependently inhibited by spermine and spermidine. Moreover, spermine competitively inhibited the uptake of trientine with a Ki value of 18.6 muM. This value is very close to the Km value for spermine (30.4 muM). These data suggested that the uptake mechanism of trientine in rat small intestinal brush-border membrane vesicles was almost identical to that of spermine and spermidine, and that the physiological polyamines seem to have the ability to inhibit the absorption of trientine from the gastrointestinal tract.

  12. Guide to Children Affected by Parental Drug Abuse

    ERIC Educational Resources Information Center

    Davies, Leah

    2010-01-01

    A conservative estimate is that one in six children in school today has a parent dependent on or addicted to alcohol or other drugs. This places these students at high risk for social and emotional problems, as well as for school failure, drug use, and delinquency. Schools, however, are a logical place to reach them. Identifying children of those…

  13. Factors affecting the reversal of antimicrobial-drug resistance.

    PubMed

    Johnsen, Pål J; Townsend, Jeffrey P; Bøhn, Thomas; Simonsen, Gunnar S; Sundsfjord, Arnfinn; Nielsen, Kaare M

    2009-06-01

    The persistence or loss of acquired antimicrobial-drug resistance in bacterial populations previously exposed to drug-selective pressure depends on several biological processes. We review mechanisms promoting or preventing the loss of resistance, including rates of reacquisition, effects of resistance traits on bacterial fitness, linked selection, and segregational stability of resistance determinants. As a case study, we discuss the persistence of glycopeptide-resistant enterococci in Norwegian and Danish poultry farms 12 years after the ban of the animal growth promoter avoparcin. We conclude that complete eradication of antimicrobial resistance in bacterial populations following relaxed drug-selective pressures is not straightforward. Resistance determinants may persist at low, but detectable, levels for many years in the absence of the corresponding drugs. PMID:19467475

  14. FACTORS AFFECTING THE DEPOSITION OF INHALED POROUS DRUG PARTICLES

    EPA Science Inventory

    Abstract
    Recent findings indicate that the inhalation of large manufactured porous particles may be particularly effective for drug delivery. In this study, a mathematical model was employed to systematically investigate the effects of particle size, particle density, aerosol ...

  15. Prenatal drug exposure affects neonatal brain functional connectivity.

    PubMed

    Salzwedel, Andrew P; Grewen, Karen M; Vachet, Clement; Gerig, Guido; Lin, Weili; Gao, Wei

    2015-04-01

    Prenatal drug exposure, particularly prenatal cocaine exposure (PCE), incurs great public and scientific interest because of its associated neurodevelopmental consequences. However, the neural underpinnings of PCE remain essentially uncharted, and existing studies in school-aged children and adolescents are confounded greatly by postnatal environmental factors. In this study, leveraging a large neonate sample (N = 152) and non-invasive resting-state functional magnetic resonance imaging, we compared human infants with PCE comorbid with other drugs (such as nicotine, alcohol, marijuana, and antidepressant) with infants with similar non-cocaine poly drug exposure and drug-free controls. We aimed to characterize the neural correlates of PCE based on functional connectivity measurements of the amygdala and insula at the earliest stage of development. Our results revealed common drug exposure-related connectivity disruptions within the amygdala-frontal, insula-frontal, and insula-sensorimotor circuits. Moreover, a cocaine-specific effect was detected within a subregion of the amygdala-frontal network. This pathway is thought to play an important role in arousal regulation, which has been shown to be irregular in PCE infants and adolescents. These novel results provide the earliest human-based functional delineations of the neural-developmental consequences of prenatal drug exposure and thus open a new window for the advancement of effective strategies aimed at early risk identification and intervention.

  16. Prenatal drug exposure affects neonatal brain functional connectivity.

    PubMed

    Salzwedel, Andrew P; Grewen, Karen M; Vachet, Clement; Gerig, Guido; Lin, Weili; Gao, Wei

    2015-04-01

    Prenatal drug exposure, particularly prenatal cocaine exposure (PCE), incurs great public and scientific interest because of its associated neurodevelopmental consequences. However, the neural underpinnings of PCE remain essentially uncharted, and existing studies in school-aged children and adolescents are confounded greatly by postnatal environmental factors. In this study, leveraging a large neonate sample (N = 152) and non-invasive resting-state functional magnetic resonance imaging, we compared human infants with PCE comorbid with other drugs (such as nicotine, alcohol, marijuana, and antidepressant) with infants with similar non-cocaine poly drug exposure and drug-free controls. We aimed to characterize the neural correlates of PCE based on functional connectivity measurements of the amygdala and insula at the earliest stage of development. Our results revealed common drug exposure-related connectivity disruptions within the amygdala-frontal, insula-frontal, and insula-sensorimotor circuits. Moreover, a cocaine-specific effect was detected within a subregion of the amygdala-frontal network. This pathway is thought to play an important role in arousal regulation, which has been shown to be irregular in PCE infants and adolescents. These novel results provide the earliest human-based functional delineations of the neural-developmental consequences of prenatal drug exposure and thus open a new window for the advancement of effective strategies aimed at early risk identification and intervention. PMID:25855194

  17. Development of a Triplet-Triplet Absorption Ruler: DNA- and Chromatin-Mediated Drug Molecule Release from a Nanosurface.

    PubMed

    Chakraborty, Sudeshna Das; Sau, Abhishek; Kuznetsov, Denis V; Banerjee, Amrita; Bardhan, Munmun; Bhattacharya, Maireyee; Dasgupta, Dipak; Basu, Samita; Senapati, Dulal

    2016-07-14

    Triplet-triplet (T-T) absorption spectroscopy has been used successfully as a molecular ruler to understand the actual release process of sanguinarine as a drug molecule from a gold nanoparticle surface in the presence of cell components, that is, DNA and chromatin. The obtained results have been verified by fluorescence and surface-enhanced Raman spectroscopy (SERS), and a plausible explanation has been put forward to describe the underestimation and overestimation of the percentage (%) of the release of drug molecules measured by fluorescence- and SERS-based techniques, respectively, over the highlighted T-T absorption spectroscopy. Because of the intrinsic nature of absorption, the reported T-T absorption spectroscopic assay overpowers fluorescence- and SERS-based assays, which are limited by the long-range interaction and nonlinear dependence of the concentration of analytes, respectively. PMID:27284775

  18. The global extrapolation of numerical methods for computing concentration profiles in percutaneous drug absorption.

    PubMed

    Twizell, E H

    1989-01-01

    A family of numerical methods is developed and analyzed for the numerical solution of the parabolic partial differential equation together with the associated initial and boundary conditions, which arise in a mathematical model of the transient stage of percutaneous drug absorption. Two global extrapolation procedures are described, the first in time only, the second in both space and time, for improving the accuracy of the computed concentration profiles. The behaviours of two members of the family of methods, before and after extrapolation, are examined by repeating a number of experiments reported in the literature. Modifications to the algorithms, which are necessary in computing concentration profiles after the ointment is removed at the steady state, are outlined.

  19. [Inhibitory effect of nasal mucus on the absorption of drugs through respiratory epithelium].

    PubMed

    Hayashi, H

    1990-01-01

    The absorption of Dibekacin (DKB) through rabbit's tracheal mucosa with and without nasal mucus were examined in vitro. The modified double chamber method was used for the purpose of this study. DKB solution (20 mg/ml) and Hanks' balanced salt solution were put into the donor compartment (DC) and the receiver compartment (RC), respectively. A plate with a hole and the tracheal mucosa were inserted between the compartments in the order of DC, dialytic membrane, the plate, the rabbit tracheal mucosa and RC. The hole of the plate was filled with nasal mucus or Hanks' solution. The latter was used as the control. The chamber was incubated in a humidified atmosphere of 5% CO2 in air for 3 hours at 37 degrees C. The absorption rate (AR) was obtained by dividing the concentration of DKB in RC by that in DC. The nasal mucus from patients with chronic sinusitis significantly decreased the AR of DKB compared with that in the control (P less than 0.05). The AR significantly decreased with increments in the thickness of nasal mucus by chronic sinusitis. This decreased AR was improved by the addition of N-Acetyl-L-cysteine (NAC) to DKB solution in DC. NAC can cleave disulfied bonds of mucus glycoprotein and this results in the decrease of viscoelasticity of nasal mucus. The results indicate that nasal mucus by chronic sinusitis intercept the absorption of drugs through respiratory epithelium in vitro. One of the mechanisms of the intercepter may be due to the high molecular-reticular structure of nasal mucus. PMID:2319385

  20. [Inhibitory effect of nasal mucus on the absorption of drugs through respiratory epithelium].

    PubMed

    Hayashi, H

    1990-01-01

    The absorption of Dibekacin (DKB) through rabbit's tracheal mucosa with and without nasal mucus were examined in vitro. The modified double chamber method was used for the purpose of this study. DKB solution (20 mg/ml) and Hanks' balanced salt solution were put into the donor compartment (DC) and the receiver compartment (RC), respectively. A plate with a hole and the tracheal mucosa were inserted between the compartments in the order of DC, dialytic membrane, the plate, the rabbit tracheal mucosa and RC. The hole of the plate was filled with nasal mucus or Hanks' solution. The latter was used as the control. The chamber was incubated in a humidified atmosphere of 5% CO2 in air for 3 hours at 37 degrees C. The absorption rate (AR) was obtained by dividing the concentration of DKB in RC by that in DC. The nasal mucus from patients with chronic sinusitis significantly decreased the AR of DKB compared with that in the control (P less than 0.05). The AR significantly decreased with increments in the thickness of nasal mucus by chronic sinusitis. This decreased AR was improved by the addition of N-Acetyl-L-cysteine (NAC) to DKB solution in DC. NAC can cleave disulfied bonds of mucus glycoprotein and this results in the decrease of viscoelasticity of nasal mucus. The results indicate that nasal mucus by chronic sinusitis intercept the absorption of drugs through respiratory epithelium in vitro. One of the mechanisms of the intercepter may be due to the high molecular-reticular structure of nasal mucus.

  1. Skin aging modulates percutaneous drug absorption: the impact of ultraviolet irradiation and ovariectomy.

    PubMed

    Hung, Chi-Feng; Chen, Wei-Yu; Aljuffali, Ibrahim A; Lin, Yin-Ku; Shih, Hui-Chi; Fang, Jia-You

    2015-01-01

    Ultraviolet (UV) exposure and menopause are known as the inducers of damage to the skin structure. The combination of these two factors accelerates the skin aging process. In this study, we aimed to evaluate the influence of UV and ovariectomy (OVX) on the permeation of drugs through the skin. The role of tight junctions (TJs) and adherens junctions (AJs) in the cutaneous absorption of extremely lipophilic permeants and macromolecules was explored. The OVX nude mouse underwent bilateral ovary removal. Both UVA and UVB were employed to irradiate the skin. The physiological and biochemical changes of the skin structure were examined with focus on transepidermal water loss (TEWL), skin color, immunohistochemistry, and mRNA levels of proteins. UVB and OVX increased TEWL, resulting in stratum corneum (SC) integrity disruption and dehydration. A hyperproliferative epidermis was produced by UVB. UVA caused a pale skin color tone due to keratinocyte apoptosis in the epidermis. E-cadherin and β-catenin showed a significant loss by both UVA and UVB. OVX downregulated the expression of filaggrin and involucrin. A further reduction was observed when UV and OVX were combined. The in vitro cutaneous absorption demonstrated that UV increased the skin permeation of tretinoin by about twofold. However, skin accumulation and flux of estradiol were not modified by photoaging. OVX basically revealed a negligible effect on altering the permeation of small permeants. OVX increased tretinoin uptake by the appendages from 1.36 to 3.52 μg/cm(2). A synergistic effect on tretinoin follicular uptake enhancement was observed for combined UV and OVX. However, the intervention of OVX to photoaged skin resulted in less macromolecule (dextran, molecular weight = 4 kDa) accumulation in the skin reservoir because of retarded partitioning into dry skin. The in vivo percutaneous absorption of lipophilic dye examined by confocal microscopy had indicated that the SC was still important to

  2. Site-dependent factors affecting the economic feasibility of solar powered absorption cooling

    NASA Technical Reports Server (NTRS)

    Bartlett, J. C.

    1977-01-01

    A procedure has been developed which can be used to determine the economic feasibility of solar powered absorption cooling systems. This procedure has been used in a study to investigate the influence of the site-dependent parameters on the economic feasibility of solar absorption cooling. The purpose of this study was to make preliminary site selections for solar powered absorption cooling systems. This paper summarizes the results of that study.

  3. Genetic polymorphisms affect efficacy and adverse drug reactions of DMARDs in rheumatoid arthritis.

    PubMed

    Zhang, Ling Ling; Yang, Sen; Wei, Wei; Zhang, Xue Jun

    2014-11-01

    Disease-modifying antirheumatic drugs (DMARDs) and biological agents are critical in preventing the severe complications of rheumatoid arthritis (RA). However, the outcome of treatment with these drugs in RA patients is quite variable and unpredictable. Drug-metabolizing enzymes (dihydrofolate reductase, cytochrome P450 enzymes, N-acetyltransferases, etc.), drug transporters (ATP-binding cassette transporters), and drug targets (tumor necrosis factor-α receptors) are coded for by variant alleles. These gene polymorphisms may influence the pharmacokinetics, pharmacodynamics, and side effects of medicines. The cause for differences in efficacy and adverse drug reactions may be genetic variation in drug metabolism among individuals. Polymorphisms in drug transporter genes may change the distribution and excretion of medicines, and the sensitivity of the targets to drugs is strongly influenced by genetic variations. In this article, we review the genetic polymorphisms that affect the efficacy of DMARDs or the occurrence of adverse drug reactions associated with DMARDs in RA.

  4. Viscosity-mediated negative food effect on oral absorption of poorly-permeable drugs with an absorption window in the proximal intestine: In vitro experimental simulation and computational verification.

    PubMed

    Cvijić, Sandra; Parojčić, Jelena; Langguth, Peter

    2014-09-30

    Concomitant food intake can diminish oral absorption of drugs with limited permeability and an absorption window in the proximal intestine, due to viscosity-mediated decrease in dosage form disintegration time and drug dissolution rate. Three poorly-permeable drugs (atenolol, metformin hydrochloride, and furosemide) exhibiting negative food effect, and one highly-soluble and highly-permeable (metoprolol tartrate), serving as a negative control, were selected for the study. In vitro and in silico tools were used to evaluate the influence of media viscosity on drug bioperformance under fasted and fed conditions. The obtained results demonstrated that increased medium viscosity in the presence of food is one of the key factors limiting oral absorption of drugs with limited permeability and absorption restricted to the upper parts of the intestine, while having negligible effect on pharmacokinetic profile of drugs with pH- and site-independent absorption. Dissolution medium pH 4.6 with the addition of hydroxypropyl methylcellulose was suggested to simulate postprandial gastric conditions for drugs whose solubility under these conditions is not the limiting factor for drug absorption. In addition, drug formulation was found to be an interfering factor in relation to the impact of medium viscosity on the rate and extent of drug absorption.

  5. Development of a Unified Dissolution and Precipitation Model and Its Use for the Prediction of Oral Drug Absorption.

    PubMed

    Jakubiak, Paulina; Wagner, Björn; Grimm, Hans Peter; Petrig-Schaffland, Jeannine; Schuler, Franz; Alvarez-Sánchez, Rubén

    2016-02-01

    Drug absorption is a complex process involving dissolution and precipitation, along with other kinetic processes. The purpose of this work was to (1) establish an in vitro methodology to study dissolution and precipitation in early stages of drug development where low compound consumption and high throughput are necessary, (2) develop a mathematical model for a mechanistic explanation of generated in vitro dissolution and precipitation data, and (3) extrapolate in vitro data to in vivo situations using physiologically based models to predict oral drug absorption. Small-scale pH-shift studies were performed in biorelevant media to monitor the precipitation of a set of poorly soluble weak bases. After developing a dissolution-precipitation model from this data, it was integrated into a simplified, physiologically based absorption model to predict clinical pharmacokinetic profiles. The model helped explain the consequences of supersaturation behavior of compounds. The predicted human pharmacokinetic profiles closely aligned with the observed clinical data. In summary, we describe a novel approach combining experimental dissolution/precipitation methodology with a mechanistic model for the prediction of human drug absorption kinetics. The approach unifies the dissolution and precipitation theories and enables accurate predictions of in vivo oral absorption by means of physiologically based modeling.

  6. Self-nanoemulsifying drug delivery system (SNEDDS) for oral delivery of protein drugs: III. In vivo oral absorption study.

    PubMed

    Rao, Sripriya Venkata Ramana; Yajurvedi, Kavya; Shao, Jun

    2008-10-01

    To use self-nanoemulsifying drug delivery system (SNEDDS) to deliver hydrophilic proteins orally. beta-Lactamase (BLM), a 29 kDa protein was used as a model protein, and formulated into the oil phase of a SNEDDS through solid dispersion technique. The oral absorption of BLM in rats when delivered by such a SNEDDS was investigated. Oral delivery of 4500 mU/kg of BLM in SNEDDS nanoemulsion resulted in the relative bioavailability of 6.34%, C(max) of 1.9 mU/ml and mean residence time of 12.12h which was 1.5-, 2.7- and 1.3-fold higher than that by free solution, respectively. Delivery of BLM in the aqueous phase of the nanoemulsion resulted in a PK profile similar to that by the free solution. BLM when loaded in oil phase of SNEDDS, can significantly enhance the oral bioavailability of BLM. SNEDDS has a great potential for oral protein delivery.

  7. Meals and dephytinization affect calcium and zinc absorption in Nigerian children with rickets

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Nutritional rickets resulting from calcium insufficiency is common in Nigeria, and high dietary phytate is thought to inhibit calcium and zinc absorption. We compared the effects of a high-phytate meal and enzymatic dephytinization on calcium and zinc absorption in Nigerian children with and without...

  8. Effect on the Gastrointestinal Absorption of Drugs from Different Classes in the Biopharmaceutics Classification System, When Treating with Liraglutide.

    PubMed

    Malm-Erjefält, Monika; Ekblom, Marianne; Vouis, Jan; Zdravkovic, Milan; Lennernäs, Hans

    2015-11-01

    Like other GLP-1 receptor agonists used for treatment of type 2 diabetes, liraglutide delays gastric emptying. In this clinical absorption study, the primary objective was to investigate the effect of liraglutide (at steady state) on the rate and/or extent of gastrointestinal (GI) absorption of concomitantly orally taken drugs from three classes of the Biopharmaceutics Classification System (BCS). To provide a general prediction on liraglutide drug-drug absorption interaction, single-dose pharmacokinetics of drugs representing BCS classes II (low solubility-high permeability; atorvastatin 40 mg and griseofulvin 500 mg), III (high solubility-low permeability; lisinopril 20 mg), and IV (low solubility-low permeability; digoxin 1 mg) were studied in healthy subjects at steady state of liraglutide 1.8 mg, or placebo, in a two-period crossover design. With liraglutide, the oral drugs atorvastatin, lisinopril, and digoxin showed delayed tmax (by ≤2 h) and did not meet the criterion for bioequivalence for Cmax (reduced Cmax by 27-38%); griseofulvin had similar tmax and 37% increased Cmax. Although the prespecified bioequivalence criterion was not met by all drugs, the overall plasma exposure (AUC) of griseofulvin, atorvastatin, lisinopril, and digoxin only exhibited minor changes and was not considered to be of clinical relevance.

  9. Inulin and fructooligosaccharide affect in vitro calcium uptake and absorption from calcium-enriched gluten-free bread.

    PubMed

    Krupa-Kozak, U; Swiątecka, D; Bączek, N; Brzóska, M M

    2016-04-01

    Compromised intestinal calcium absorption affecting a deterioration of bone state is a sign of coeliac disease. Experimental calcium-fortified gluten-free bread (GFB) of improved calcium bioavailability could increase calcium content in the diets of coeliac disease patients, allowing them to obtain the amount of calcium they need for therapeutic use. Prebiotics, including inulin-type fructans (IFs) have a beneficial effect on calcium bioavailability. In the present study, the in vitro model composed of the intestinal-like Caco-2 cells and the human intestinal bacteria (Lactobacillus, Enterococcus and Enterobacteriaceae) were used to analyse the effect of inulin and fructooligosaccharide (FOS) of different chain lengths, on calcium uptake and absorption from experimental GFB. Analysed IFs, especially short-chain FOS, significantly (p < 0.05) increased cellular calcium uptake from GFB digest and stimulated the intestinal bacteria applied in the cultures to the intensive synthesis of organic acids. In particular, the concentration of butyric, valeric and lactic acids increased significantly. Similarly, in the calcium absorption experiment, IFs increased the cellular calcium retention but concomitantly reduced its content in basolateral filtrates. The results obtained suggest that the applied IFs affected differentially calcium uptake and absorption from the experimental calcium-enriched GFB, therefore a further study is needed to assess whether these observations made in vitro contribute to IF effects on calcium absorption from experimental GFB in vivo. PMID:26965706

  10. Inulin and fructooligosaccharide affect in vitro calcium uptake and absorption from calcium-enriched gluten-free bread.

    PubMed

    Krupa-Kozak, U; Swiątecka, D; Bączek, N; Brzóska, M M

    2016-04-01

    Compromised intestinal calcium absorption affecting a deterioration of bone state is a sign of coeliac disease. Experimental calcium-fortified gluten-free bread (GFB) of improved calcium bioavailability could increase calcium content in the diets of coeliac disease patients, allowing them to obtain the amount of calcium they need for therapeutic use. Prebiotics, including inulin-type fructans (IFs) have a beneficial effect on calcium bioavailability. In the present study, the in vitro model composed of the intestinal-like Caco-2 cells and the human intestinal bacteria (Lactobacillus, Enterococcus and Enterobacteriaceae) were used to analyse the effect of inulin and fructooligosaccharide (FOS) of different chain lengths, on calcium uptake and absorption from experimental GFB. Analysed IFs, especially short-chain FOS, significantly (p < 0.05) increased cellular calcium uptake from GFB digest and stimulated the intestinal bacteria applied in the cultures to the intensive synthesis of organic acids. In particular, the concentration of butyric, valeric and lactic acids increased significantly. Similarly, in the calcium absorption experiment, IFs increased the cellular calcium retention but concomitantly reduced its content in basolateral filtrates. The results obtained suggest that the applied IFs affected differentially calcium uptake and absorption from the experimental calcium-enriched GFB, therefore a further study is needed to assess whether these observations made in vitro contribute to IF effects on calcium absorption from experimental GFB in vivo.

  11. The antiepileptic drug carbamazepine affects sodium transport in toad epithelium.

    PubMed

    Suwalsky, Mario; Mennickent, Sigrid; Norris, Beryl; Cardenas, Hernán

    2006-09-01

    The present work investigates the effects of the antiepileptic drug carbamazepine (CBZ) on sodium transport in the isolated skin of the toad Pleurodema thaul. A submaximal concentration of the drug (0.2 mM) applied to the outer surface of the epithelium increased the electrical parameters short-circuit current (Isc) and potential difference (PD) by over 28%, whereas only a higher concentration (1 mM) induced over a 45% decrease in these parameters when applied to the inner surface. The amiloride test showed that the outer surface stimulatory effect was accompanied by an increase and the inner surface inhibitory effect by a decrease in the sodium electromotive force (ENa). Exploration of these effects of CBZ on the outer surface showed that 0.2 mM increased net Na+ (22Na) influx by 20% and 0.6 mM CBZ decreased Na+ mucosa-serosa flux by 19%, a result in agreement with the finding that higher concentrations of CBZ applied to the inner surface not only decreased ENa but also sodium conductance (GNa). PMID:16542818

  12. A modified physiological BCS for prediction of intestinal absorption in drug discovery.

    PubMed

    Zaki, Noha M; Artursson, Per; Bergström, Christel A S

    2010-10-01

    In this study, the influence of physiologically relevant media on the compound position in a biopharmaceutical classification system (BCS) which resembled the intestinal absorption was investigated. Both solubility and permeability limited compounds (n = 22) were included to analyze the importance of each of these on the final absorption. Solubility was determined in three different dissolution media, phosphate buffer pH 6.5 (PhB 6.5), fasted state simulated intestinal fluid (FaSSIF), and fed state simulated intestinal fluid (FeSSIF) at 37 °C, and permeability values were determined using the 2/4/A1 cell line. The solubility data and membrane permeability values were used for sorting the compounds into a BCS modified to reflect the fasted and fed state. Three of the seven compounds sorted as BCS II in PhB 6.5 (high permeability, low solubility) changed their position to BCS I when dissolved in FaSSIF and/or FeSSIF (high permeability, high solubility). These were low dosed (20 mg or less) lipophilic molecules displaying solvation limited solubility. In contrast, compounds having solid-state limited solubility had a minor increase in solubility when dissolved in FaSSIF and/or FeSSIF. Although further studies are needed to enable general cutoff values, our study indicates that low dosed BCS Class II compounds which have solubility normally restricted by poor solvation may behave as BCS Class I compounds in vivo. The large series of compounds investigated herein reveals the importance of investigating solubility and dissolution under physiologically relevant conditions in all stages of the drug discovery process to push suitable compounds forward, to select proper formulations, and to reduce the risk of food effects.

  13. A carrier-mediated prodrug approach to improve the oral absorption of antileukemic drug decitabine.

    PubMed

    Zhang, Youxi; Sun, Jin; Gao, Yikun; Jin, Ling; Xu, Youjun; Lian, He; Sun, Yongbing; Sun, Yinghua; Liu, Jianyu; Fan, Rui; Zhang, Tianhong; He, Zhonggui

    2013-08-01

    Decitabine (5-aza-2'-deoxycytidine, DAC) is a novel DNA methyltransferase (DNMT) inhibitor for the treatment of myelodysplastic syndrome, acute and chronic myeloid leukemia. However, it exhibits a low oral bioavailability (only 9% in mice), because of low permeability across the intestine membrane and rapid metabolism to inactive metabolite. To utilize the carrier-mediated prodrug approach for improved absorption of decitabine, a series of amino acid-decitabine conjugates were synthesized to target the intestinal membrane transporter, hPepT1. The Caco-2 permeability of the prodrugs was screened, and two l-val (aliphatic, compound 4a) and l-phe (aromatic, compound 4c) prodrugs with higher permeability were selected for further studies. The uptake of Gly-Sar by Caco-2 cells could be competitively inhibited by compounds 4a and 4c, with IC50 being 2.20 ± 0.28 mM and 3.46 ± 0.16 mM, respectively. The uptake of compounds 4a and 4c was markedly increased in the leptin-treated Caco-2 cells compared with the control Caco-2 cells, suggesting that hPepT1-mediated transport contributes to oral absorption of compounds 4a and 4c. The prodrugs were evaluated for their stability in various phosphate buffers, rat plasma, tissue homogenates, and gastrointestinal fluids. Compounds 4a and 4c were stable in gastrointestinal tract at pH 6.0 but could be quickly converted into DAC in plasma and tissue homogenates after absorption. The oral absolute bioavailability of DAC was 46.7%, 50.9%, and 26.9% after compounds 4a, 4c, and DAC were orally administered to rats at a dose of 15 mg/kg, respectively. The bioavailability of compounds 4a and 4c in rats was both reduced to about 32% when orally coadministrated with typical hPepT1 substrate Gly-Sar (150 mg/kg). Overall, compounds 4a and 4c can significantly enhance the intestinal membrane permeability of DAC, followed by rapid and mostly bioactivation to parent drug in intestinal and hepatic tissues before entry into systemic circulation

  14. Soluplus-coated colloidal silica nanomatrix system for enhanced supersaturation and oral absorption of poorly water-soluble drugs.

    PubMed

    Kim, Min-Soo

    2013-12-01

    In this study, a Soluplus-coated colloidal silica nanomatrix (SCCSN) formulation for the entrapment of poorly water-soluble drugs was devised. The maximum supersaturation of the drug-loaded nanomatrix was higher than that of a physical mixture as indicated by the results of in vitro kinetic solubility studies. For atorvastatin calcium, dutasteride, and sorafenib tosylate, there were 2.8-, 326-, and 46.4-fold increases in solubility, respectively. For dutasteride, a promising 4.7-fold increase for in vivo oral drug absorption in the entrapped nanomatrix was observed as compared to the free physical mixture, supported by statistical significance testing of pharmacokinetic parameters.

  15. Anticancer efficacy and absorption, distribution, metabolism, and toxicity studies of aspergiolide A in early drug development.

    PubMed

    Wang, Yuanyuan; Qi, Xin; Li, Dehai; Zhu, Tianjiao; Mo, Xiaomei; Li, Jing

    2014-01-01

    Since the first anthracycline was discovered, many other related compounds have been studied in order to overcome its defects and improve efficacy. In the present paper, we investigated the anticancer effects of a new anthracycline, aspergiolide A (ASP-A), from a marine-derived fungus in vitro and in vivo, and we evaluated the absorption, distribution, metabolism, and toxicity drug properties in early drug development. We found that ASP-A had activity against topoisomerase II that was comparable to adriamycin. ASP-A decreased the growth of various human cancer cells in vitro and induced apoptosis in BEL-7402 cells via a caspase-dependent pathway. The anticancer efficacy of ASP-A on the growth of hepatocellular carcinoma xenografts was further assessed in vivo. Results showed that, compared with the vehicle group, ASP-A exhibited significant anticancer activity with less loss of body weight. A pharmacokinetics and tissue distribution study revealed that ASP-A was rapidly cleared in a first order reaction kinetics manner, and was enriched in cancer tissue. The maximal tolerable dose (MTD) of ASP-A was more than 400 mg/kg, and ASP-A was not considered to be potentially genotoxic or cardiotoxic, as no significant increase of micronucleus rates or inhibition of the hERG channel was seen. Finally, an uptake and transport assay of ASP-A was performed in monolayers of Caco-2 cells, and ASP-A was shown to be absorbed through the active transport pathway. Altogether, these results indicate that ASP-A has anticancer activity targeting topoisomerase II, with a similar structure and mechanism to adriamycin, but with much lower toxicity. Nonetheless, further molecular structure optimization is necessary.

  16. Evaluating Potential P-gp Substrates: Main Aspects to Choose the Adequate Permeability Model for Assessing Gastrointestinal Drug Absorption.

    PubMed

    da Silva Junior, João Batista; Dezani, Thaisa Marinho; Dezani, André Bersani; dos Reis Serra, Cristina Helena

    2015-01-01

    The success of an oral drug route administration depends on many factors that interfere in its bioavailability, therapeutic efficacy and clinical safety. In human cells, ATP-dependent efflux transporter proteins, such as P-glycoprotein (P-gp), BCRP and MRP2, reduce the absorption of drugs. A tiered approach chosen to evaluate drugs as substrates or inhibitors of efflux pumps, particularly P-gp, should be carefully selected, since each study method has advantages and intrinsic limitations to their processes. Depending on the adopted study conditions, the results may not correspond to the real characteristics of the drug regarding to its modulation by specific efflux proteins. This mini-review aims at summarizing the role of P-gp in the drugs oral absorption and correlating some of the most used permeability methods to determine the drug condition as P-gp substrate. Studies about P-gp have shown that it is a dynamic protein, facilitating secretion of endogenous compounds, as aldosterone, and protecting cells against xenobiotics. Different efflux assays are employed to evaluate drugs as P-gp substrates. In an initial planning, MDCK-MDR1 tend to be the chosen method for efflux studies due its ability of express P-gp, followed by studies conducted in Caco-2 models. However, it is necessary to evaluate the advantages and disadvantages of each method to generate sound results and to set the correlation in vitro x in situ x in vivo. PMID:25963568

  17. Zinc Absorption from Micronutrient Powder Is Low but Is not Affected by Iron in Kenyan Infants

    PubMed Central

    Esamai, Fabian; Liechty, Edward; Ikemeri, Justus; Westcott, Jamie; Kemp, Jennifer; Culbertson, Diana; Miller, Leland V.; Hambidge, K. Michael; Krebs, Nancy F.

    2014-01-01

    Interference with zinc absorption is a proposed explanation for adverse effects of supplemental iron in iron-replete children in malaria endemic settings. We examined the effects of iron in micronutrient powder (MNP) on zinc absorption after three months of home fortification with MNP in maize-based diets in rural Kenyan infants. In a double blind design, six-month-old, non-anemic infants were randomized to MNP containing 5 mg zinc, with or without 12.5 mg of iron (MNP + Fe and MNP − Fe, respectively); a control (C) group received placebo powder. After three months, duplicate diet collections and zinc stable isotopes were used to measure intake from MNP + non-breast milk foods and fractional absorption of zinc (FAZ) by dual isotope ratio method; total absorbed zinc (TAZ, mg/day) was calculated from intake × FAZ. Mean (SEM) TAZ was not different between MNP + Fe (n = 10) and MNP − Fe (n = 9) groups: 0.85 (0.22) and 0.72 (0.19), respectively, but both were higher than C (n = 9): 0.24 (0.03) (p = 0.04). Iron in MNP did not significantly alter zinc absorption, but despite intakes over double estimated dietary requirement, both MNP groups’ mean TAZ barely approximated the physiologic requirement for age. Impaired zinc absorption may dictate need for higher zinc doses in vulnerable populations. PMID:25493942

  18. Factors affecting drug-induced liver injury: antithyroid drugs as instances.

    PubMed

    Heidari, Reza; Niknahad, Hossein; Jamshidzadeh, Akram; Abdoli, Narges

    2014-09-01

    Methimazole and propylthiouracil have been used in the management of hyperthyroidism for more than half a century. However, hepatotoxicity is one of the most deleterious side effects associated with these medications. The mechanism(s) of hepatic injury induced by antithyroid agents is not fully recognized yet. Furthermore, there are no specific tools for predicting the occurrence of hepatotoxicity induced by these drugs. The purpose of this article is to give an overview on possible susceptibility factors in liver injury induced by antithyroid agents. Age, gender, metabolism characteristics, alcohol consumption, underlying diseases, immunologic mechanisms, and drug interactions are involved in enhancing antithyroid drugs-induced hepatic damage. An outline on the clinically used treatments for antithyroid drugs-induced hepatotoxicity and the potential therapeutic strategies found to be effective against this complication are also discussed.

  19. Factors affecting drug-induced liver injury: antithyroid drugs as instances

    PubMed Central

    Niknahad, Hossein; Jamshidzadeh, Akram; Abdoli, Narges

    2014-01-01

    Methimazole and propylthiouracil have been used in the management of hyperthyroidism for more than half a century. However, hepatotoxicity is one of the most deleterious side effects associated with these medications. The mechanism(s) of hepatic injury induced by antithyroid agents is not fully recognized yet. Furthermore, there are no specific tools for predicting the occurrence of hepatotoxicity induced by these drugs. The purpose of this article is to give an overview on possible susceptibility factors in liver injury induced by antithyroid agents. Age, gender, metabolism characteristics, alcohol consumption, underlying diseases, immunologic mechanisms, and drug interactions are involved in enhancing antithyroid drugs-induced hepatic damage. An outline on the clinically used treatments for antithyroid drugs-induced hepatotoxicity and the potential therapeutic strategies found to be effective against this complication are also discussed. PMID:25320726

  20. Site dependent factors affecting the economic feasibility of solar powered absorption cooling

    NASA Technical Reports Server (NTRS)

    Bartlett, J. C.

    1978-01-01

    A procedure was developed to evaluate the cost effectiveness of combining an absorption cycle chiller with a solar energy system. A basic assumption of the procedure is that a solar energy system exists for meeting the heating load of the building, and that the building must be cooled. The decision to be made is to either cool the building with a conventional vapor compression cycle chiller or to use the existing solar energy system to provide a heat input to the absorption chiller. Two methods of meeting the cooling load not supplied by solar energy were considered. In the first method, heat is supplied to the absorption chiller by a boiler using fossil fuel. In the second method, the load not met by solar energy is net by a conventional vapor compression chiller. In addition, the procedure can consider waste heat as another form of auxiliary energy. Commercial applications of solar cooling with an absorption chiller were found to be more cost effective than the residential applications. In general, it was found that the larger the chiller, the more economically feasible it would be. Also, it was found that a conventional vapor compression chiller is a viable alternative for the auxiliary cooling source, especially for the larger chillers. The results of the analysis gives a relative rating of the sites considered as to their economic feasibility of solar cooling.

  1. Black carbon absorption at the global scale is affected by particle-scale diversity in composition.

    PubMed

    Fierce, Laura; Bond, Tami C; Bauer, Susanne E; Mena, Francisco; Riemer, Nicole

    2016-01-01

    Atmospheric black carbon (BC) exerts a strong, but uncertain, warming effect on the climate. BC that is coated with non-absorbing material absorbs more strongly than the same amount of BC in an uncoated particle, but the magnitude of this absorption enhancement (Eabs) is not well constrained. Modelling studies and laboratory measurements have found stronger absorption enhancement than has been observed in the atmosphere. Here, using a particle-resolved aerosol model to simulate diverse BC populations, we show that absorption is overestimated by as much as a factor of two if diversity is neglected and population-averaged composition is assumed across all BC-containing particles. If, instead, composition diversity is resolved, we find Eabs=1-1.5 at low relative humidity, consistent with ambient observations. This study offers not only an explanation for the discrepancy between modelled and observed absorption enhancement, but also demonstrates how particle-scale simulations can be used to develop relationships for global-scale models. PMID:27580627

  2. Black carbon absorption at the global scale is affected by particle-scale diversity in composition

    NASA Astrophysics Data System (ADS)

    Fierce, Laura; Bond, Tami C.; Bauer, Susanne E.; Mena, Francisco; Riemer, Nicole

    2016-09-01

    Atmospheric black carbon (BC) exerts a strong, but uncertain, warming effect on the climate. BC that is coated with non-absorbing material absorbs more strongly than the same amount of BC in an uncoated particle, but the magnitude of this absorption enhancement (Eabs) is not well constrained. Modelling studies and laboratory measurements have found stronger absorption enhancement than has been observed in the atmosphere. Here, using a particle-resolved aerosol model to simulate diverse BC populations, we show that absorption is overestimated by as much as a factor of two if diversity is neglected and population-averaged composition is assumed across all BC-containing particles. If, instead, composition diversity is resolved, we find Eabs=1-1.5 at low relative humidity, consistent with ambient observations. This study offers not only an explanation for the discrepancy between modelled and observed absorption enhancement, but also demonstrates how particle-scale simulations can be used to develop relationships for global-scale models.

  3. Black Carbon Absorption at the Global Scale Is Affected by Particle-Scale Diversity in Composition

    NASA Technical Reports Server (NTRS)

    Fierce, Laura; Bond, Tami C.; Bauer, Susanne E.; Mena, Francisco; Riemer, Nicole

    2016-01-01

    Atmospheric black carbon (BC) exerts a strong, but uncertain, warming effect on the climate. BC that is coated with non-absorbing material absorbs more strongly than the same amount of BC in an uncoated particle, but the magnitude of this absorption enhancement (E(sub abs)) is not well constrained. Modelling studies and laboratory measurements have found stronger absorption enhancement than has been observed in the atmosphere. Here, using a particle-resolved aerosol model to simulate diverse BC populations, we show that absorption is overestimated by as much as a factor of two if diversity is neglected and population-averaged composition is assumed across all BC-containing particles. If, instead, composition diversity is resolved, we find E(sub abs) = 1 - 1.5 at low relative humidity, consistent with ambient observations. This study offers not only an explanation for the discrepancy between modelled and observed absorption enhancement, but also demonstrates how particle-scale simulations can be used to develop relationships for global-scale models.

  4. Black carbon absorption at the global scale is affected by particle-scale diversity in composition

    PubMed Central

    Fierce, Laura; Bond, Tami C.; Bauer, Susanne E.; Mena, Francisco; Riemer, Nicole

    2016-01-01

    Atmospheric black carbon (BC) exerts a strong, but uncertain, warming effect on the climate. BC that is coated with non-absorbing material absorbs more strongly than the same amount of BC in an uncoated particle, but the magnitude of this absorption enhancement (Eabs) is not well constrained. Modelling studies and laboratory measurements have found stronger absorption enhancement than has been observed in the atmosphere. Here, using a particle-resolved aerosol model to simulate diverse BC populations, we show that absorption is overestimated by as much as a factor of two if diversity is neglected and population-averaged composition is assumed across all BC-containing particles. If, instead, composition diversity is resolved, we find Eabs=1−1.5 at low relative humidity, consistent with ambient observations. This study offers not only an explanation for the discrepancy between modelled and observed absorption enhancement, but also demonstrates how particle-scale simulations can be used to develop relationships for global-scale models. PMID:27580627

  5. Comparison of Deconvolution-Based and Absorption Modeling IVIVC for Extended Release Formulations of a BCS III Drug Development Candidate.

    PubMed

    Kesisoglou, Filippos; Xia, Binfeng; Agrawal, Nancy G B

    2015-11-01

    In vitro-in vivo correlations (IVIVC) are predictive mathematical models describing the relationship between dissolution and plasma concentration for a given drug compound. The traditional deconvolution/convolution-based approach is the most common methodology to establish a level A IVIVC that provides point to point relationship between the in vitro dissolution and the in vivo input rate. The increasing application of absorption physiologically based pharmacokinetic model (PBPK) has provided an alternative IVIVC approach. The current work established and compared two IVIVC models, via the traditional deconvolution/convolution method and via absorption PBPK modeling, for two types of modified release (MR) formulations (matrix and multi-particulate tablets) of MK-0941, a BCS III drug development candidate. Three batches with distinct release rates were studied for each formulation technology. A two-stage linear regression model was used for the deconvolution/convolution approach while optimization of the absorption scaling factors (a model parameter that relates permeability and input rate) in Gastroplus(TM) Advanced Compartmental Absorption and Transit model was used for the absorption PBPK approach. For both types of IVIVC models established, and for either the matrix or the multiparticulate formulations, the average absolute prediction errors for AUC and C max were below 10% and 15%, respectively. Both the traditional deconvolution/convolution-based and the absorption/PBPK-based level A IVIVC model adequately described the compound pharmacokinetics to guide future formulation development. This case study highlights the potential utility of absorption PBPK model to complement the traditional IVIVC approaches for MR products.

  6. Poor permeability and absorption affect the activity of four alkaloids from Coptis.

    PubMed

    Cui, Han-Ming; Zhang, Qiu-Yan; Wang, Jia-Long; Chen, Jian-Long; Zhang, Yu-Ling; Tong, Xiao-Lin

    2015-11-01

    Coptidis rhizoma (Coptis) and its alkaloids exert various pharmacological functions in cells and tissues; however, the oral absorption of these alkaloids requires further elucidation. The present study aimed to examine the mechanism underlying the poor absorption of alkaloids, including berberine (BER), coptisine (COP), palmatine (PAL) and jatrorrhizine (JAT). An ultra‑performance liquid chromatography (UPLC) method was validated for the determination of BER, COP, PAL and JAT in the above experimental medium. In addition, the apparent oil‑water partition coefficient (Po/w); apparent permeability coefficient (Papp), determined using a parallel artificial membrane permeability assay (PAMPA) plate; membrane retention coefficient (R %); and effect of P‑glycoprotein (P‑gp) inhibitor on the Papp of the four alkaloids were investigated. The intestinal absorption rate constant (Ka) and absorption percentage (A %) of the four alkaloids were also determined. The results of the present study demonstrated that the Po/w of the four alkaloids in 0.1 mol·l‑1 HCl medium was significantly higher (P<0.01), compared with those of the alkaloids in phosphate buffer (pH 7.4). The Papp of BER was 1.0‑1.2x10‑6 cm·s‑1, determined using a PAMPA plate, and the Papp of BER, COP, PAL and JAT decreased sequentially. The concentrations of the four alkaloids on the apical‑to‑basolateral (AP‑BL) surface and the basolateral‑to‑apical (BL‑AP) surface increased in a linear manner, with increasing concentrations between 10 and 100 µmol. In addition, the transportation of BER on the BL‑AP surface was significantly faster (P<0.01), compared with that on the AP‑BL surface and, following the addition of verpamil (a P‑gp inhibitor), the Papp (AP‑BL) of the four alkaloids increased, whereas the Papp (BL‑AP) was significantly decreased (P<0.01). The rat intestinal perfusion experiment demonstrated that the four alkaloids were poorly absorbed; however, the Ka of BER

  7. Impact of Luminal Fluid Volume on the Drug Absorption After Oral Administration: Analysis Based on In Vivo Drug Concentration-Time Profile in the Gastrointestinal Tract.

    PubMed

    Tanaka, Yusuke; Goto, Takanori; Kataoka, Makoto; Sakuma, Shinji; Yamashita, Shinji

    2015-09-01

    The objective of this study is to clarify the influence of fluid volume in the gastrointestinal (GI) tract on the oral drug absorption. In vivo rat luminal concentrations of FITC-dextran (FD-4), a nonabsorbable marker, and drugs (metoprolol and atenolol) after oral coadministration as solutions with different osmolarity were determined by direct sampling of residual water in each segment of the GI tract. The luminal FD-4 concentration after oral administration as hyposmotic solution was significantly higher than that after administration as isosmotic or hyperosmotic solution. As the change in FD-4 concentration reflects the change in the volume of luminal fluid, it indicated that the luminal volume was greatly influenced by osmolality of solution ingested orally. Then, fraction of drug absorbed (Fa) in these segments was calculated by comparing the area under the luminal concentration-time curve of FD-4 with those of drugs. Fa values of two model drugs in each GI segment decreased with increase in luminal fluid volume, and the impact of the fluid volume was marked for Fa of atenolol (a low permeable drug) than for that of metoprolol (a high permeable drug). These findings should be beneficial to assure the effectiveness and safety of oral drug therapy. PMID:25821198

  8. Rapid screening and identification of illicit drugs by IR absorption spectroscopy and gas chromatography

    NASA Astrophysics Data System (ADS)

    Mengali, Sandro; Liberatore, Nicola; Luciani, Domenico; Viola, Roberto; Cardinali, Gian Carlo; Elmi, Ivan; Poggi, Antonella; Zampolli, Stefano; Biavardi, Elisa; Dalcanale, Enrico; Bonadio, Federica; Delemont, Olivier; Esseiva, Pierre; Romolo, Francesco S.

    2013-01-01

    Analytical instruments based on InfraRed Absorption Spectroscopy (IRAS) and Gas Chromatography (GC) are today available only as bench-top instrumentation for forensic labs and bulk analysis. Within the 'DIRAC' project funded by the European Commission, we are developing an advanced portable sensor, that combines miniaturized GC as its key chemical separation tool, and IRAS in a Hollow Fiber (HF) as its key analytical tool, to detect and recognize illicit drugs and key precursors, as bulk and as traces. The HF-IRAS module essentially consists of a broadly tunable External Cavity (EC) Quantum Cascade Laser (QCL), thermo-electrically cooled MCT detectors, and an infrared hollow fiber at controlled temperature. The hollow fiber works as a miniaturized gas cell, that can be connected to the output of the GC column with minimal dead volumes. Indeed, the module has been coupled to GC columns of different internal diameter and stationary phase, and with a Vapour Phase Pre-concentrator (VPC) that selectively traps target chemicals from the air. The presentation will report the results of tests made with amphetamines and precursors, as pure substances, mixtures, and solutions. It will show that the sensor is capable of analyzing all the chemicals of interest, with limits of detection ranging from a few nanograms to about 100-200 ng. Furthermore, it is suitable to deal with vapours directly trapped from the headspace of a vessel, and with salts treated in a basic solution. When coupled to FAST GC columns, the module can analyze multi-components mixes in less than 5 minutes.

  9. Endocrine tumour in kidney affecting small bowel structure, motility, and absorptive function 1

    PubMed Central

    Gleeson, M. H.; Bloom, S. R.; Polak, J. M.; Henry, K.; Dowling, R. H.

    1971-01-01

    A 44-year-old woman is described with an endocrine tumour arising in the kidney. There were associated abnormalities of small intestinal morphology, motility, and absorptive function. These abnormalities reversed on removal of the tumour. Detailed studies showed that the tumour contained, and was secreting, glucagon. It is postulated that the intestinal abnormalities may have resulted from glucagon itself or another, as yet unidentified, hormone. ImagesFig. 1Fig. 2Fig. 3Fig. 4Fig. 5Fig. 6 PMID:4941684

  10. Nanostructure of liquid crystalline matrix determines in vitro sustained release and in vivo oral absorption kinetics for hydrophilic model drugs.

    PubMed

    Lee, Kathy W Y; Nguyen, Tri-Hung; Hanley, Tracey; Boyd, Ben J

    2009-01-01

    Nanostructured lipid-based liquid crystalline systems have been proposed as sustained oral drug delivery systems, but the interplay between their intrinsic release rates, susceptibility to digestive processes, and the manner in which these effects impact on their application in vivo, are not well understood. In this study, two different bicontinuous cubic phases, prepared from glyceryl monooleate and phytantriol, and a reversed hexagonal phase formed by addition of a small amount of vitamin E to phytantriol (Q(II GMO), Q(II PHYT) and H(II PHYT+VitEA), respectively) were prepared. The release kinetics for a number of model hydrophilic drugs with increasing molecular weights (glucose, Allura Red and FITC-dextrans) was determined in in vitro release experiments. Diffusion-controlled release was observed in all cases as anticipated from previous studies with liquid crystalline systems, and it was discovered that the release rates of each drug decreased as the matrix was changed from Q(II GMO) to Q(II PHYT) to H(II PHYT+VitEA). Formulations containing (14)C-glucose, utilized as a rapidly absorbed marker of drug release, were then orally administered to rats to determine the relative in vivo absorption rates from the different formulations. The results showed a trend by which the rate of absorption of (14)C-glucose followed that observed in the corresponding in vitro release studies, providing the first indication that the nanostructure of these materials may provide the ability to tailor the absorption kinetics of hydrophilic drugs in vivo, and hence form the basis of a new drug delivery system.

  11. Erbium:YAG laser resurfacing increases skin permeability and the risk of excessive absorption of antibiotics and sunscreens: the influence of skin recovery on drug absorption.

    PubMed

    Lee, Woan-Ruoh; Shen, Shing-Chuan; Al-Suwayeh, Saleh A; Li, Yi-Ching; Fang, Jia-You

    2012-06-01

    While laser skin resurfacing is expected to result in reduced barrier function and increased risk of drug absorption, the extent of the increment has not yet been systematically investigated. We aimed to establish the skin permeation profiles of tetracycline and sunscreens after exposure to the erbium:yttrium-aluminum-garnet (Er:YAG) laser during postoperative periods. Physiological and histopathological examinations were carried out for 5 days after laser treatment on nude mice. Percutaneous absorption of the permeants was determined by an in vitro Franz cell. Ablation depths varied in reaching the stratum corneum (10 μm, 2.5 J/cm²) to approach the epidermis (25 μm, 6.25 J/cm²) and upper dermis (40 μm, 10 J/cm²). Reepithelialization evaluated by transepidermal water loss was complete within 2-4 days and depended on the ablation depth. Epidermal hyperplasia was observed in the 40-μm-treated group. The laser was sufficient to disrupt the skin barrier and allow the transport of the permeants into and across the skin. The laser fluence was found to play an important role in modulating skin absorption. A 25-μm ablation depth increased tetracycline flux 84-fold. A much smaller enhancement (3.3-fold) was detected for tetracycline accumulation within the skin. The laser with different fluences produced enhancement of oxybenzone skin deposition of 3.4-6.4-fold relative to the untreated group. No penetration across the skin was shown regardless of whether titanium dioxide was applied to intact or laser-treated skin. However, laser resurfacing increased the skin deposition of titanium dioxide from 46 to 109-188 ng/g. Tetracycline absorption had recovered to the level of intact skin after 5 days, while more time was required for oxybenzone absorption. The in vivo skin accumulation and plasma concentration revealed that the laser could increase tetracycline absorption 2-3-fold. The experimental results indicated that clinicians should be cautious when determining the

  12. Spectroscopic investigation of amber color silicate glasses and factors affecting the amber related absorption bands.

    PubMed

    Morsi, Morsi M; El-Sherbiny, Samya I; Mohamed, Karam M

    2015-06-15

    The effects of carbon, Fe2O3 and Na2SO4 contents on the amber color of glass with composition (wt%) 64.3 SiO2, 25.7 CaO, 10 Na2O were studied. The effect of some additives that could be found in glass batch or cullets on the amber related absorption band(s) was also studied. An amber related absorption band due to the chromophore Fe(3+)O3S(2-) was recorded at 420 nm with shoulder at 440 nm. A second amber related band recorded at 474 nm with shoulder at 483 nm was assigned to FeS. Increasing melting time at 1400°C up to 6h caused fainting of the amber color, decreases the intensities of the amber related bands and shifted the first band to 406 nm. Addition of ZnO, Cu2O and NaNO3 to the glass produced decolorizing effect and vanishing of the amber related bands. The effects of melting time and these additives were explained on the bases of destruction the amber chromophore and its conversion into Fe(3+) in tetrahedral sites or ZnS. Addition of Se intensifies the amber related bands and may cause dark coloration due to the formation of Se° and polyselenide. Amber color can be monitored through measuring the absorption in the range 406-420 nm.

  13. Spectroscopic investigation of amber color silicate glasses and factors affecting the amber related absorption bands

    NASA Astrophysics Data System (ADS)

    Morsi, Morsi M.; El-sherbiny, Samya I.; Mohamed, Karam M.

    2015-06-01

    The effects of carbon, Fe2O3 and Na2SO4 contents on the amber color of glass with composition (wt%) 64.3 SiO2, 25.7 CaO, 10 Na2O were studied. The effect of some additives that could be found in glass batch or cullets on the amber related absorption band(s) was also studied. An amber related absorption band due to the chromophore Fe3+O3S2- was recorded at 420 nm with shoulder at 440 nm. A second amber related band recorded at 474 nm with shoulder at 483 nm was assigned to FeS. Increasing melting time at 1400 °C up to 6 h caused fainting of the amber color, decreases the intensities of the amber related bands and shifted the first band to 406 nm. Addition of ZnO, Cu2O and NaNO3 to the glass produced decolorizing effect and vanishing of the amber related bands. The effects of melting time and these additives were explained on the bases of destruction the amber chromophore and its conversion into Fe3+ in tetrahedral sites or ZnS. Addition of Se intensifies the amber related bands and may cause dark coloration due to the formation of Se° and polyselenide. Amber color can be monitored through measuring the absorption in the range 406-420 nm.

  14. Visualization of drug translocation in the nasal cavity and pharmacokinetic analysis on nasal drug absorption using positron emission tomography in the rat.

    PubMed

    Shingaki, Tomotaka; Katayama, Yumiko; Nakaoka, Takayoshi; Irie, Satsuki; Onoe, Kayo; Okauchi, Takashi; Hayashinaka, Emi; Yamaguchi, Masataka; Tanki, Nobuyoshi; Ose, Takayuki; Hayashi, Takuya; Wada, Yasuhiro; Furubayashi, Tomoyuki; Cui, Yilong; Sakane, Toshiyasu; Watanabe, Yasuyoshi

    2016-02-01

    We performed positron emission tomography (PET) using 2-deoxy-2-[(18)F]fluoro-D-glucose ([(18)F]FDG) to evaluate the pharmacokinetics of nasal drug absorption in the rat. The dosing solution of [(18)F]FDG was varied in volume (ranging from 5 to 25 μl) and viscosity (using 0% to 3% concentrations of hydroxypropylcellulose). We modeled the pharmacokinetic parameters regarding the nasal cavity and pharynx using mass balance equations, and evaluated the values that were obtained by fitting concentration-time profiles using WinNonlin® software. The regional nasal permeability was also estimated using the active surface area derived from the PET images. The translocation of [(18)F]FDG from the nasal cavity was visualized using PET. Analysis of the PET imaging data revealed that the pharmacokinetic parameters were independent of the dosing solution volume; however, the viscosity increased the absorption rate constant and decreased the mucociliary clearance rate constant. Nasal permeability was initially higher but subsequently decreased until the end of the study, indicating regional differences in permeability in the nasal cavity. We concluded that the visualization of drug translocation in the nasal cavity in the rat using PET enables quantitative analysis of nasal drug absorption, thereby facilitating the development of nasal formulations for human use.

  15. Effects of the mucoadhesive polymer polycarbophil on the intestinal absorption of a peptide drug in the rat.

    PubMed

    Lehr, C M; Bouwstra, J A; Kok, W; De Boer, A G; Tukker, J J; Verhoef, J C; Breimer, D D; Junginger, H E

    1992-05-01

    The absorption across rat intestinal tissue of the model peptide drug 9-desglycinamide, 8-arginine vasopressin from bioadhesive formulations was studied in-vitro, in a chronically isolated internal loop in-situ and after intraduodenal administration in-vivo. A controlled-release bioadhesive drug delivery system was tested, consisting of microspheres of poly(2-hydroxyethyl methacrylate) with a mucoadhesive Polycarbophil-coating, as well as fast-release formulation consisting of an aqueous solution of the peptide in a suspension of Polycarbophil particles. Using the controlled-release system, a slight improvement of peptide absorption was found in-vitro in comparison with a non-adhesive control system, but not in-situ or in-vivo. In contrast, bioavailability was significantly increased in all three models from the Polycarbophil suspension in comparison with a solution of the drug in saline. The effect appeared to be dose-dependent, indicative of intrinsic penetration-enhancing properties of the mucoadhesive polymer. A prolongation of the absorption phase in-vitro and in the chronically isolated loop in-situ suggested that the polymer was able to protect the peptide from proteolytic degradation. This could be confirmed by degradation studies in-vitro. The duration of the penetration enhancing/enzyme inhibiting effect was diminished with increasing complexity of the test model, in the same way as was previously found for the bioadhesive effect. This interrelationship suggests that the observed improvement in peptide absorption and the mucoadhesive properties of this polymer are associated. The development of a fast-release oral dosage form for peptide drugs on the basis of Polycarbophil appears to be possible.

  16. How could preventive therapy affect the prevalence of drug resistance? Causes and consequences

    PubMed Central

    Kunkel, Amber; Colijn, Caroline; Lipsitch, Marc; Cohen, Ted

    2015-01-01

    Various forms of preventive and prophylactic antimicrobial therapies have been proposed to combat HIV (e.g. pre-exposure prophylaxis), tuberculosis (e.g. isoniazid preventive therapy) and malaria (e.g. intermittent preventive treatment). However, the potential population-level effects of preventative therapy (PT) on the prevalence of drug resistance are not well understood. PT can directly affect the rate at which resistance is acquired among those receiving PT. It can also indirectly affect resistance by altering the rate at which resistance is acquired through treatment for active disease and by modifying the level of competition between transmission of drug-resistant and drug-sensitive pathogens. We propose a general mathematical model to explore the ways in which PT can affect the long-term prevalence of drug resistance. Depending on the relative contributions of these three mechanisms, we find that increasing the level of coverage of PT may result in increases, decreases or non-monotonic changes in the overall prevalence of drug resistance. These results demonstrate the complexity of the relationship between PT and drug resistance in the population. Care should be taken when predicting population-level changes in drug resistance from small pilot studies of PT or estimates based solely on its direct effects. PMID:25918446

  17. How could preventive therapy affect the prevalence of drug resistance? Causes and consequences.

    PubMed

    Kunkel, Amber; Colijn, Caroline; Lipsitch, Marc; Cohen, Ted

    2015-06-01

    Various forms of preventive and prophylactic antimicrobial therapies have been proposed to combat HIV (e.g. pre-exposure prophylaxis), tuberculosis (e.g. isoniazid preventive therapy) and malaria (e.g. intermittent preventive treatment). However, the potential population-level effects of preventative therapy (PT) on the prevalence of drug resistance are not well understood. PT can directly affect the rate at which resistance is acquired among those receiving PT. It can also indirectly affect resistance by altering the rate at which resistance is acquired through treatment for active disease and by modifying the level of competition between transmission of drug-resistant and drug-sensitive pathogens. We propose a general mathematical model to explore the ways in which PT can affect the long-term prevalence of drug resistance. Depending on the relative contributions of these three mechanisms, we find that increasing the level of coverage of PT may result in increases, decreases or non-monotonic changes in the overall prevalence of drug resistance. These results demonstrate the complexity of the relationship between PT and drug resistance in the population. Care should be taken when predicting population-level changes in drug resistance from small pilot studies of PT or estimates based solely on its direct effects.

  18. Physiologically Based In vitro Models to Predict the Oral Dissolution and Absorption of a Solid Drug Delivery System.

    PubMed

    Li, Ziqiang; He, Xin

    2015-01-01

    To understand the sophisticated dynamic behaviors of drug elution and permeation in the gastrointestinal tract (GIT), researchers have tried to reemerge it by employing various in vitro experimental models. However, official in vitro apparatuses routinely used for quality control purposes, employ simple, non-physiologic buffers, and hydrodynamics conditions, and can not accurately perform continuous, dynamic in vivo pharmacokinetics (PK) behaviors. Therefore, different angles of GI physiology information are incorporate into novel models to forecast the dissolution and permeation of drug solid dosage forms. This review, in general, discusses some related studies of physiologically-based mechanical models to predict human absorption following oral administration in four sections. First the GIT, taken out of a complex physiological environment, where the drug is absorbed, distributed, metabolized and excreted (ADME) in the human body, is considered as the physiological basis for active pharmaceutics ingredients (API) dissolved and permeated through the epithelial cell. The second part embodies the theoretical foundation of in vitro models to predict human absorption and the corresponding in vitro.in vivo correlations (IVIVC). The third section summarizes physiologically based dissolution models developed recently, ranging from dynamic compartmental dissolution models, to biorelevant dissolution models based on certain physiological factors, to biphasic dissolution models. The last part is devoted to combined dissolution and absorption models that can be employed to simulate the continuous, dynamic behavior of oral drug delivery being dissolved and subsequently permeated across the GIT. Along with physiologically-based mechanically models spring up, pharmaceutical researchers will harvest better level A IVIVC for oral drug delivery systems, especially for sustained and controlled release preparations. On the other way hand, it will successively promote more effective

  19. Mechanism of enhanced oral absorption of morin by phospholipid complex based self-nanoemulsifying drug delivery system.

    PubMed

    Zhang, Jinjie; Li, Jianbo; Ju, Yuan; Fu, Yao; Gong, Tao; Zhang, Zhirong

    2015-02-01

    Phospholipid complex (PLC) based self-nanoemulsifying drug delivery system (PLC-SNEDDS) has been developed for efficient delivery of drugs with poor solubility and low permeability. In the present study, a BCS class IV drug and a P-glycoprotein (P-gp) substrate, morin, was selected as the model drug to elucidate the oral absorption mechanism of PLC-SNEDDS. PLC-SNEDDS was superior to PLC in protecting morin from degradation by intestinal enzymes in vitro. In situ perfusion study showed increased intestinal permeability by PLC was duodenum-specific. In contrast, PLC-SNEDDS increased morin permeability in all intestinal segments and induced a change in the main absorption site of morin from colon to ileum. Moreover, ileum conducted the lymphatic transport of PLC-SNEDDS, which was proven by microscopic intestinal visualization of Nile red labeled PLC-SNEDDS and lymph fluids in vivo. Low cytotoxicity and increased Caco-2 cell uptake suggested a safe and efficient delivery of PLC-SNEDDS. The increased membrane fluidity and disrupted actin filaments were closely associated with the increased cell uptake of PLC-SNEDDS. PLC-SNEDDS could be internalized into enterocytes as an intact form in a cholesterol-dependent manner via clathrin-mediated endocytosis and macropinocytosis. The enhanced oral absorption of morin was attributed to the P-gp inhibition by Cremophor RH and the intact internalization of M-PLC-SNEDDS into Caco-2 cells bypassing P-gp recognition. Our findings thus provide new insights into the development of novel nanoemulsions for poorly absorbed drugs.

  20. Interplay of metabolism and transport in determining oral drug absorption and gut wall metabolism: a simulation assessment using the "Advanced Dissolution, Absorption, Metabolism (ADAM)" model.

    PubMed

    Darwich, A S; Neuhoff, S; Jamei, M; Rostami-Hodjegan, A

    2010-11-01

    Bioavailability of orally administered drugs can be influenced by a number of factors including release from the formulation, dissolution, stability in the gastrointestinal (GI) environment, permeability through the gut wall and first-pass gut wall and hepatic metabolism. Although there are various enzymes in the gut wall which may contribute to gut first pass metabolism, Cytochrome P450 (CYP) 3A has been shown to play a major role. The efflux transporter P-glycoprotein (P-gp; MDR1/ABCB1) is the most extensively studied drug efflux transporter in the gut and might have a significant role in the regulation of GI absorption. Although not every CYP3A substrate will have a high extent of gut wall first-pass extraction, being a substrate for the enzyme increases the likelihood of a higher first-pass extraction. Similarly, being a P-gp substrate does not necessarily pose a problem with the gut wall absorption however it may reduce bioavailability in some cases (e.g. when drug has low passive permeability). An on-going debate has focused on the issue of the interplay between CYP3A and P-gp such that high affinity to P-gp increases the exposure of drug to CYP3A through repeated cycling via passive diffusion and active efflux, decreasing the fraction of drug that escapes first pass gut metabolism (F(G)). The presence of P-gp in the gut wall and the high affinity of some CYP3A substrates to this transporter are postulated to reduce the potential for saturating the enzymes, thus increasing gut wall first-pass metabolism for compounds which otherwise would have saturated CYP3A. Such inferences are based on assumptions in the modelling of oral drug absorption. These models should be as mechanistic as possible and tractable using available in vitro and in vivo information. We review, through simulation, this subject and examine the interplay between gut wall metabolism and efflux transporters by studying the fraction of dose absorbed into enterocytes (F(a)) and F(G) via

  1. A Comparative Study of Molecular Structure, pKa, Lipophilicity, Solubility, Absorption and Polar Surface Area of Some Antiplatelet Drugs

    PubMed Central

    Remko, Milan; Remková, Anna; Broer, Ria

    2016-01-01

    Theoretical chemistry methods have been used to study the molecular properties of antiplatelet agents (ticlopidine, clopidogrel, prasugrel, elinogrel, ticagrelor and cangrelor) and several thiol-containing active metabolites. The geometries and energies of most stable conformers of these drugs have been computed at the Becke3LYP/6-311++G(d,p) level of density functional theory. Computed dissociation constants show that the active metabolites of prodrugs (ticlopidine, clopidogrel and prasugrel) and drugs elinogrel and cangrelor are completely ionized at pH 7.4. Both ticagrelor and its active metabolite are present at pH = 7.4 in neutral undissociated form. The thienopyridine prodrugs ticlopidine, clopidogrel and prasugrel are lipophilic and insoluble in water. Their lipophilicity is very high (about 2.5–3.5 logP values). The polar surface area, with regard to the structurally-heterogeneous character of these antiplatelet drugs, is from very large interval of values of 3–255 Å2. Thienopyridine prodrugs, like ticlopidine, clopidogrel and prasugrel, with the lowest polar surface area (PSA) values, exhibit the largest absorption. A high value of polar surface area (PSA) of cangrelor (255 Å2) results in substantial worsening of the absorption in comparison with thienopyridine drugs. PMID:27007371

  2. Henderson-Hasselbalch equation is inadequate for the measurement of transmembrane diffusion of drugs and buccal drug absorption is a useful alternative.

    PubMed

    Randhawa, M A; Iqbal, A; Nasimullah, M; Akhtar, M; Yousaf, S M; Turner, P

    1995-07-01

    1. The transmembrane diffusion of weakly acidic or basic drugs is being commonly assessed from their degree of ionization or ratio unionized/ionized forms (ratio U/I) as calculated from Henderson-Hasselbalch equation (HHEq). 2. Buccal drug absorption (BA) at pH 5-9 has been proposed as an in vivo model for passage of drugs across lipid membranes. 3. Area under the curve (AUC) of BA against pH 5-9 of 18 basic drugs has been reported to be significantly related to their pH dependent renal excretion. 4. We have calculated, using HHEq, ratios U/I of 10 weak bases at pH 5-9 and 10 weak acids at pH 4-8, whose percentage BA at these pH levels was available in the literature. 5. These ratios were not related to their %BA at corresponding pH levels. 6. Therefore it is proposed that HHEq is inadequate in the anticipation of transmembrane diffusion of drugs and AUC of %BA of drugs at pH 4-9 is a useful alternative.

  3. Prenatal exposure to recreational drugs affects global motion perception in preschool children.

    PubMed

    Chakraborty, Arijit; Anstice, Nicola S; Jacobs, Robert J; LaGasse, Linda L; Lester, Barry M; Wouldes, Trecia A; Thompson, Benjamin

    2015-01-01

    Prenatal exposure to recreational drugs impairs motor and cognitive development; however it is currently unknown whether visual brain areas are affected. To address this question, we investigated the effect of prenatal drug exposure on global motion perception, a behavioural measure of processing within the dorsal extrastriate visual cortex that is thought to be particularly vulnerable to abnormal neurodevelopment. Global motion perception was measured in one hundred and forty-five 4.5-year-old children who had been exposed to different combinations of methamphetamine, alcohol, nicotine and marijuana prior to birth and 25 unexposed children. Self-reported drug use by the mothers was verified by meconium analysis. We found that global motion perception was impaired by prenatal exposure to alcohol and improved significantly by exposure to marijuana. Exposure to both drugs prenatally had no effect. Other visual functions such as habitual visual acuity and stereoacuity were not affected by drug exposure. Prenatal exposure to methamphetamine did not influence visual function. Our results demonstrate that prenatal drug exposure can influence a behavioural measure of visual development, but that the effects are dependent on the specific drugs used during pregnancy. PMID:26581958

  4. Prenatal exposure to recreational drugs affects global motion perception in preschool children

    PubMed Central

    Chakraborty, Arijit; Anstice, Nicola S.; Jacobs, Robert J.; LaGasse, Linda L.; Lester, Barry M.; Wouldes, Trecia A.; Thompson, Benjamin

    2015-01-01

    Prenatal exposure to recreational drugs impairs motor and cognitive development; however it is currently unknown whether visual brain areas are affected. To address this question, we investigated the effect of prenatal drug exposure on global motion perception, a behavioural measure of processing within the dorsal extrastriate visual cortex that is thought to be particularly vulnerable to abnormal neurodevelopment. Global motion perception was measured in one hundred and forty-five 4.5-year-old children who had been exposed to different combinations of methamphetamine, alcohol, nicotine and marijuana prior to birth and 25 unexposed children. Self-reported drug use by the mothers was verified by meconium analysis. We found that global motion perception was impaired by prenatal exposure to alcohol and improved significantly by exposure to marijuana. Exposure to both drugs prenatally had no effect. Other visual functions such as habitual visual acuity and stereoacuity were not affected by drug exposure. Prenatal exposure to methamphetamine did not influence visual function. Our results demonstrate that prenatal drug exposure can influence a behavioural measure of visual development, but that the effects are dependent on the specific drugs used during pregnancy. PMID:26581958

  5. Improved oral absorption of dutasteride via Soluplus®-based supersaturable self-emulsifying drug delivery system (S-SEDDS).

    PubMed

    Lee, Dong Hoon; Yeom, Dong Woo; Song, Ye Seul; Cho, Ha Ra; Choi, Yong Seok; Kang, Myung Joo; Choi, Young Wook

    2015-01-15

    A novel supersaturable self-emulsifying drug delivery system (S-SEDDS) was formulated to improve the oral absorption of dutasteride (DTS), a 5α-reductase inhibitor that is poorly water-soluble. A supersaturable system was prepared by employing Soluplus(®) (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer) as a precipitation inhibitor with a conventional SEDDS vehicle consisted of Capryol™ 90, Cremophor(®) EL and Transcutol(®) HP (DTS:SEDDS vehicle:Soluplus(®)=1.0:67.6:10.0 w/v/w). In an in vitro dissolution test in a non-sink condition, the drug dissolution rate from SEDDS was rapidly increased to 72% for an initial period of 5min, but underwent rapid drug precipitation within 2h, decreasing the amount of drug dissolved to one-seventh of its original amount. On the other hand, S-SEDDS resulted in a slower crystallization of DTS by virtue of a precipitation inhibitor, maintaining a 3 times greater dissolution rate after 2h compared to SEDDS. In an in vivo pharmacokinetic study in rats, the S-SEDDS formulation exhibited 3.9-fold greater area-under-curve value than that of the drug suspension and 1.3-fold greater than that of SEDDS. The maximum plasma concentration of S-SEDDS was 5.6- and 2.0-fold higher compared to drug suspension and SEDDS, respectively. The results of this study suggest that the novel supersaturable system may be a promising tool for improving the physicochemical property and oral absorption of the 5α-reductase inhibitor. PMID:25437113

  6. Physiologically Based Absorption Modeling to Impact Biopharmaceutics and Formulation Strategies in Drug Development-Industry Case Studies.

    PubMed

    Kesisoglou, Filippos; Chung, John; van Asperen, Judith; Heimbach, Tycho

    2016-09-01

    In recent years, there has been a significant increase in use of physiologically based pharmacokinetic models in drug development and regulatory applications. Although most of the published examples have focused on aspects such as first-in-human (FIH) dose predictions or drug-drug interactions, several publications have highlighted the application of these models in the biopharmaceutics field and their use to inform formulation development. In this report, we present 5 case studies of use of such models in this biopharmaceutics/formulation space across different pharmaceutical companies. The case studies cover different aspects of biopharmaceutics or formulation questions including (1) prediction of absorption prior to FIH studies; (2) optimization of formulation and dissolution method post-FIH data; (3) early exploration of a modified-release formulation; (4) addressing bridging questions for late-stage formulation changes; and (5) prediction of pharmacokinetics in the fed state for a Biopharmaceutics Classification System class I drug with fasted state data. The discussion of the case studies focuses on how such models can facilitate decisions and biopharmaceutic understanding of drug candidates and the opportunities for increased use and acceptance of such models in drug development and regulatory interactions. PMID:26886317

  7. Influence of food on the absorption of metoprolol administered as an Oros drug delivery system to man.

    PubMed

    Lecaillon, J B; Massias, P; Schoeller, J P; Abadie, F

    1985-01-01

    The influence of food on the release, absorption and metabolism of metoprolol has been studied after single administration of a 19/190 Oros system to eight healthy volunteers on four occasions, once after an overnight fast, and just before each of three daily meals (breakfast, lunch and dinner). The plasma concentration-time profiles under the four test conditions were virtually identical, and no statistically significant differences in mean areas under the curves between 0 and 32 h, peak concentrations, or times to peak, were detected. The absorption of metoprolol was unaffected by food intake, with 80-90% of the amount absorbed reaching the systemic circulation within 10 h. The ratios of areas under the curve for alpha-hydroxymetoprolol to its parent drug were in the same range for the four treatments, and similar to those reported after conventional tablets. The in vivo release and absorption of drug from the Oros system and its systemic availability, were not influenced by concomitant ingestion of food.

  8. In silico prediction of drug dissolution and absorption with variation in intestinal pH for BCS class II weak acid drugs: ibuprofen and ketoprofen.

    PubMed

    Tsume, Yasuhiro; Langguth, Peter; Garcia-Arieta, Alfredo; Amidon, Gordon L

    2012-10-01

    The FDA Biopharmaceutical Classification System guidance allows waivers for in vivo bioavailability and bioequivalence studies for immediate-release solid oral dosage forms only for BCS class I. Extensions of the in vivo biowaiver for a number of drugs in BCS class III and BCS class II have been proposed, in particular, BCS class II weak acids. However, a discrepancy between the in vivo BE results and in vitro dissolution results for BCS class II acids was recently observed. The objectives of this study were to determine the oral absorption of BCS class II weak acids via simulation software and to determine if the in vitro dissolution test with various dissolution media could be sufficient for in vitro bioequivalence studies of ibuprofen and ketoprofen as models of carboxylic acid drugs. The oral absorption of these BCS class II acids from the gastrointestinal tract was predicted by GastroPlus™. Ibuprofen did not satisfy the bioequivalence criteria at lower settings of intestinal pH of 6.0. Further the experimental dissolution of ibuprofen tablets in a low concentration phosphate buffer at pH 6.0 (the average buffer capacity 2.2 mmol l (-1) /pH) was dramatically reduced compared with the dissolution in SIF (the average buffer capacity 12.6 mmol l (-1) /pH). Thus these predictions for the oral absorption of BCS class II acids indicate that the absorption patterns depend largely on the intestinal pH and buffer strength and must be considered carefully for a bioequivalence test. Simulation software may be a very useful tool to aid the selection of dissolution media that may be useful in setting an in vitro bioequivalence dissolution standard.

  9. Fate of ingested fluids: factors affecting gastric emptying and intestinal absorption of beverages in humans.

    PubMed

    Leiper, John B

    2015-09-01

    The volume of fluid ingested for rehydration is essential in determining the restoration of euhydration because it must be in excess of the water lost since the individual was last euhydrated. The formulation of any ingested beverage is also important as this affects the rate at which the fluid is emptied from the stomach, absorbed in the small intestine, and hence assimilated into the body water pool. This review highlights the essential role of the gastrointestinal tract in the maintenance of hydration status.

  10. Administration of a probiotic can change drug pharmacokinetics: effect of E. coli Nissle 1917 on amidarone absorption in rats.

    PubMed

    Matuskova, Zuzana; Anzenbacherova, Eva; Vecera, Rostislav; Tlaskalova-Hogenova, Helena; Kolar, Milan; Anzenbacher, Pavel

    2014-01-01

    The growing interest in the composition and effects of microbiota raised the question how drug pharmacokinetics could be influenced by concomitant application of probiotics. The aim of this study was to find whether probiotic E. coli strain Nissle 1917 (EcN) influences the pharmacokinetics of concomitantly taken antiarrhythmic drug amiodarone (AMI). Live bacterial suspension of probiotic EcN (or non-probiotic E. coli strain ATCC 25922) was applied orally to male Wistar rats for seven days, while a control group of rats was treated with a saline solution. On the eighth day, the amiodarone hydrochloride was administered as one single oral dose (50 mg/kg) to all rats (N = 60). After 0, 1, 2, 3, 4, 5.5, 7, 9, 14, 22, and 30 hours, blood samples were taken from the rat abdominal aorta. The plasma level of AMI and its metabolite N-desethylamiodarone (DEA) was determined using the HPLC with UV detection. Administration of EcN led to a 43% increase of AMI AUC0-30 in comparison with control samples. However, this effect was not observed if EcN was replaced by a reference non-probiotic E. coli strain. Thus, EcN administration was most probably responsible for better drug absorption from the gastrointestinal tract. Plasma levels of DEA were also increased in plasma samples from animals treated with EcN. This change was again not found in the experiment with the reference non-probiotic strain. Higher DEA levels in samples from EcN-treated rats may be explained either by better absorption of AMI and/or by an increased activity of CYP2C forms, known to participate in metabolism of this drug, after EcN administration. In this paper, it is documented that concomitantly taken probiotic EcN may modulate pharmacokinetics of a drug; in this case, it led to an increased bioavailability of AMI. PMID:24505278

  11. Drug Issues Affecting Chinese, Indian and Pakistani People Living in Greater Glasgow

    ERIC Educational Resources Information Center

    Ross, A. J.; Heim, D.; Bakshi, N.; Davies, J. B.; Flatley, K. J.; Hunter, S. C.

    2004-01-01

    This paper describes research on drug issues affecting Chinese, Indian and Pakistani people living in Greater Glasgow. There were two strands: (i) a questionnaire-based survey of young people and focus groups; (ii) interviews with young people and adults. The primary aims were to gather prevalence data and to investigate perceptions about current…

  12. Resources Related to Children and Their Families Affected by Alcohol and Other Drugs. 3rd Edition.

    ERIC Educational Resources Information Center

    Melner, Joan; Shackelford, Jo; Hargrove, Elisabeth; Daulton, Deb

    This document identifies resources that serve young children and their families affected by alcohol and other drug use. The resources are organized into three sections: National Training and Information Resources, State Programs and Agencies, and Federal Funding Sources. Information on locating grant funds from federal agencies, private…

  13. Influence of the hydrophilicity of suppository bases on rectal absorption of carprofen, a lipophilic nonsteroidal anti-inflammatory drug.

    PubMed

    Schmitt, M; Guentert, T W

    1990-04-01

    The influence of the hydrophilicity of fatty suppository bases on the rectal absorption of the lipophilic drug carprofen (octanol-buffer, pH 7.4; partition coefficient, 40) was investigated in dogs. Five animals received each of six carprofen formulations in a random sequence: intravenous, oral, and rectal solutions, and three suppository formulations. The suppository vehicles tested were semisynthetic glycerides containing saturated fatty acids mainly in the range of C10 to C18 [Massa Estarinum A (MEA), Massa Estarinum B (MEB), and Massa Estarinum 299 (ME299)]; their hydroxyl values increased from 1 for ME299, through 24 for MEB, to 45 for MEA. Following every drug administration, blood samples were collected over a period of 104 h and carprofen plasma concentrations were measured by a specific HPLC method with UV detection. The rate and extent of carprofen absorption were characterized by evaluation of the maximum plasma concentrations (Cmax), the time of their occurrence (tmax), absolute bioavailabilities, statistical moments, and by deconvolution. Carprofen was rapidly and completely absorbed from the oral solution. The maximum concentrations obtained with oral solutions were significantly higher than those observed with rectal solutions and with the three suppository formulations. Results obtained with the rectal solution exhibited a high degree of intersubject variability. After rectal administration of suppositories, the rate and extent of carprofen absorption increased with the hydroxyl value of the suppository base; the mean absorption times (MAT) and tmax were shorter with MEA (2.15 and 1.7 h, respectively) than with the less hydrophilic vehicles (MEB: 4.09 and 2.1 h, respectively; ME299: 4.22 and 2.4 h, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

  14. Biorelevant media for transport experiments in the Caco-2 model to evaluate drug absorption in the fasted and the fed state and their usefulness.

    PubMed

    Markopoulos, C; Thoenen, F; Preisig, D; Symillides, M; Vertzoni, M; Parrott, N; Reppas, C; Imanidis, G

    2014-04-01

    In this work we developed and characterized transport media that simulate the composition of micellar phase of intestinal fluids in the fasted and, especially, in the fed state and are appropriate for evaluating intestinal drug permeability characteristics using the Caco-2 model (FaSSIF-TM(Caco) and FeSSIF-TM(Caco), respectively). Media composition was based on FaSSIF-V2 and FeSSIF-V2 and recently reported data on total lipid concentrations in the micellar phase of contents of the upper small intestine in the fasted and the fed state and was adapted for cell culture compatibility. Permeation data were evaluated by compartmental kinetic modeling. Permeability coefficients, P, of hydrophilic drugs were not affected by media composition. In contrast, P values of a series of lipophilic compounds measured with FaSSIF-TM(Caco) and FeSSIF-TM(Caco), and reflecting transport by diffusion were smaller than those obtained with a purely aqueous reference transport medium, aq-TM(Caco), following the rank order aq-TM(Caco)>FaSSIF-TM(Caco)>FeSSIF-TM(Caco). The decline of permeability values was stronger as lipophilicity of the compounds increased. Compared with values estimated using aq-TM(Caco), permeability was reduced, depending on the compound, by more than 20- to 100-fold when measured with FeSSIF-TM(Caco) whereas compound ranking in regard to the permeability characteristics was also affected. The impact of reduced P value on flux through the mucosa, hence on drug absorption, in combination with the drug amount loaded on colloidal particles needs to be taken into consideration in PBPK modeling especially when the food effect is evaluated.

  15. Current Approaches for Absorption, Distribution, Metabolism, and Excretion Characterization of Antibody-Drug Conjugates: An Industry White Paper.

    PubMed

    Kraynov, Eugenia; Kamath, Amrita V; Walles, Markus; Tarcsa, Edit; Deslandes, Antoine; Iyer, Ramaswamy A; Datta-Mannan, Amita; Sriraman, Priya; Bairlein, Michaela; Yang, Johnny J; Barfield, Matthew; Xiao, Guangqing; Escandon, Enrique; Wang, Weirong; Rock, Dan A; Chemuturi, Nagendra V; Moore, David J

    2016-05-01

    An antibody-drug conjugate (ADC) is a unique therapeutic modality composed of a highly potent drug molecule conjugated to a monoclonal antibody. As the number of ADCs in various stages of nonclinical and clinical development has been increasing, pharmaceutical companies have been exploring diverse approaches to understanding the disposition of ADCs. To identify the key absorption, distribution, metabolism, and excretion (ADME) issues worth examining when developing an ADC and to find optimal scientifically based approaches to evaluate ADC ADME, the International Consortium for Innovation and Quality in Pharmaceutical Development launched an ADC ADME working group in early 2014. This white paper contains observations from the working group and provides an initial framework on issues and approaches to consider when evaluating the ADME of ADCs.

  16. Do androgen deprivation drugs affect the immune cross-talk between mononuclear and prostate cancer cells?

    PubMed

    Salman, Hertzel; Bergman, Michael; Blumberger, Naava; Djaldetti, Meir; Bessler, Hanna

    2014-02-01

    The aim of the study was to examine the effect of androgen deprivation drugs, i.e. leuprolide and bicalutamide on the immune cross-talk between human peripheral blood mononuclear cells (PBMC) and cells from PC-3 and LNCaP human prostate cancer lines. PBMC, PC-3 and LNCaP were separately incubated without and with two androgen-deprivation drugs, i.e. leuprolide and bicalutamide, and the secretion of IL-1β, IL-6, IL-1ra and IL-10 was examined. In addition, the effect of both drugs on the production of those cytokines was carried out after 24 hours incubation of PBMC with both types of cancer cells. Leuprolide or bicalutamide did not affect the production of the cytokines by PBMC or by the prostate cancer cells from the two lines. Incubation of PBMC with PC-3 or LNCaP cells caused increased production of IL-1β, IL-6 and IL-10 as compared with PBMC incubated without malignant cells. While 10(-7) M and 10(-8) M of leuprolide caused a decreased secretion of IL-1β by PBMC previously incubated with prostate cancer cells without the drug, bicalutamide did not affect this PBMC activity at any drug concentration. This observation suggests the existence of an additional mechanism explaining the effect of androgen deprivation therapy in prostate cancer patients.

  17. Drug addiction: An affective-cognitive disorder in need of a cure.

    PubMed

    Fattore, Liana; Diana, Marco

    2016-06-01

    Drug addiction is a compulsive behavioral abnormality. In spite of pharmacological treatments and psychosocial support to reduce or eliminate drug intake, addiction tends to persist over time. Preclinical and human observations have converged on the hypothesis that addiction represents the pathological deterioration of neural processes that normally serve affective and cognitive functioning. The major elements of persistent compulsive drug use are hypothesized to be structural, cellular and molecular that underlie enduring changes in several forebrain circuits that receive input from midbrain dopamine neurons and are involved in affective (e.g. ventral striatum) and cognitive (e.g. prefrontal cortex) mechanisms. Here we review recent progress in identifying crucial elements useful to understand the pathophysiology of the disease and its treatments. Manipulation of neuropeptides brain systems and pharmacological targeting of κ-opioid receptors and/or drug metabolism may hold beneficial effects at affective and cognitive level. Non-pharmacological, highly innovative approaches such as Transcranial Magnetic Stimulation may reveal unsuspected potential and promise to be the first neurobiology-based therapeutics in addiction. PMID:27095547

  18. Enhancement of in-vitro drug dissolution of ketoconazole for its optimal in-vivo absorption using Nanoparticles and Solid Dispersion forms of the drug

    NASA Astrophysics Data System (ADS)

    Syed, Mohammed Irfan

    was modified to include 0.02%, 0.05% and 0.1% sodium lauryl sulfate. Here, after 2 hours, the amount of drug dissolved was calculated to be 10% from controls, 21% from solid dispersion and 36% from nanoparticles in SIF with 0.02% SLS. Drug release was 20% from controls, 41% from solid dispersion and 52% from nanoparticle formulation in SIF with 0.05% SLS. Whereas amount of drug released in SIF with 0.1% SLS showed 21% from the control, 62% from solid dispersion and 85% from Nanoparticles respectively. This data supports that the ketoconazole Nanoparticles and its solid-dispersion exhibit many fold increase in dissolution of the drug, which could lead to a less variable and enhanced in-vivo drug absorption profiles. In addition, the data from the Physical Characterization (DSC, XRD and FTIR) supports that there were no interaction within the ingredients occurred in Nanoparticles and solid-dispersion formulations of the drug sample. Wet Bead Milling and Hot Melt methods proved useful in developing the Nanoparticles and solid dispersion form of ketoconazole. Results from particle size analysis were in correlation with data obtained from Scanning electron Microscopy and size of the nanoparticles was below 100nm. The dissolution studies with the modified simulated intestinal fluid (SIF) exhibited several fold increase in the dissolution of the drug compared to the pure drug powder and the commercial products used as the control. Also, the results from the physical characterization studies clearly support the stability of ketoconazole in both of these formulations.

  19. Recent advances in delivery systems and therapeutics of cinnarizine: a poorly water soluble drug with absorption window in stomach.

    PubMed

    Raghuvanshi, Smita; Pathak, Kamla

    2014-01-01

    Low solubility causing low dissolution in gastrointestinal tract is the major problem for drugs meant for systemic action after oral administration, like cinnarizine. Pharmaceutical products of cinnarizine are commercialized globally as immediate release preparations presenting low absorption with low and erratic bioavailability. Approaches to enhance bioavailability are widely cited in the literature. An attempt has been made to review the bioavailability complications and clinical therapeutics of poorly water soluble drug: cinnarizine. The interest of writing this paper is to summarize the pharmacokinetic limitations of drug with special focus on strategies to improvise bioavailability along with effectiveness of novel dosage forms to circumvent the obstacle. The paper provides insight to the approaches to overcome low and erratic bioavailability of cinnarizine by cyclodextrin complexes and novel dosage forms: self-nanoemulsifying systems and buoyant microparticulates. Nanoformulations need to systematically explored in future, for their new clinical role in prophylaxis of migraine attacks in children. Clinical reports have affirmed the role of cinnarizine in migraine prophylaxis. Research needs to be dedicated to develop dosage forms for efficacious bioavailability and drug directly to brain. PMID:25478230

  20. Statistical Design of Experiments on Fabrication of Bilayer Tablet of Narrow Absorption Window Drug: Development and In vitro characterisation.

    PubMed

    Jivani, R R; Patel, C N; Jivani, N P

    2012-07-01

    The current study involves the fabrication of oral bioadhesive bilayer matrices of narrow absorption window drug baclofen and the optimisation of their in vitro drug release and characterisation. Statistical design of experiments, a computer-aided optimisation technique, was used to identify critical factors, their interactions and ideal process conditions that accomplish the targeted response(s). A central composite design was employed to systematically optimise the drug delivery containing a polymer, filler and compression force. The values of ratio of different grades of hydroxypropyl methylcellulose, microcrystalline cellulose and compression force were varied to be fitted in design. Drug release at 1 h (Q1), 4 h (Q4), 8 h (Q8), 12 h (Q12), and hardness were taken as responses. Tablets were prepared by direct compression methods. The compressed tablets were evaluated for their hardness, weight variation, friability, content uniformity and diameter. Counter plots were drawn and optimum formulation was selected by desirability function. The formulations were checked for their ex vivo mucoadhesion. The experimental value of Q1, Q4, Q8, Q12 and hardness for check-point batch was found to be 31.64, 45.82, 73.27, 98.95% and 4.4 kg/cm(2), respectively. The release profile indicates Highuchi kinetics (Fickian transport) mechanism. The results of the statistical analysis of the data demonstrated significant interactions amongst the formulation variables, and the desirability function was demonstrated to be a powerful tool to predict the optimal formulation for the bilayer tablet.

  1. Recent Advances in Delivery Systems and Therapeutics of Cinnarizine: A Poorly Water Soluble Drug with Absorption Window in Stomach

    PubMed Central

    Pathak, Kamla

    2014-01-01

    Low solubility causing low dissolution in gastrointestinal tract is the major problem for drugs meant for systemic action after oral administration, like cinnarizine. Pharmaceutical products of cinnarizine are commercialized globally as immediate release preparations presenting low absorption with low and erratic bioavailability. Approaches to enhance bioavailability are widely cited in the literature. An attempt has been made to review the bioavailability complications and clinical therapeutics of poorly water soluble drug: cinnarizine. The interest of writing this paper is to summarize the pharmacokinetic limitations of drug with special focus on strategies to improvise bioavailability along with effectiveness of novel dosage forms to circumvent the obstacle. The paper provides insight to the approaches to overcome low and erratic bioavailability of cinnarizine by cyclodextrin complexes and novel dosage forms: self-nanoemulsifying systems and buoyant microparticulates. Nanoformulations need to systematically explored in future, for their new clinical role in prophylaxis of migraine attacks in children. Clinical reports have affirmed the role of cinnarizine in migraine prophylaxis. Research needs to be dedicated to develop dosage forms for efficacious bioavailability and drug directly to brain. PMID:25478230

  2. Evaluation of chromatographic descriptors for the prediction of gastro-intestinal absorption of drugs.

    PubMed

    Deconinck, E; Ates, H; Callebaut, N; Van Gyseghem, E; Vander Heyden, Y

    2007-01-01

    The use of chromatographic descriptors in QSAR was evaluated. Therefore, retentions were measured on an immobilized artificial membrane system, 2 micellar liquid chromatography systems and 17 orthogonal or disimilar reversed-phase liquid chromatographic systems. It was investigated whether it was possible to model gastro-intestinal absorption as a function of chromatographic retentions applying two linear and one non-linear multivariate modeling technique. In a second step it was evaluated if models built with theoretical descriptors could be improved by adding the measured retention factors to the data set of descriptive variables. It was seen that gastro-intestinal absorption could be modelled in function of chromatographic retention using the non-linear modeling technique multivariate adaptive regression splines (MARS). The best models were obtained using a combination of theoretical and chromatographic descriptors with MARS as modeling technique.

  3. Colorimetric and atomic absorption spectrometric determination of mucolytic drug ambroxol through ion-pair formation with iron and thiocyanate.

    PubMed

    Levent, Abdulkadir; Sentürk, Zühre

    2010-09-01

    Colorimetric and atomic absorption spectrometric methods have been developed for the determination of mucolytic drug Ambroxol. These procedures depend upon the reaction of iron(III) metal ion with the drug in the presence of thiocyanate ion to form stable ion-pair complex which extractable chloroform. The red-coloured complex was determined either colorimetrically at 510 nm or by indirect atomic absorption spectrometry (AAS) via the determination of the iron content in the formed complex. The optimum experimental conditions for pH, concentrations of Fe(3+) and SCN(-), shaking time, phase ratio, and the number of extractions were determined. Under the proposed conditions, linearity was obeyed in the concentration ranges 4.1x10(-6) - 5.7x10(-5) M (1.7-23.6 µg mL(-1)) using both methods, with detection limits of 4.6x10(-7) M (0.19 µg mL(-1)) for colorimetry and 1.1x10(-6) M (0.46 µg mL(-1)) for AAS. The proposed methods were applied for the determination of Ambroxol in tablet dosage forms. The results obtained were statistically analyzed and compared with those obtained by applying the high-performance liquid chromatographic method with diode-array detection.

  4. Early pharmaceutical profiling to predict oral drug absorption: current status and unmet needs.

    PubMed

    Bergström, Christel A S; Holm, René; Jørgensen, Søren Astrup; Andersson, Sara B E; Artursson, Per; Beato, Stefania; Borde, Anders; Box, Karl; Brewster, Marcus; Dressman, Jennifer; Feng, Kung-I; Halbert, Gavin; Kostewicz, Edmund; McAllister, Mark; Muenster, Uwe; Thinnes, Julian; Taylor, Robert; Mullertz, Anette

    2014-06-16

    Preformulation measurements are used to estimate the fraction absorbed in vivo for orally administered compounds and thereby allow an early evaluation of the need for enabling formulations. As part of the Oral Biopharmaceutical Tools (OrBiTo) project, this review provides a summary of the pharmaceutical profiling methods available, with focus on in silico and in vitro models typically used to forecast active pharmaceutical ingredient's (APIs) in vivo performance after oral administration. An overview of the composition of human, animal and simulated gastrointestinal (GI) fluids is provided and state-of-the art methodologies to study API properties impacting on oral absorption are reviewed. Assays performed during early development, i.e. physicochemical characterization, dissolution profiles under physiological conditions, permeability assays and the impact of excipients on these properties are discussed in detail and future demands on pharmaceutical profiling are identified. It is expected that innovative computational and experimental methods that better describe molecular processes involved in vivo during dissolution and absorption of APIs will be developed in the OrBiTo. These methods will provide early insights into successful pathways (medicinal chemistry or formulation strategy) and are anticipated to increase the number of new APIs with good oral absorption being discovered.

  5. Drugs and the Brain: An Introduction to Neuropharmacology. Pamphlet Series.

    ERIC Educational Resources Information Center

    Brick, John

    The thousands of different drugs on the market can be separated into two categories: drugs that affect behavior, called psychoactive drugs, and drugs that do not affect behavior. Drugs get into the body by mouth, inhalation into the lungs, by injection into a vein, muscle or under the skin, and by absorption through mucous membranes. Regardless of…

  6. Factors affecting treatment outcomes in drug-resistant tuberculosis cases in the Northern Cape, South Africa.

    PubMed

    Elliott, E; Draper, H R; Baitsiwe, P; Claassens, M M

    2014-09-21

    The Northern Cape Province has low cure rates (21%) for multidrug-resistant tuberculosis (TB). We audited the programme to identify factors affecting treatment outcomes. Cases admitted to two drug-resistant TB units from 2007 to 2009 had data extracted from clinical folders. Unfavourable treatment outcomes were found in 58% of the 272 cases. A multivariable regression analysis found that male sex was associated with unfavourable outcome (P = 0.009). Weight at diagnosis (P < 0.001) and oral drug adherence (P < 0.001) were also associated with an unfavourable outcome; however, injectable drug adherence was not (P = 0.395). Positive baseline smear and human immunodeficiency virus positive status were not associated with unfavourable outcome. Shorter, more patient-friendly regimens may go a long way to improving adherence and outcomes.

  7. Factors Affecting the Timing of Signal Detection of Adverse Drug Reactions.

    PubMed

    Hashiguchi, Masayuki; Imai, Shungo; Uehara, Keiko; Maruyama, Junya; Shimizu, Mikiko; Mochizuki, Mayumi

    2015-01-01

    We investigated factors affecting the timing of signal detection by comparing variations in reporting time of known and unknown ADRs after initial drug release in the USA. Data on adverse event reactions (AERs) submitted to U.S. FDA was used. Six ADRs associated with 6 drugs (rosuvastatin, aripiprazole, teriparatide, telithromycin, exenatide, varenicline) were investigated: Changes in the proportional reporting ratio, reporting odds ratio, and information component as indexes of signal detection were followed every 3 months after each drugs release, and the time for detection of signals was investigated. The time for the detection of signal to be detected after drug release in the USA was 2-10 months for known ADRs and 19-44 months for unknown ones. The median lag time for known and unknown ADRs was 99.0-122.5 days and 185.5-306.0 days, respectively. When the FDA released advisory information on rare but potentially serious health risks of an unknown ADR, the time lag to report from the onset of ADRs to the FDA was shorter. This study suggested that one factor affecting signal detection time is whether an ADR was known or unknown at release. PMID:26641634

  8. Factors determining drug residence in skin during transdermal absorption: studies on beta-blocking agents.

    PubMed

    Yagi, S; Nakayama, K; Kurosaki, Y; Higaki, K; Kimura, T

    1998-11-01

    The factors determining drug residence in skin during penetration across rat abdominal skin were investigated using five beta-blocking agents with different lipophilicities as model drugs in vivo and in vitro. The amount of beta-blocking agent in the skin at steady state correlated well with lipophilicity. The distribution of beta-blocking agents to the stratum corneum and the contribution of intercellular lipids in the stratum corneum to their skin distribution were also correlated with their lipophilicity, suggesting that the stratum corneum, especially intercellular lipids in the stratum corneum, would be responsible for the residence of beta-blocking agents in the skin. Furthermore, cholesterol-3-sulfate, palmitic acid, stearic acid and oleic acid were found to interact with the beta-blocking agents, which are cationized under the physiological condition, and were assumed to play an important role in the skin accumulation. On the other hand, the binding to keratinocyte was so small that keratinocyte might have little effect on the skin accumulation of the beta-blocking agents. Drug transport from the stratum corneum to viable skin was suggested to be regulated by the lipophilicity of these agents. To investigate the residence of these drugs in viable skin, in vitro transport studies using stripped skin were performed. The transport rate constant across viable skin to receptor cells (k23) was inversely correlated with the lipophilicity of the drugs. The elimination rate constants from viable skin (k(vs)) obtained in the in vivo study were much smaller than the values of k23 obtained in the in vitro study, and they were inversely correlated with the binding to cytosol components of viable skin but not the lipophilicity. The viable skin-to-muscle concentration ratio of these drugs, obtained at the beta-phase of the plasma concentration-time curve after intravenous administration, was also inversely correlated with the binding to the cytosol components of viable

  9. Mechanistic adaptability of cancer cells strongly affects anti-migratory drug efficacy.

    PubMed

    Sun, Wei; Lim, Chwee Teck; Kurniawan, Nicholas Agung

    2014-10-01

    Cancer metastasis involves the dissemination of cancer cells from the primary tumour site and is responsible for the majority of solid tumour-related mortality. Screening of anti-metastasis drugs often includes functional assays that examine cancer cell invasion inside a three-dimensional hydrogel that mimics the extracellular matrix (ECM). Here, we built a mechanically tuneable collagen hydrogel model to recapitulate cancer spreading into heterogeneous tumour stroma and monitored the three-dimensional invasion of highly malignant breast cancer cells, MDA-MB-231. Migration assays were carried out in the presence and the absence of drugs affecting four typical molecular mechanisms involved in cell migration, as well as under five ECMs with different biophysical properties. Strikingly, the effects of the drugs were observed to vary strongly with matrix mechanics and microarchitecture, despite the little dependence of the inherent cancer cell migration on the ECM condition. Specifically, cytoskeletal contractility-targeting drugs reduced migration speed in sparse gels, whereas migration in dense gels was retarded effectively by inhibiting proteolysis. The results corroborate the ability of cancer cells to switch their multiple invasion mechanisms depending on ECM condition, thus suggesting the importance of factoring in the biophysical properties of the ECM in anti-metastasis drug screenings.

  10. Assessment of In Vivo Clinical Product Performance of a Weak Basic Drug by Integration of In Vitro Dissolution Tests and Physiologically Based Absorption Modeling.

    PubMed

    Ding, Xuan; Gueorguieva, Ivelina; Wesley, James A; Burns, Lee J; Coutant, Carrie A

    2015-11-01

    Effective integration of in vitro tests and absorption modeling can greatly improve our capability in understanding, comparing, and predicting in vivo performances of clinical drug products. In this case, we used a proprietary drug candidate galunisertib to describe the procedures of designing key in vitro tests, analyzing relevant experimental and trial data, and integrating them into physiologically based absorption models to evaluate the performances of its clinical products. By simulating the preclinical study result, we estimated high in vivo permeability for the drug. Given the high sensitivity of its solubility to pH, supersaturation may play an important role in the absorption of galunisertib. Using the dynamic dissolution test, i.e., artificial stomach-duodenum (ASD) model and simulation, we concluded galunisertib in solution or tablet products could maintain supersaturation during the transit in the gastrointestinal tract (GIT). A physiologically based absorption model was established by incorporating these key inputs in the simulation of Trial 1 results of galunisertib solution. To predict the performance of three tablet products, we developed z-factor dissolution models from the multi-pH USP dissolution results and integrate them into the absorption model. The resultant biopharmaceutical models provided good prediction of the extent of absorption of all three products, but underestimated the rate of absorption of one tablet product. Leveraging the ASD result and optimization with the dissolution model, we identified the limitation of the model due to complexity of estimating the dissolution parameter z and its in vitro-in vivo correlation.

  11. Consumption of organic diets does not affect intake and absorption of zinc and copper in men - evidence from two cross-over trials.

    PubMed

    Mark, Alicja Budek; Kápolna, Emese; Laursen, Kristian H; Halekoh, Ulrich; Rasmussen, Søren K; Husted, Søren; Larsen, Erik H; Bügel, Susanne

    2013-02-26

    Agricultural methods may affect the nutritional composition of plants and cause complex changes in the food matrix. Whether this affects the dietary absorption of minerals that are important for maintaining health thorough life remains unclear. We compared the effects of organic and conventional diets on intake and absorption of zinc and copper in men. Two double-blinded, cross-over, intervention trials (3 dietary periods of 12 days with 2-week-long wash-out) were performed in 2008 (n = 17) and 2009 (n = 16) in young men. The diets were based on 9 crops grown in rigidly controlled organic and conventional systems in 2 replications over 2 years. The primary outcomes were intake and absorption of zinc and copper. The absorption was determined by faecal excretion of stable enriched isotopes extrinsically added to the entire menu. Within each year, the intake and absorption of zinc (overall mean ± SD; 12.35 ± 0.47 mg per 10 MJ and 44.6% ± 12.1, respectively) and copper (overall mean ± SD; 2.12 ± 0.28 mg per 10 MJ and 41.2% ± 13.2, respectively) were not different between the organic and conventional diets. The growing season had no effect on zinc intake and absorption, but the copper intake was higher (P = 0.01) and absorption lower (P < 0.005) in 2008 compared with 2009 (overall mean absorption ± SD; 35.3% ± 13.5 in 2008 and 54.0% ± 10.7 in 2009). In conclusion, organic agriculture does not affect the intake and absorption of copper and zinc in men. Consequently, it does not seem to promote the health beneficial role of these minerals in vivo.

  12. Characterization of the activities of actin-affecting drugs on tumor cell migration

    SciTech Connect

    Hayot, Caroline; Debeir, Olivier; Ham, Philippe van; Damme, Marc van; Kiss, Robert; Decaestecker, Christine . E-mail: cdecaes@ulb.ac.be

    2006-02-15

    Metastases kill 90% of cancer patients. It is thus a major challenge in cancer therapy to inhibit the spreading of tumor cells from primary tumor sites to those particular organs where metastases are likely to occur. Whereas the actin cytoskeleton is a key component involved in cell migration, agents targeting actin dynamics have been relatively poorly investigated. Consequently, valuable in vitro pharmacological tools are needed to selectively identify this type of agent. In response to the absence of any standardized process, the present work aims to develop a multi-assay strategy for screening actin-affecting drugs with anti-migratory potentials. To validate our approach, we used two cancer cell lines (MCF7 and A549) and three actin-affecting drugs (cytochalasin D, latrunculin A, and jasplakinolide). We quantified the effects of these drugs on the kinetics of actin polymerization in tubes (by means of spectrofluorimetry) and on the dynamics of actin cytoskeletons within whole cells (by means of fluorescence microscopy). Using quantitative videomicroscopy, we investigated the actual effects of the drugs on cell motility. Finally, the combined drug effects on cell motility and cell growth were evaluated by means of a scratch-wound assay. While our results showed concordant drug-induced effects on actin polymerization occurring in vitro in test tubes and within whole cells, the whole cell assay appeared more sensitive than the tube assay. The inhibition of actin polymerization induced by cytochalasin D was paralleled by a decrease in cell motility for both cell types. In the case of jasplakinolide, which induces actin polymerization, while it significantly enhanced the locomotion of the A549 cells, it significantly inhibited that of the MCF-7 ones. All these effects were confirmed by means of the scratch-wound assay except of the jasplakinolide-induced effects on MCF-7 cell motility. These later seemed compensated by an additional effect occurring during wound

  13. Generation of enterocyte-like cells from human induced pluripotent stem cells for drug absorption and metabolism studies in human small intestine

    PubMed Central

    Ozawa, Tatsuya; Takayama, Kazuo; Okamoto, Ryota; Negoro, Ryosuke; Sakurai, Fuminori; Tachibana, Masashi; Kawabata, Kenji; Mizuguchi, Hiroyuki

    2015-01-01

    Enterocytes play an important role in drug absorption and metabolism. However, a widely used enterocyte model, Caco-2 cell, has difficulty in evaluating both drug absorption and metabolism because the expression levels of some drug absorption and metabolism-related genes in these cells differ largely from those of human enterocytes. Therefore, we decided to generate the enterocyte-like cells from human induced pluripotent stem (iPS) cells (hiPS-ELCs), which are applicable to drug absorption and metabolism studies. The efficiency of enterocyte differentiation from human iPS cells was significantly improved by using EGF, SB431542, and Wnt3A, and extending the differentiation period. The gene expression levels of cytochrome P450 3A4 (CYP3A4) and peptide transporter 1 in the hiPS-ELCs were higher than those in Caco-2 cells. In addition, CYP3A4 expression in the hiPS-ELCs was induced by treatment with 1, 25-dihydroxyvitamin D3 or rifampicin, which are known to induce CYP3A4 expression, indicating that the hiPS-ELCs have CYP3A4 induction potency. Moreover, the transendothelial electrical resistance (TEER) value of the hiPS-ELC monolayer was approximately 240 Ω*cm2, suggesting that the hiPS-ELC monolayer could form a barrier. In conclusion, we succeeded in establishing an enterocyte model from human iPS cells which have potential to be applied for drug absorption and metabolism studies. PMID:26559489

  14. Generation of enterocyte-like cells from human induced pluripotent stem cells for drug absorption and metabolism studies in human small intestine.

    PubMed

    Ozawa, Tatsuya; Takayama, Kazuo; Okamoto, Ryota; Negoro, Ryosuke; Sakurai, Fuminori; Tachibana, Masashi; Kawabata, Kenji; Mizuguchi, Hiroyuki

    2015-11-12

    Enterocytes play an important role in drug absorption and metabolism. However, a widely used enterocyte model, Caco-2 cell, has difficulty in evaluating both drug absorption and metabolism because the expression levels of some drug absorption and metabolism-related genes in these cells differ largely from those of human enterocytes. Therefore, we decided to generate the enterocyte-like cells from human induced pluripotent stem (iPS) cells (hiPS-ELCs), which are applicable to drug absorption and metabolism studies. The efficiency of enterocyte differentiation from human iPS cells was significantly improved by using EGF, SB431542, and Wnt3A, and extending the differentiation period. The gene expression levels of cytochrome P450 3A4 (CYP3A4) and peptide transporter 1 in the hiPS-ELCs were higher than those in Caco-2 cells. In addition, CYP3A4 expression in the hiPS-ELCs was induced by treatment with 1, 25-dihydroxyvitamin D3 or rifampicin, which are known to induce CYP3A4 expression, indicating that the hiPS-ELCs have CYP3A4 induction potency. Moreover, the transendothelial electrical resistance (TEER) value of the hiPS-ELC monolayer was approximately 240 Ω*cm(2), suggesting that the hiPS-ELC monolayer could form a barrier. In conclusion, we succeeded in establishing an enterocyte model from human iPS cells which have potential to be applied for drug absorption and metabolism studies.

  15. Alpha-lactalbumin and casein-glycomacropeptide do not affect iron absorption from formula in healthy term infants

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Iron absorption from infant formula is relatively low. Alpha-lactalbumin and casein-glycomacropeptide have been suggested to enhance mineral absorption. We therefore assessed the effect of alpha-lactalbumin and casein-glycomacropeptide on iron absorption from infant formula in healthy term infants. ...

  16. Non-Destructive and Discriminating Identification of Illegal Drugs by Transient Absorption Spectroscopy in the Visible and Near-IR Wavelength Range

    NASA Astrophysics Data System (ADS)

    Sato, Chie; Furube, Akihiro; Katoh, Ryuzi; Nonaka, Hidehiko; Inoue, Hiroyuki

    2008-11-01

    We have tested the possibility of identifying illegal drugs by means of nanosecond transient absorption spectroscopy with a 10-ns UV-laser pulse for the excitation light and visible-to-near-IR light for the probe light. We measured the transient absorption spectra of acetonitrile solutions of d-methamphetamine, dl-3,4-methylenedioxymethamphetamine hydrochloride (MDMA), and dl-N-methyl-1-(1,3-benzodioxol-5-yl)-2-butanamine hydrochloride (MBDB), which are illegal drugs widely consumed in Japan. Transient absorption signals of these drugs were observed between 400 and 950 nm, a range in which they are transparent in the ground state. By analyzing the spectra in terms of exponential and Gaussian functions, we could identify the drugs and discriminate them from chemical substances having similar structures. We propose that transient absorption spectroscopy will be a useful, non-destructive method of inspecting for illegal drugs, especially when they are dissolved in liquids. Such a method may even be used for drugs packed in opaque materials if it is further extended to utilize intense femtosecond laser pulses.

  17. Mode of oral iron administration and the amount of iron habitually consumed do not affect iron absorption, systemic iron utilisation or zinc absorption in iron-sufficient infants: a randomised trial.

    PubMed

    Szymlek-Gay, Ewa A; Domellöf, Magnus; Hernell, Olle; Hurrell, Richard F; Lind, Torbjörn; Lönnerdal, Bo; Zeder, Christophe; Egli, Ines M

    2016-09-01

    Different metabolic pathways of supplemental and fortification Fe, or inhibition of Zn absorption by Fe, may explain adverse effects of supplemental Fe in Fe-sufficient infants. We determined whether the mode of oral Fe administration or the amount habitually consumed affects Fe absorption and systemic Fe utilisation in infants, and assessed the effects of these interventions on Zn absorption, Fe and Zn status, and growth. Fe-sufficient 6-month-old infants (n 72) were randomly assigned to receive 6·6 mg Fe/d from a high-Fe formula, 1·3 mg Fe/d from a low-Fe formula or 6·6 mg Fe/d from Fe drops and a formula with no added Fe for 45 d. Fractional Fe absorption, Fe utilisation and fractional Zn absorption were measured with oral (57Fe and 67Zn) and intravenous (58Fe and 70Zn) isotopes. Fe and Zn status, infection and growth were measured. At 45 d, Hb was 6·3 g/l higher in the high-Fe formula group compared with the Fe drops group, whereas serum ferritin was 34 and 35 % higher, respectively, and serum transferrin 0·1 g/l lower in the high-Fe formula and Fe drops groups compared with the low-Fe formula group (all P<0·05). No intervention effects were observed on Fe absorption, Fe utilisation, Zn absorption, other Fe status indices, plasma Zn or growth. We concluded that neither supplemental or fortification Fe nor the amount of Fe habitually consumed altered Fe absorption, Fe utilisation, Zn absorption, Zn status or growth in Fe-sufficient infants. Consumption of low-Fe formula as the only source of Fe was insufficient to maintain Fe stores.

  18. Mode of oral iron administration and the amount of iron habitually consumed do not affect iron absorption, systemic iron utilisation or zinc absorption in iron-sufficient infants: a randomised trial.

    PubMed

    Szymlek-Gay, Ewa A; Domellöf, Magnus; Hernell, Olle; Hurrell, Richard F; Lind, Torbjörn; Lönnerdal, Bo; Zeder, Christophe; Egli, Ines M

    2016-09-01

    Different metabolic pathways of supplemental and fortification Fe, or inhibition of Zn absorption by Fe, may explain adverse effects of supplemental Fe in Fe-sufficient infants. We determined whether the mode of oral Fe administration or the amount habitually consumed affects Fe absorption and systemic Fe utilisation in infants, and assessed the effects of these interventions on Zn absorption, Fe and Zn status, and growth. Fe-sufficient 6-month-old infants (n 72) were randomly assigned to receive 6·6 mg Fe/d from a high-Fe formula, 1·3 mg Fe/d from a low-Fe formula or 6·6 mg Fe/d from Fe drops and a formula with no added Fe for 45 d. Fractional Fe absorption, Fe utilisation and fractional Zn absorption were measured with oral (57Fe and 67Zn) and intravenous (58Fe and 70Zn) isotopes. Fe and Zn status, infection and growth were measured. At 45 d, Hb was 6·3 g/l higher in the high-Fe formula group compared with the Fe drops group, whereas serum ferritin was 34 and 35 % higher, respectively, and serum transferrin 0·1 g/l lower in the high-Fe formula and Fe drops groups compared with the low-Fe formula group (all P<0·05). No intervention effects were observed on Fe absorption, Fe utilisation, Zn absorption, other Fe status indices, plasma Zn or growth. We concluded that neither supplemental or fortification Fe nor the amount of Fe habitually consumed altered Fe absorption, Fe utilisation, Zn absorption, Zn status or growth in Fe-sufficient infants. Consumption of low-Fe formula as the only source of Fe was insufficient to maintain Fe stores. PMID:27546308

  19. Study of in vitro drug release and percutaneous absorption of fluconazole from topical dosage forms.

    PubMed

    Salerno, Claudia; Carlucci, Adriana M; Bregni, Carlos

    2010-06-01

    The present study aimed to evaluate different dosage forms, emulsions, emulgels, lipogels, and thickened microemulsion-based hydrogel, as fluconazole topical delivery systems with the purpose of determining a formulation with the capacity to deliver the whole active compound and maintain it within the skin so as to be considered a useful formulation either for topical mycosis treatment or as adjuvant in a combined therapy for Cutaneous Leishmaniasis. Propylene glycol and diethyleneglycol monoethyl ether were used for each dosage form as solvent for the drug and also as penetration enhancers. In vitro drug release after application of a clinically relevant dose of each formulation was evaluated and then microemulsions and lipogels were selected for the in vitro penetration and permeation study. Membranes of mixed cellulose esters and full-thickness pig ear skin were used for the in vitro studies. Candida albicans was used to test antifungal activity. A microemulsion containing diethyleneglycol monoethyl ether was found to be the optimum formulation as it was able to deliver the whole contained dose and enhance its skin penetration. Also this microemulsion showed the best performance in the antifungal activity test compared with the one containing propylene glycol. These results are according to previous reports of the advantages of microemulsions for topical administration and they are very promising for further clinical evaluation.

  20. Aminoclay-lipid hybrid composite as a novel drug carrier of fenofibrate for the enhancement of drug release and oral absorption.

    PubMed

    Yang, Liang; Shao, Yating; Han, Hyo-Kyung

    2016-01-01

    This study aimed to prepare the aminoclay-lipid hybrid composite to enhance the drug release and improve the oral bioavailability of poorly water-soluble fenofibrate. Antisolvent precipitation coupled with an immediate freeze-drying method was adopted to incorporate fenofibrate into aminoclay-lipid hybrid composite (ALC). The optimal composition of the ALC formulation was determined as the ratios of aminoclay to krill oil of 3:1 (w/w), krill oil to fenofibrate of 2:1 (w/w), and antisolvent to solvent of 6:4 (v/v). The morphological characteristics of ALC formulation were determined using scanning electron microscopy, differential scanning calorimetry, and X-ray powder diffraction, which indicated microcrystalline state of fenofibrate in ALC formulation. The ALC formulation achieved almost complete dissolution within 30 minutes, whereas the untreated powder and physical mixture exhibited less than 15% drug release. Furthermore, ALC formulation effectively increased the peak plasma concentration (C max) and area under the curve (AUC) of fenofibric acid (an active metabolite) in rats by approximately 13- and seven-fold, respectively. Furthermore, ALC formulation exhibited much lower moisture sorption behavior than the lyophilized formulation using sucrose as a cryoprotectant. Taken together, the present findings suggest that ALC formulation is promising for improving the oral absorption of poorly soluble fenofibrate. PMID:27042061

  1. Aminoclay–lipid hybrid composite as a novel drug carrier of fenofibrate for the enhancement of drug release and oral absorption

    PubMed Central

    Yang, Liang; Shao, Yating; Han, Hyo-Kyung

    2016-01-01

    This study aimed to prepare the aminoclay–lipid hybrid composite to enhance the drug release and improve the oral bioavailability of poorly water-soluble fenofibrate. Antisolvent precipitation coupled with an immediate freeze-drying method was adopted to incorporate fenofibrate into aminoclay–lipid hybrid composite (ALC). The optimal composition of the ALC formulation was determined as the ratios of aminoclay to krill oil of 3:1 (w/w), krill oil to fenofibrate of 2:1 (w/w), and antisolvent to solvent of 6:4 (v/v). The morphological characteristics of ALC formulation were determined using scanning electron microscopy, differential scanning calorimetry, and X-ray powder diffraction, which indicated microcrystalline state of fenofibrate in ALC formulation. The ALC formulation achieved almost complete dissolution within 30 minutes, whereas the untreated powder and physical mixture exhibited less than 15% drug release. Furthermore, ALC formulation effectively increased the peak plasma concentration (Cmax) and area under the curve (AUC) of fenofibric acid (an active metabolite) in rats by approximately 13- and seven-fold, respectively. Furthermore, ALC formulation exhibited much lower moisture sorption behavior than the lyophilized formulation using sucrose as a cryoprotectant. Taken together, the present findings suggest that ALC formulation is promising for improving the oral absorption of poorly soluble fenofibrate. PMID:27042061

  2. The affective dimension of pain as a risk factor for drug and alcohol addiction.

    PubMed

    LeBlanc, Dana M; McGinn, M Adrienne; Itoga, Christy A; Edwards, Scott

    2015-12-01

    Addiction, or substance use disorder (SUD), is a devastating psychiatric disease composed of multiple elemental features. As a biobehavioral disorder, escalation of drug and/or alcohol intake is both a cause and consequence of molecular neuroadaptations in central brain reinforcement circuitry. Multiple mesolimbic areas mediate a host of negative affective and motivational symptoms that appear to be central to the addiction process. Brain stress- and reinforcement-related regions such as the central amygdala (CeA), prefrontal cortex (PFC), and nucleus accumbens (NAc) also serve as central processors of ascending nociceptive input. We hypothesize that a sensitization of brain mechanisms underlying the processing of persistent and maladaptive pain contributes to a composite negative affective state to drive the enduring, relapsing nature of addiction, particularly in the case of alcohol and opioid use disorder. At the neurochemical level, pain activates central stress-related neuropeptide signaling, including the dynorphin and corticotropin-releasing factor (CRF) systems, and by this process may facilitate negative affect and escalated drug and alcohol use over time. Importantly, the widespread prevalence of unresolved pain and associated affective dysregulation in clinical populations highlights the need for more effective analgesic medications with reduced potential for tolerance and dependence. The burgeoning epidemic of prescription opioid abuse also demands a closer investigation into the neurobiological mechanisms of how pain treatment could potentially represent a significant risk factor for addiction in vulnerable populations. Finally, the continuing convergence of sensory and affective neuroscience fields is expected to generate insight into the critical balance between pain relief and addiction liability, as well as provide more effective therapeutic strategies for chronic pain and addiction.

  3. Physicochemical characteristics and gastrointestinal absorption behaviors of S-propargyl-cysteine, a potential new drug candidate for cardiovascular protection and antitumor treatment.

    PubMed

    Ma, Guo; Zhang, Lin; Zhang, Peng; Bao, Xingfei; Zhou, Ning; Shi, Qingling; Zheng, Yuanting; Liu, Hongrui; Bu, Fengjiao; Zhang, Ying; Huang, Wenjie; Wang, Fen; Zhu, Yizhun; Cai, Weimin

    2015-04-01

    1. As a potential new drug candidate for cardiovascular protection and antitumor treatment, the physicochemical properties, gastrointestinal (GI) absorption behaviors and mechanisms of S-propargyl-cysteine (SPRC) were investigated in this study. 2. SPRC exhibited favorable solubility in aqueous media. The log P and log D values were low (≤1.93 ± 0.08). The pKa in the acidic and basic regions was 2.08 ± 0.02 and 8.72 ± 0.03, respectively. The isoelectric point was 5.40 ± 0.02. SPRC was stable in the rat GI fluids, and showed no obvious adsorption and metabolism in the rat GI tract. 3. SPRC displayed poor gastric absorption and favorable intestinal absorption in the rat in situ GI perfusion model. Absorption rate constants (ka), hourly absorption percentage (P) and apparent permeability coefficient (Papp) of SPRC in the small intestine were ≥0.77 ± 0.06 h(-1), 59.25 ± 4.02% and (7.99 ± 0.88) × 10(-5 )cm/s, respectively. Absorption of SPRC exhibited a certain dependence on physiological pH and absorption region. Absorption of SPRC was not inhibited by l-methionine and 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid. 4. SPRC showed favorable oral absorption. It can be categorized as a BCS class I drug. The membrane pore transport appeared to be one of the predominant absorption modes for SPRC.

  4. Enhanced Oral Delivery of Protein Drugs Using Zwitterion-Functionalized Nanoparticles to Overcome both the Diffusion and Absorption Barriers.

    PubMed

    Shan, Wei; Zhu, Xi; Tao, Wei; Cui, Yi; Liu, Min; Wu, Lei; Li, Lian; Zheng, Yaxian; Huang, Yuan

    2016-09-28

    Oral delivery of protein drugs based on nanoparticulate delivery system requires permeation of the nanoparticles through the mucus layer and subsequent absorption via epithelial cells. However, overcoming these two barriers requires very different or even contradictory surface properties of the nanocarriers, which greatly limits the oral bioavailability of macromolecular drugs. Here we report a simple zwitterions-based nanoparticle (NP) delivery platform, which showed a great potency in simultaneously overcoming both the mucus and epithelium barriers. The dense and hydrophilic coating of zwitterions endows the NPs with excellent mucus penetrating ability. Moreover, the zwitterions-based NPs also possessed excellent affinity with epithelial cells, which significantly improved (4.5-fold) the cellular uptake of DLPC NPs, compared to PEGylated NPs. Our results also indicated that this affinity was due to the interaction between zwitterions and the cell surface transporter PEPT1. Moreover, the developed NPs loaded with insulin could induce a prominent hypoglycemic response in diabetic rats following oral administration. These results suggest that zwitterions-based NPs might provide a new perspective for oral delivery of protein therapeutics.

  5. Translating Human Effective Jejunal Intestinal Permeability to Surface-Dependent Intrinsic Permeability: a Pragmatic Method for a More Mechanistic Prediction of Regional Oral Drug Absorption.

    PubMed

    Olivares-Morales, Andrés; Lennernäs, Hans; Aarons, Leon; Rostami-Hodjegan, Amin

    2015-09-01

    Regional intestinal effective permeability (P(eff)) values are key for the understanding of drug absorption along the whole length of the human gastrointestinal (GI) tract. The distal regions of the GI tract (i.e. ileum, ascending-transverse colon) represent the main sites for GI absorption when there is incomplete absorption in the upper GI tract, e.g. for modified release formulations. In this work, a new and pragmatic method for the estimation of (passive) intestinal permeability in the different intestinal regions is being proposed, by translating the observed differences in the available mucosal surface area along the human GI tract into corrections of the historical determined jejunal P(eff) values. These new intestinal P(eff) values or "intrinsic" P(eff)(P(eff,int)) were subsequently employed for the prediction of the ileal absorption clearance (CL(abs,ileum)) for a set of structurally diverse compounds. Additionally, the method was combined with a semi-mechanistic absorption PBPK model for the prediction of the fraction absorbed (f(abs)). The results showed that P(eff,int) can successfully be employed for the prediction of the ileal CL(abs) and the f(abs). P(eff,int) also showed to be a robust predictor of the f(abs) when the colonic absorption was allowed in the PBPK model, reducing the overprediction of f(abs) observed for lowly permeable compounds when using the historical P(eff) values. Due to its simplicity, this approach provides a useful alternative for the bottom-up prediction of GI drug absorption, especially when the distal GI tract plays a crucial role for a drug's GI absorption.

  6. Meal conditions affect the absorption of supplemental vitamin D3 but not the plasma 25-hydroxyvitamin D response to supplementation

    Technology Transfer Automated Retrieval System (TEKTRAN)

    It is sometimes assumed that dietary fat is required for vitamin D absorption, although the impact of different amounts of dietary fat on vitamin D absorption is not established. This study was conducted to determine whether the presence of a meal and the fat content of the meal influences vitamin D...

  7. Ultrasonic Vocalizations as a Measure of Affect in Preclinical Models of Drug Abuse: A Review of Current Findings.

    PubMed

    Barker, David J; Simmons, Steven J; West, Mark O

    2015-01-01

    The present review describes ways in which ultrasonic vocalizations (USVs) have been used in studies of substance abuse. Accordingly, studies are reviewed which demonstrate roles for affective processing in response to the presentation of drug-related cues, experimenter- and self-administered drug, drug withdrawal, and during tests of relapse/reinstatement. The review focuses on data collected from studies using cocaine and amphetamine, where a large body of evidence has been collected. Data suggest that USVs capture animals' initial positive reactions to psychostimulant administration and are capable of identifying individual differences in affective responding. Moreover, USVs have been used to demonstrate that positive affect becomes sensitized to psychostimulants over acute exposure before eventually exhibiting signs of tolerance. In the drug-dependent animal, a mixture of USVs suggesting positive and negative affect is observed, illustrating mixed responses to psychostimulants. This mixture is predominantly characterized by an initial bout of positive affect followed by an opponent negative emotional state, mirroring affective responses observed in human addicts. During drug withdrawal, USVs demonstrate the presence of negative affective withdrawal symptoms. Finally, it has been shown that drug-paired cues produce a learned, positive anticipatory response during training, and that presentation of drug-paired cues following abstinence produces both positive affect and reinstatement behavior. Thus, USVs are a useful tool for obtaining an objective measurement of affective states in animal models of substance abuse and can increase the information extracted from drug administration studies. USVs enable detection of subtle differences in a behavioral response that might otherwise be missed using traditional measures. PMID:26411762

  8. Ultrasonic Vocalizations as a Measure of Affect in Preclinical Models of Drug Abuse: A Review of Current Findings

    PubMed Central

    Barker, David J.; Simmons, Steven J.; West, Mark O.

    2015-01-01

    The present review describes ways in which ultrasonic vocalizations (USVs) have been used in studies of substance abuse. Accordingly, studies are reviewed which demonstrate roles for affective processing in response to the presentation of drug-related cues, experimenter- and self-administered drug, drug withdrawal, and during tests of relapse/reinstatement. The review focuses on data collected from studies using cocaine and amphetamine, where a large body of evidence has been collected. Data suggest that USVs capture animals’ initial positive reactions to psychostimulant administration and are capable of identifying individual differences in affective responding. Moreover, USVs have been used to demonstrate that positive affect becomes sensitized to psychostimulants over acute exposure before eventually exhibiting signs of tolerance. In the drug-dependent animal, a mixture of USVs suggesting positive and negative affect is observed, illustrating mixed responses to psychostimulants. This mixture is predominantly characterized by an initial bout of positive affect followed by an opponent negative emotional state, mirroring affective responses observed in human addicts. During drug withdrawal, USVs demonstrate the presence of negative affective withdrawal symptoms. Finally, it has been shown that drug-paired cues produce a learned, positive anticipatory response during training, and that presentation of drug-paired cues following abstinence produces both positive affect and reinstatement behavior. Thus, USVs are a useful tool for obtaining an objective measurement of affective states in animal models of substance abuse and can increase the information extracted from drug administration studies. USVs enable detection of subtle differences in a behavioral response that might otherwise be missed using traditional measures. PMID:26411762

  9. Ex Vivo and In Situ Evaluation of 'Dispelling-Wind' Chinese Medicine Herb-Drugs on Intestinal Absorption of Chlorogenic Acid.

    PubMed

    Zhai, Lixiang; Shi, Jun; Xu, Weitong; Heinrich, Michael; Wang, Jianying; Deng, Wenji

    2015-12-01

    This study aims to investigate the additive or synergistic effects and mechanism of intestinal absorption of extracts from two commonly used 'dispelling-wind' TCM botanical drugs [roots of Angelica dahurica (Hoffm.) Benth. & Hook. f. ex Franch. & Sav. (RAD) and Saposhnikovia divaricata (Turcz.) Schischk. (RSD)] using chlorogenic acid as a marker substance. Ex vivo everted intestinal sac and in situ single pass perfusion methods using rats were employed to investigate the effects of two TCM botanical drugs extracts on the intestinal absorption of chlorogenic acid. Both the extracts of RAD and RSD showed synergistic properties on the intestinal absorption of chlorogenic acid. The verapamil (a P-gp inhibitor) and intestinal dysbacteriosis model induced by norfloxacin increased the P(app) and K(a) of intestinal absorption of chlorogenic acid. These synergistic effects on intestinal absorption in a rat model can be correlated with the inhibition of P-gp and regulation of gut microbiota. This experimental approach has helped to better understand changes in the absorption of chlorogenic acid under different conditions.

  10. Dietary inulin intake and age can significantly affect intestinal absorption of calcium and magnesium in rats: a stable isotope approach

    PubMed Central

    Coudray, Charles; Rambeau, Mathieu; Feillet-Coudray, Christine; Tressol, Jean Claude; Demigne, Christian; Gueux, Elyett; Mazur, Andrzej; Rayssiguier, Yves

    2005-01-01

    Background previous studies have shown that non-digestible inulin-type fructan intake can increase intestinal mineral absorption in both humans and animals. However, this stimulatory effect on intestinal absorption may depend on experimental conditions such as duration of fermentable fiber intake, mineral diet levels and animals' physiological status, in particular their age. Objectives the aim of this study was to determine the effect of inulin intake on Ca and Mg absorption in rats at different age stages. Methods eighty male Wistar rats of four different ages (2, 5, 10 and 20 months) were randomized into either a control group or a group receiving 3.75% inulin in their diet for 4 days and then 7.5% inulin for three weeks. The animals were fed fresh food and water ad libitum for the duration of the experiment. Intestinal absorption of Ca and Mg was determined by fecal monitoring using stable isotopic tracers. Ca and Mg status was also assessed. Results absorption of Ca and Mg was significantly lower in the aged rats (10 and 20 mo) than in the young and adult rat groups. As expected, inulin intake increased Ca and Mg absorption in all four rat groups. However, inulin had a numerically greater effect on Ca absorption in aged rats than in younger rats whereas its effect on Mg absorption remained similar across all four rat age groups. Conclusion the extent of the stimulatory effect of inulin on absorption of Ca may differ according to animal ages. Further studies are required to explore this effect over longer inulin intake periods, and to confirm these results in humans. PMID:16253138

  11. Justification of Drug Product Dissolution Rate and Drug Substance Particle Size Specifications Based on Absorption PBPK Modeling for Lesinurad Immediate Release Tablets.

    PubMed

    Pepin, Xavier J H; Flanagan, Talia R; Holt, David J; Eidelman, Anna; Treacy, Don; Rowlings, Colin E

    2016-09-01

    In silico absorption modeling has been performed, to assess the impact of in vitro dissolution on in vivo performance for ZURAMPIC (lesinurad) tablets. The dissolution profiles of lesinurad tablets generated using the quality control method were used as an input to a GastroPlus model to estimate in vivo dissolution in the various parts of the GI tract and predict human exposure. A model was set up, which accounts for differences of dosage form transit, dissolution, local pH in the GI tract, and fluid volumes available for dissolution. The predictive ability of the model was demonstrated by confirming that it can reproduce the Cmax observed for independent clinical trial. The model also indicated that drug product batches that pass the proposed dissolution specification of Q = 80% in 30 min are anticipated to be bioequivalent to the clinical reference batch. To further explore the dissolution space, additional simulations were performed using a theoretical dissolution profile below the proposed specification. The GastroPlus modeling indicates that such a batch will also be bioequivalent to standard clinical batches despite having a dissolution profile, which would fail the proposed dissolution specification of Q = 80% in 30 min. This demonstrates that the proposed dissolution specification sits comfortably within a region of dissolution performance where bioequivalence is anticipated and is not near an edge of failure for dissolution, providing additional confidence to the proposed specifications. Finally, simulations were performed using a virtual drug substance batch with a particle size distribution at the limit of the proposed specification for particle size. Based on these simulations, such a batch is also anticipated to be bioequivalent to clinical reference, demonstrating that the proposed specification limits for particle size distribution would give products bioequivalent to the pivotal clinical batches. PMID:27438964

  12. Justification of Drug Product Dissolution Rate and Drug Substance Particle Size Specifications Based on Absorption PBPK Modeling for Lesinurad Immediate Release Tablets.

    PubMed

    Pepin, Xavier J H; Flanagan, Talia R; Holt, David J; Eidelman, Anna; Treacy, Don; Rowlings, Colin E

    2016-09-01

    In silico absorption modeling has been performed, to assess the impact of in vitro dissolution on in vivo performance for ZURAMPIC (lesinurad) tablets. The dissolution profiles of lesinurad tablets generated using the quality control method were used as an input to a GastroPlus model to estimate in vivo dissolution in the various parts of the GI tract and predict human exposure. A model was set up, which accounts for differences of dosage form transit, dissolution, local pH in the GI tract, and fluid volumes available for dissolution. The predictive ability of the model was demonstrated by confirming that it can reproduce the Cmax observed for independent clinical trial. The model also indicated that drug product batches that pass the proposed dissolution specification of Q = 80% in 30 min are anticipated to be bioequivalent to the clinical reference batch. To further explore the dissolution space, additional simulations were performed using a theoretical dissolution profile below the proposed specification. The GastroPlus modeling indicates that such a batch will also be bioequivalent to standard clinical batches despite having a dissolution profile, which would fail the proposed dissolution specification of Q = 80% in 30 min. This demonstrates that the proposed dissolution specification sits comfortably within a region of dissolution performance where bioequivalence is anticipated and is not near an edge of failure for dissolution, providing additional confidence to the proposed specifications. Finally, simulations were performed using a virtual drug substance batch with a particle size distribution at the limit of the proposed specification for particle size. Based on these simulations, such a batch is also anticipated to be bioequivalent to clinical reference, demonstrating that the proposed specification limits for particle size distribution would give products bioequivalent to the pivotal clinical batches.

  13. Preformulation characterization and in vivo absorption in beagle dogs of JFD, a novel anti-obesity drug for oral delivery.

    PubMed

    Fan, Yunzhou; Yang, Meiyan; Wang, Yuli; Li, Yanyou; Zhou, Yuanda; Chen, Xiaoping; Shan, Li; Wei, Jun; Gao, Chunsheng

    2015-05-01

    JFD (N-isoleucyl-4-methyl-1,1-cyclopropyl-1-(4-chlorine)phenyl-2-amylamine·HCl) is a novel investigational anti-obesity drug without obvious cardiotoxicity. The objective of this study was to characterize the key physicochemical properties of JFD, including solution-state characterization (ionization constant, partition coefficient, aqueous and pH-solubility profile), solid-state characterization (particle size, thermal analysis, crystallinity and hygroscopicity) and drug-excipient chemical compatibility. A supporting in vivo absorption study was also carried out in beagle dogs. JFD bulk powders are prismatic crystals with a low degree of crystallinity, particle sizes of which are within 2-10 μm. JFD is highly hygroscopic, easily deliquesces to an amorphous glass solid and changes subsequently to another crystal form under an elevated moisture/temperature condition. Similar physical instability was also observed in real-time CheqSol solubility assay. pK(a) (7.49 ± 0.01), log P (5.10 ± 0.02) and intrinsic solubility (S0) (1.75 μg/ml) at 37 °C of JFD were obtained using potentiometric titration method. Based on these solution-state properties, JFD was estimated to be classified as BCS II, thus its dissolution rate may be an absorption-limiting step. Moreover, JFD was more chemically compatible with dibasic calcium phosphate, mannitol, hypromellose and colloidal silicon dioxide than with lactose and magnesium stearate. Further, JFD exhibited an acceptable pharmacokinetic profiling in beagle dogs and the pharmacokinetic parameters T(max), C(max), AUC(0-t) and absolute bioavailability were 1.60 ± 0.81 h, 0.78 ± 0.47 μg/ml, 3.77 ± 1.85 μg·h/ml and 52.30 ± 19.39%, respectively. The preformulation characterization provides valuable information for further development of oral administration of JFD. PMID:24694186

  14. Preformulation characterization and in vivo absorption in beagle dogs of JFD, a novel anti-obesity drug for oral delivery.

    PubMed

    Fan, Yunzhou; Yang, Meiyan; Wang, Yuli; Li, Yanyou; Zhou, Yuanda; Chen, Xiaoping; Shan, Li; Wei, Jun; Gao, Chunsheng

    2015-05-01

    JFD (N-isoleucyl-4-methyl-1,1-cyclopropyl-1-(4-chlorine)phenyl-2-amylamine·HCl) is a novel investigational anti-obesity drug without obvious cardiotoxicity. The objective of this study was to characterize the key physicochemical properties of JFD, including solution-state characterization (ionization constant, partition coefficient, aqueous and pH-solubility profile), solid-state characterization (particle size, thermal analysis, crystallinity and hygroscopicity) and drug-excipient chemical compatibility. A supporting in vivo absorption study was also carried out in beagle dogs. JFD bulk powders are prismatic crystals with a low degree of crystallinity, particle sizes of which are within 2-10 μm. JFD is highly hygroscopic, easily deliquesces to an amorphous glass solid and changes subsequently to another crystal form under an elevated moisture/temperature condition. Similar physical instability was also observed in real-time CheqSol solubility assay. pK(a) (7.49 ± 0.01), log P (5.10 ± 0.02) and intrinsic solubility (S0) (1.75 μg/ml) at 37 °C of JFD were obtained using potentiometric titration method. Based on these solution-state properties, JFD was estimated to be classified as BCS II, thus its dissolution rate may be an absorption-limiting step. Moreover, JFD was more chemically compatible with dibasic calcium phosphate, mannitol, hypromellose and colloidal silicon dioxide than with lactose and magnesium stearate. Further, JFD exhibited an acceptable pharmacokinetic profiling in beagle dogs and the pharmacokinetic parameters T(max), C(max), AUC(0-t) and absolute bioavailability were 1.60 ± 0.81 h, 0.78 ± 0.47 μg/ml, 3.77 ± 1.85 μg·h/ml and 52.30 ± 19.39%, respectively. The preformulation characterization provides valuable information for further development of oral administration of JFD.

  15. Polymer combination increased both physical stability and oral absorption of solid dispersions containing a low glass transition temperature drug: physicochemical characterization and in vivo study.

    PubMed

    Sakurai, Atsushi; Sakai, Toshiro; Sako, Kazuhiro; Maitani, Yoshie

    2012-01-01

    The purpose of this study was establishing a solid dispersion formulation containing a low glass transition temperature (T(g)) and poorly water-soluble drug. Drug/polymer blends with differing physicochemical stabilities and oral absorption were prepared from copolyvidone (PVP-VA), polyvinylpyrrolidone (PVP) or hydroxypropylmethylcellulose (HPMC) by a hot melt extrusion. HPMC drastically increased the drug oral absorption property, while PVP-VA or PVP stabilized solid dispersions during storage by increasing the T(g) in proportion to polymer concentration. Experimental T(g) values corresponded closely with theoretical T(g) values; indeed, the T(g) values of solid dispersion with HPMC did not increase significantly compared to the T(g) value for the drug alone. A solid dispersion formulation incorporating two different polymers-HPMC and either PVP-VA or PVP-maintained increased T(g), physicochemical stability, solubility, and bioavailability of the solid dispresions owing to each polymer. These findings suggested that both oral absorption and physicochemical stability of low-T(g) drug will be improved using less amount of solid dispersion of combined two polymers than polymer alone.

  16. Neuronal ferritin heavy chain and drug abuse affect HIV-associated cognitive dysfunction.

    PubMed

    Pitcher, Jonathan; Abt, Anna; Myers, Jaclyn; Han, Rachel; Snyder, Melissa; Graziano, Alessandro; Festa, Lindsay; Kutzler, Michele; Garcia, Fernando; Gao, Wen-Jun; Fischer-Smith, Tracy; Rappaport, Jay; Meucci, Olimpia

    2014-02-01

    Interaction of the chemokine CXCL12 with its receptor CXCR4 promotes neuronal function and survival during embryonic development and throughout adulthood. Previous studies indicated that μ-opioid agonists specifically elevate neuronal levels of the protein ferritin heavy chain (FHC), which negatively regulates CXCR4 signaling and affects the neuroprotective function of the CXCL12/CXCR4 axis. Here, we determined that CXCL12/CXCR4 activity increased dendritic spine density, and also examined FHC expression and CXCR4 status in opiate abusers and patients with HIV-associated neurocognitive disorders (HAND), which is typically exacerbated by illicit drug use. Drug abusers and HIV patients with HAND had increased levels of FHC, which correlated with reduced CXCR4 activation, within cortical neurons. We confirmed these findings in a nonhuman primate model of SIV infection with morphine administration. Transfection of a CXCR4-expressing human cell line with an iron-deficient FHC mutant confirmed that increased FHC expression deregulated CXCR4 signaling and that this function of FHC was independent of iron binding. Furthermore, examination of morphine-treated rodents and isolated neurons expressing FHC shRNA revealed that FHC contributed to morphine-induced dendritic spine loss. Together, these data implicate FHC-dependent deregulation of CXCL12/CXCR4 as a contributing factor to cognitive dysfunction in neuroAIDS.

  17. Neuronal ferritin heavy chain and drug abuse affect HIV-associated cognitive dysfunction

    PubMed Central

    Pitcher, Jonathan; Abt, Anna; Myers, Jaclyn; Han, Rachel; Snyder, Melissa; Graziano, Alessandro; Festa, Lindsay; Kutzler, Michele; Garcia, Fernando; Gao, Wen-Jun; Fischer-Smith, Tracy; Rappaport, Jay; Meucci, Olimpia

    2014-01-01

    Interaction of the chemokine CXCL12 with its receptor CXCR4 promotes neuronal function and survival during embryonic development and throughout adulthood. Previous studies indicated that μ-opioid agonists specifically elevate neuronal levels of the protein ferritin heavy chain (FHC), which negatively regulates CXCR4 signaling and affects the neuroprotective function of the CXCL12/CXCR4 axis. Here, we determined that CXCL12/CXCR4 activity increased dendritic spine density, and also examined FHC expression and CXCR4 status in opiate abusers and patients with HIV-associated neurocognitive disorders (HAND), which is typically exacerbated by illicit drug use. Drug abusers and HIV patients with HAND had increased levels of FHC, which correlated with reduced CXCR4 activation, within cortical neurons. We confirmed these findings in a nonhuman primate model of SIV infection with morphine administration. Transfection of a CXCR4-expressing human cell line with an iron-deficient FHC mutant confirmed that increased FHC expression deregulated CXCR4 signaling and that this function of FHC was independent of iron binding. Furthermore, examination of morphine-treated rodents and isolated neurons expressing FHC shRNA revealed that FHC contributed to morphine-induced dendritic spine loss. Together, these data implicate FHC-dependent deregulation of CXCL12/CXCR4 as a contributing factor to cognitive dysfunction in neuroAIDS. PMID:24401274

  18. 4-Quinolone drugs affect cell cycle progression and function of human lymphocytes in vitro.

    PubMed Central

    Forsgren, A; Schlossman, S F; Tedder, T F

    1987-01-01

    Most antibacterial agents do not affect human lymphocyte function, but a few are inhibitory. In contrast, a pronounced increase in the incorporation of [3H]thymidine in the presence of 4-quinolones was observed in these studies. The uptake of [3H]thymidine into DNA (trichloroacetic acid precipitable) was significantly increased in phytohemagglutinin-stimulated human lymphocytes when they were exposed to eight new 4-quinolone derivatives, ciprofloxacin, norfloxacin, ofloxacin, A-56619, A-56620, amifloxacin, enoxacin, and pefloxacin, at 1.6 to 6.25 micrograms/ml for 5 days. Four less antibacterially active 4-quinolones (nalidixic acid, cinoxacin, flumequine, and pipemidic acid) stimulated [3H]thymidine incorporation only at higher concentrations or not at all. Kinetic studies showed that incorporation of [3H]thymidine was not affected or slightly inhibited by ciprofloxacin 2 days after phytohemagglutinin stimulation but was increased on days 3 to 6. The total incorporation of [3H]thymidine from day 1 to day 6 after phytohemagglutinin stimulation was increased by 42 to 45% at 5 to 20 micrograms of ciprofloxacin per ml. Increased [3H]thymidine incorporation was also seen when human lymphocytes were stimulated with mitogens other than phytohemagglutinin. Ciprofloxacin added at the start of the culture had a more pronounced effect on [3H]thymidine incorporation than when added later. In spite of the apparent increase in DNA synthesis, lymphocyte growth was inhibited by 20 micrograms of ciprofloxacin per ml, and cell cycle analysis showed that ciprofloxacin inhibited progression through the cell cycle. In addition, immunoglobulin secretion by human lymphocytes stimulated by pokeweed mitogen for Epstein-Barr virus was inhibited by approximately 50% at 5 micrograms of ciprofloxacin per ml. These results suggest that the 4-quinolone drugs may also affect eucaryotic cell function in vitro, but additional studies are needed to establish an in vivo relevance. PMID:3606076

  19. Immunological control of drug absorption from the gastrointestinal tract: the mechanism whereby intestinal anaphylaxis interferes with the intestinal absorption of bromthymol blue in the rat.

    PubMed

    Yamamoto, A; Utsumi, E; Sakane, T; Hamaura, T; Nakamura, J; Hashida, M; Sezaki, H

    1986-05-01

    Rats were immunized intraperitoneally with ovalbumin and the disappearance of bromthymol blue (BTB) from the intestinal lumen, its accumulation in the tissue, and its net absorption were examined by means of an in-situ recirculation technique during local anaphylaxis. The disappearance of BTB from the intestinal lumen and its net absorption were significantly reduced, but there was no significant effect on its accumulation in the tissue. The pH value of the luminal solution and the perfusate volume were not influenced by intraluminal challenge with the antigen in ovalbumin-immunized rats. In addition, no significant effect was observed on intestinal permeability to BTB in the in-vitro everted sac technique. The intestinal blood flow, measured by a hydrogen clearance method, was not reduced significantly by the intraluminal exposure to antigen. There was enhanced Evans Blue leakage and mucus release in the perfusate after intraluminal challenge with ovalbumin in ovalbumin-immunized rats, but not in non-immunized rats. A significant increase of BTB binding with macromolecular substances in the perfusate was observed during the local anaphylaxis. These findings suggest that the decreased absorption of BTB is due to the interaction with the macromolecular substances in the perfusate during local anaphylaxis. PMID:2872311

  20. Infant iron status affects iron absorption in Peruvian breastfed infants at 2 and 5 mo of age

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Effects of prenatal iron supplementation on maternal postpartum iron status and early infant iron homeostasis remain largely unknown. We examined iron absorption and growth in exclusively breastfed infants in relation to fetal iron exposure and iron status during early infancy. Longitudinal, paired ...

  1. Evaluation of factors affecting gastrointestinal absorption of a novel anticoagulant FX-93 for development of oral formulation.

    PubMed

    Takemura, Shigeo; Kondo, Hiromu; Suzumura, Kenichi; Ogawara, Ken-Ichi; Watanabe, Shunsuke; Sako, Kazuhiro; Higaki, Kazutaka

    2012-06-01

    To find out factors causing the low bioavailability of FX-93, a novel anticoagulant, its solubility, membrane permeability, and the effect of bile salt on the absorption of FX-93 were investigated. The solubility of FX-93 under physiological conditions ranged from 0.3 to 18.3 mg/mL and the dose number was calculated to be 0.02-0.27, suggesting that the intrinsic solubility of FX-93 should not be a limiting factor for oral absorption. Apparent permeability of FX-93 across Caco-2 cell monolayer suggested that its fraction of dose absorbed would range between 30% and 40% in humans. Furthermore, FX-93 was substantially absorbed from each segment of rat intestine. However, the decrease in the gastrointestinal transit rate significantly decreased maximum plasma concentration and area under the plasma concentration-time curve of FX-93 after oral dosing in dogs, suggesting that FX-93 absorption would be suppressed by some components in the small intestinal lumen. An in situ rat administration study indicated that bile significantly decreased the intestinal absorption of FX-93 by two-thirds, which could be attributed to the decrease in FX-93 solubility by the interaction with bile or bile acid. Nuclear magnetic resonance spectroscopy analysis suggested that FX-93 would interact with bile salt between the naphthalene ring of FX-93 and steroidal backbone of bile salt. PMID:22422596

  2. Energy absorption during impact on the proximal femur is affected by body mass index and flooring surface.

    PubMed

    Bhan, Shivam; Levine, Iris C; Laing, Andrew C

    2014-07-18

    Impact mechanics theory suggests that peak loads should decrease with increase in system energy absorption. In light of the reduced hip fracture risk for persons with high body mass index (BMI) and for falls on soft surfaces, the purpose of this study was to characterize the effects of participant BMI, gender, and flooring surface on system energy absorption during lateral falls on the hip with human volunteers. Twenty university-aged participants completed the study with five men and five women in both low BMI (<22.5 kg/m(2)) and high BMI (>27.5 kg/m(2)) groups. Participants underwent lateral pelvis release experiments from a height of 5 cm onto two common floors and four safety floors mounted on a force plate. A motion-capture system measured pelvic deflection. The energy absorbed during the initial compressive phase of impact was calculated as the area under the force-deflection curve. System energy absorption was (on average) 3-fold greater for high compared to low BMI participants, but no effects of gender were observed. Even after normalizing for body mass, high BMI participants absorbed 1.8-fold more energy per unit mass. Additionally, three of four safety floors demonstrated significantly increased energy absorption compared to a baseline resilient-rolled-sheeting system (% increases ranging from 20.7 to 28.3). Peak system deflection was larger for high BMI persons and for impacts on several safety floors. This study indicates that energy absorption may be a common mechanism underlying the reduced risk of hip fracture for persons with high BMI and for those who fall on soft surfaces.

  3. Meal conditions affect the absorption of supplemental vitamin D3 but not the plasma 25-hydroxyvitamin D response to supplementation.

    PubMed

    Dawson-Hughes, Bess; Harris, Susan S; Palermo, Nancy J; Ceglia, Lisa; Rasmussen, Helen

    2013-08-01

    It is sometimes assumed that dietary fat is required for vitamin D absorption, although the impact of different amounts of dietary fat on vitamin D absorption is not established. This study was conducted to determine whether the presence of a meal and the fat content of the meal influences vitamin D absorption or the 25-hydroxyvitamin D [25(OH)D] response to supplemental vitamin D3 . Based on earlier studies in rats we postulated that absorption would be greatest in the low-fat meal group. Sixty-two healthy older men and women were randomly assigned to one of three meal groups: no meal, high-fat meal, or low-fat meal; each was given a monthly 50,000 IU vitamin D3 supplement with the test breakfast meal (or after a fast for the no-meal group) and followed for 90 days. Plasma vitamin D3 was measured by liquid chromatography-mass spectroscopy (LC/MS) before and 12 hours after the first dose; plasma 25(OH)D was measured by radioimmunoassay at baseline and after 30 and 90 days. The mean 12-hour increments in vitamin D3 , after adjusting for age and sex, were 200.9 nmol/L in the no-meal group, 207.4 nmol/L in the high-fat meal group, and 241.1 nmol/L in the low-fat meal group (p = 0.038), with the increase in the low-fat group being significantly greater than the increases in the other two groups. However, increments in 25(OH)D levels at 30 and 90 days did not differ significantly in the three groups. We conclude that absorption was increased when a 50,000 IU dose of vitamin D was taken with a low-fat meal, compared with a high-fat meal and no meal, but that the greater absorption did not result in higher plasma 25(OH)D levels in the low-fat meal group.

  4. Nonlinear absorption kinetics of self-emulsifying drug delivery systems (SEDDS) containing tocotrienols as lipophilic molecules: in vivo and in vitro studies.

    PubMed

    Alqahtani, Saeed; Alayoubi, Alaadin; Nazzal, Sami; Sylvester, Paul W; Kaddoumi, Amal

    2013-07-01

    Self-emulsifying drug delivery systems (SEDDS) have been broadly used to promote the oral absorption of poorly water-soluble drugs. The purpose of the current study was to evaluate the in vivo oral bioavailability of vitamin E isoforms, δ-tocotrienol (δ-T3) and γ-tocotrienol (γ-T3) administered as SEDDS, as compared to commercially available UNIQUE E® Tocotrienols capsules. Results from studies in rats showed that low dose treatment with δ-T3 (90%) and γ-T3 (10%) formulated SEDDS showed bioavailability of 31.5% and 332%, respectively. However, bioavailability showed a progressive decrease with increased treatment dose that displayed nonlinear absorption kinetics. Additional in vitro studies examining cellular uptake studies in Caco 2 cells revealed that the SEDDS formulation increased passive permeability of δ-T3 and γ-T3 by threefold as compared to the commercial capsule formulation. These studies also showed that free surfactants decreased δ-T3 and γ-T3 absorption. Specifically, combined treatment cremophor EL or labrasol with tocotrienols caused a 60-85% reduction in the cellular uptake of δ-T3 and γ-T3 and these effects appear to result from surfactant-induced inhibition of the δ-T3 and γ-T3 transport protein Niemann-Pick C1-like 1 (NPC1L1). In summary, results showed that SEDDS formulation significantly increases the absorption and bioavailability δ-T3 and γ-T3. However, this effect is self-limiting because treatment with increasing doses of SEDDS appears to be associated with a corresponding increase in free surfactants levels that directly and negatively impact tocotrienol transport protein function and results in nonlinear absorption kinetics and a progressive decrease in δ-T3 and γ-T3 absorption and bioavailability.

  5. Impaired drug absorption due to high stomach pH: a review of strategies for mitigation of such effect to enable pharmaceutical product development.

    PubMed

    Mitra, Amitava; Kesisoglou, Filippos

    2013-11-01

    Published reports have clearly shown that weakly basic drugs which have low solubility at high pH could have impaired absorption in patients with high gastric pH thus leading to reduced and variable bioavailability. Since such reduction in exposure can lead to significant loss of efficacy, it is imperative to (1) understand the behavior of the compound as a function of stomach pH to inform of any risk of bioavailability loss in clinical studies and (2) develop a robust formulation which can provide adequate exposure in achlorhydric patients. In this review paper, we provide an overview of the factors that can cause high gastric pH in human, discuss clinical and preclinical pharmacokinetic data for weak bases under conditions of normal and high gastric pH, and give examples of formulation strategies to minimize or mitigate the reduced absorption of weakly basic drugs under high gastric pH conditions. It should be noted that the ability to overcome pH sensitivity issues is highly compound dependent and there are no obvious and general solutions to overcome such effect. Further, we discuss, along with several examples, the use of biopharmaceutical tools such as in vitro dissolution, absorption modeling, and gastric pH modified animal models to assess absorption risk of weak bases in high gastric pH and also the use of these tools to enable development of formulations to mitigate such effects.

  6. Transpiration, water absorption, and internal water balance of cotton plants as affected by light and changes in saturation deficit.

    PubMed

    Ehrler, W L; van Bavel, C H; Nakayama, F S

    1966-01-01

    In controlled environment studies of cotton plants (Gossypium barbadense L.) a light-induced acceleration of transpiration upset the water balance established in the dark because of a lag in water absorption. A plant-water deficit could be generated either by sudden illumination at a given saturation deficit (sd) of the air, or by raising the sd in conjunction with illumination, without different effects.Direct water balance measurements were confirmed in every experiment by beta ray gauge detection of changes in leaf-water content resulting from unequal gain and loss of water by the whole plant.Recovery from the initial loss of turgidity always was faster and more complete at the higher than at the lower values of sd. Recovery occurred even in the light at the higher values of sd, but was enhanced by return to darkness and a lower sd, which at times resulted in superhydration.Rehydration in the light could be attributed to at least 2 processes: A) a diminished transpiration rate if earlier water loss was sufficient to induce stomatal closure, and B) an increased rate of water absorption. The data suggest that a water deficit, temporary or persisting, does not cause a significantly lowered transpiration rate; thus, recovery must depend on increased absorption. The communicative link between the 2 processes appears weak, transmitting strong signals only.

  7. Enhancement of the dissolution rate and gastrointestinal absorption of pranlukast as a model poorly water-soluble drug by grinding with gelatin.

    PubMed

    Chono, Sumio; Takeda, Eri; Seki, Toshinobu; Morimoto, Kazuhiro

    2008-01-22

    The effect of grinding with gelatin on the dissolution behavior and gastrointestinal absorption of a poorly water-soluble drug was evaluated using the antiasthmatic agent, pranlukast, as a model poorly water-soluble drug. A ground pranlukast-gelatin mixture was prepared by grinding equal quantities of pranlukast and gelatin. In the dissolution testing, the dissolution rate of pranlukast in the suspension of the ground pranlukast-gelatin mixture under conditions of pH 3.0, 5.0 and 7.0 was markedly faster than that in the suspension of pranlukast. According to powder X-ray diffractometry (PXRD) and differential scanning calorimetry (DSC) analysis, the enhanced dissolution rate of pranlukast produced by grinding with gelatin was caused by changing the crystalline state of pranlukast into an amorphous state. In an animal experiment, the bioavailability of pranlukast following oral administration of the ground pranlukast-gelatin mixture to rats was threefold greater than that following administration of pranlukast. In the in vitro permeation experiment, the amount of permeated pranlukast through Caco-2 cell monolayers after application of the ground pranlukast-gelatin mixture was greater than that after application of pranlukast. These results suggest that the enhancement of the gastrointestinal absorption of pranlukast by grinding with gelatin is due to enhancement of the dissolution rate. Grinding a poorly water-soluble drug with gelatin is a useful method of enhancing its gastrointestinal absorption.

  8. Immunosuppressive drugs affect high-mannose/hybrid N-glycans on human allostimulated leukocytes.

    PubMed

    Pocheć, Ewa; Bocian, Katarzyna; Ząbczyńska, Marta; Korczak-Kowalska, Grażyna; Lityńska, Anna

    2015-01-01

    N-glycosylation plays an important role in the majority of physiological and pathological processes occurring in the immune system. Alteration of the type and abundance of glycans is an element of lymphocyte differentiation; it is also common in the development of immune-mediated inflammatory diseases. The N-glycosylation process is very sensitive to different environmental agents, among them the pharmacological environment of immunosuppressive drugs. Some results show that high-mannose oligosaccharides have the ability to suppress different stages of the immune response. We evaluated the effects of cyclosporin A (CsA) and rapamycin (Rapa) on high-mannose/hybrid-type glycosylation in human leukocytes activated in a two-way mixed leukocyte reaction (MLR). CsA significantly reduced the number of leukocytes covered by high-mannose/hybrid N-glycans, and the synergistic action of CsA and Rapa led to an increase of these structures on the remaining leukocytes. This is the first study indicating that β1 and β3 integrins bearing high-mannose/hybrid structures are affected by Rapa and CsA. Rapa taken separately and together with CsA changed the expression of β1 and β3 integrins and, by regulating the protein amount, increased the oligomannose/hybrid-type N-glycosylation on the leukocyte surface. We suggest that the changes in the glycosylation profile of leukocytes may promote the development of tolerance in transplantation.

  9. Immunosuppressive Drugs Affect High-Mannose/Hybrid N-Glycans on Human Allostimulated Leukocytes

    PubMed Central

    Pocheć, Ewa; Bocian, Katarzyna; Ząbczyńska, Marta; Korczak-Kowalska, Grażyna; Lityńska, Anna

    2015-01-01

    N-glycosylation plays an important role in the majority of physiological and pathological processes occurring in the immune system. Alteration of the type and abundance of glycans is an element of lymphocyte differentiation; it is also common in the development of immune-mediated inflammatory diseases. The N-glycosylation process is very sensitive to different environmental agents, among them the pharmacological environment of immunosuppressive drugs. Some results show that high-mannose oligosaccharides have the ability to suppress different stages of the immune response. We evaluated the effects of cyclosporin A (CsA) and rapamycin (Rapa) on high-mannose/hybrid-type glycosylation in human leukocytes activated in a two-way mixed leukocyte reaction (MLR). CsA significantly reduced the number of leukocytes covered by high-mannose/hybrid N-glycans, and the synergistic action of CsA and Rapa led to an increase of these structures on the remaining leukocytes. This is the first study indicating that β1 and β3 integrins bearing high-mannose/hybrid structures are affected by Rapa and CsA. Rapa taken separately and together with CsA changed the expression of β1 and β3 integrins and, by regulating the protein amount, increased the oligomannose/hybrid-type N-glycosylation on the leukocyte surface. We suggest that the changes in the glycosylation profile of leukocytes may promote the development of tolerance in transplantation. PMID:26339568

  10. Does prenatal methamphetamine exposure affect the drug-seeking behavior of adult male rats?

    PubMed

    Slamberová, Romana; Schutová, Barbora; Hrubá, Lenka; Pometlová, Marie

    2011-10-10

    Methamphetamine (MA) is one of the most frequently used illicit drugs worldwide and also one of the most common drugs abused by pregnant women. Repeated administration of psychostimulants induces behavioral sensitization in response to treatment of the same or related drugs in rodents. The effect of prenatal MA exposure on sensitivity to drugs in adulthood is not yet fully determined. Because our most recent studies demonstrated that prenatal MA (5mg/kg) exposure makes adult rats more sensitive to acute injection of the same drug, we were interested whether the increased sensitivity corresponds with the increased drug-seeking behavior. The aim of the present study was to examine the effect of prenatal MA exposure on drug-seeking behavior of adult male rats tested in the conditioned place preference (CPP). The following psychostimulant drugs were used as a challenge in adulthood: MA (5mg/kg), amphetamine (5mg/kg) and cocaine (10mg/kg). All psychostimulant drugs induced increased drug-seeking behavior in adult male rats. However, while MA and amphetamine-induced increase in drug-seeking behavior did not differ based on the prenatal drug exposure, prenatally MA-exposed rats displayed tolerance effect to cocaine in adulthood. In addition, prenatally MA-exposed rats had decreased weight gain after administration of MA or amphetamine, while the weight of prenatally MA-exposed rats stayed unchanged after cocaine administration. Defecation was increased by all the drugs (MA, amphetamine and cocaine), while only amphetamine increased the tail temperature. In conclusion, our results did not confirm our hypothesis that prenatal MA exposure increases drug-seeking behavior in adulthood in the CPP test.

  11. Factors affecting the experiences of drug use by adolescents in a Bangkok slum.

    PubMed

    Laoniramai, Patrapan; Laosee, Orapin C; Somrongthong, Ratana; Wongchalee, Sunanta; Sitthi-Amorn, Chitr

    2005-07-01

    The purpose of this research was to study the demography, financial status, social status, knowledge of amphetamines, perceived harmfulness of amphetamines, and life skills in the prevention of drug abuse in adolescents. The factors leading to drug use among young people were also studied. The study group was composed of 354 subjects aged 12 to 22 years, living in 2 slums in Bangkok. The research showed that about 7% of the sample group had used drugs before. Four percent had never used drugs, but someone had tried to talk them into using them. Almost 20% had friends who had used drugs, and 11% had friends who were still using drugs. About 13% of the adolescents in the study group had family members who used drugs and another 9% had family members who were still using drugs. In our study, we found that the most common drug group was amphetamines. On average, the participants had a low level of understanding about drug abuse, especially of the symptoms, side effects, and legal penalties. Most of the adolescents realized how harmful amphetamines and other drugs were and had a high degree life skills. Factors influencing adolescent drug use were (1) personal factors, such as monthly income/allowance and life skills; (2) family environment, such as drug abuse history in the family; and (3) social environment, such as a drug abuse history among friends. When studying the life skill factors of the adolescents, which is an independent factor capable of influencing the experience with drugs, the researchers found that the time spent with other members of the family and the family members' drug experiences were the only factors leading to life skills in the prevention of drug abuse in adolescents. In addition to letting children learn on their own, training them to acquire life skills is beneficial when faced with problematic situations. Creating relationships between adolescents and other members of the family, friends, and society can increase their life skills

  12. Removal of SO/sub 2/ from simulated flue gas by magnesia spray absorption: parameters affecting removal efficiency and products

    SciTech Connect

    Egan, Z.; Felker, L.K.

    1986-04-01

    A bench-scale apparatus simulating a spray dryer was used to study magnesia flue gas desulfurization (FGD) technology combined with spray absorption techniques for the removal of SO/sub 2/ from flue gas. The use of magnesia spray absorption technology requires fewer processing steps, reduces slurry and sludge handling as compared with limestone slurry systems, and yields a saleable sulfur byproduct. Simulated flue gases (SO/sub 2/ in N/sub 2/) were mixed with heated Mg(OH)/sub 2/ slurries and sprayed into a heated glass vessel. The inlet and exit gases were monitored for SO/sub 2/ concentration. Ranges of experimental conditions were as follows: gas flow rate, 7-10 L/min; SO/sub 2/ concentration in the inlet gas, 0.099-1.07%; slurry composition, 0.5-10% Mg(OH)/sub 2/; slurry flow rate, 1-7 mL/min; inlet gas temperature, 107-115 /sup 0/C; and dryer temperature, 73-114 /sup 0/C. The SO/sub 2/ removal efficiency ranged from 28% to nearly 100%, depending primarily on the reaction stoichiometry (Mg(OH)/sub 2//SO/sub 2/ mole ratio). The solid products were MgSO/sub 3/.3H/sub 2/O and MgSO/sub 3/.6H/sub 2/O, with the hexahydrate predominating at lower temperatures and higher humidities.

  13. Studies on effective atomic numbers for photon energy absorption and electron density of some narcotic drugs in the energy range 1 keV-20 MeV

    NASA Astrophysics Data System (ADS)

    Gounhalli, Shivraj G.; Shantappa, Anil; Hanagodimath, S. M.

    2013-04-01

    Effective atomic numbers for photon energy absorption ZPEA,eff, photon interaction ZPI,eff and for electron density Nel, have been calculated by a direct method in the photon-energy region from 1 keV to 20 MeV for narcotic drugs, such as Heroin (H), Cocaine (CO), Caffeine (CA), Tetrahydrocannabinol (THC), Cannabinol (CBD), Tetrahydrocannabivarin (THCV). The ZPEA,eff, ZPI,eff and Nel values have been found to change with energy and composition of the narcotic drugs. The energy dependence ZPEA,eff, ZPI,eff and Nel is shown graphically. The maximum difference between the values of ZPEA,eff, and ZPI,eff occurs at 30 keV and the significant difference of 2 to 33% for the energy region 5-100 keV for all drugs. The reason for these differences is discussed.

  14. Interaction of Nanostructured Calcium Silicate Hydrate with Ibuprofen Drug Molecules: X-ray Absorption Near Edge Structure (XANES) Study at the Ca, Si and O K-edge

    NASA Astrophysics Data System (ADS)

    Guo, X. X.; Sham, T. K.; Zhu, Y. J.; Hu, Y. F.

    2013-04-01

    Mesoporous calcium silicate hydrate (CSH) nanostructure has been proven to be bioactive and biocompatible, and has a bright future in the application of bone treatment among other applications. X-ray absorption near edge structure (XANES) is a powerful tool for the study of the interactions of calcium silicate hydrates with drug molecules because it is element specific and it probes the unoccupied electronic states. Herein, we report the use of the calcium, silicon and oxygen K-edge XANES spectroscopy to identify how drug molecules interact with different groups in calcium silicate hydrate mesoporous nano-carriers with different morphologies. Significant changes are observed in XANES spectra after drug loading into the calcium silicate hydrate system, especially at the Si and O K-edge. The implications of these findings are discussed.

  15. Psychoactive-drug response is affected by acute low-level microwave irradiation

    SciTech Connect

    Lai, H.; Horita, A.; Chou, C.K.; Guy, A.W.

    1983-01-01

    The effects of various psychoactive drugs were studied in rats exposed for 45 min in a circularly polarized, pulsed microwave field (2450 MHz; SAR 0.6 W/kg; 2-microseconds pulses, 500 pps). Apomorphine-induced hypothermia and stereotypy were enhanced by irradiation. Amphetamine-induced hyperthermia was attenuated while stereotypy was unaffected. Morphine-induced catalepsy and lethality were enhanced by irradiation at certain dosages of the drug. Since these drugs have different modes of action on central neural mechanisms and the effects of microwaves depend on the particular drug studied, these results show the complex nature of the effect of microwave irradiation on brain functions.

  16. Does Recent Physical and Sexual Victimization Affect Further Substance Use for Adult Drug-Involved Offenders?

    ERIC Educational Resources Information Center

    Zweig, Janine M.; Yahner, Jennifer; Rossman, Shelli B.

    2012-01-01

    This study examined whether physical and sexual victimization experiences were related to further substance use for a sample of drug-involved adult offenders and whether this increase could be attributed to depression experienced after the victimization occurred. A total of 674 men and 284 women from the longitudinal Multisite Adult Drug Court…

  17. Occupational dermal exposure to nanoparticles and nano-enabled products: Part I-Factors affecting skin absorption.

    PubMed

    Larese Filon, Francesca; Bello, Dhimiter; Cherrie, John W; Sleeuwenhoek, Anne; Spaan, Suzanne; Brouwer, Derk H

    2016-08-01

    The paper reviews and critically assesses the evidence on the relevance of various skin uptake pathways for engineered nanoparticles, nano-objects, their agglomerates and aggregates (NOAA). It focuses especially in occupational settings, in the context of nanotoxicology, risk assessment, occupational medicine, medical/epidemiological surveillance efforts, and the development of relevant exposure assessment strategies. Skin uptake of nanoparticles is presented in the context of local and systemic health effects, especially contact dermatitis, skin barrier integrity, physico-chemical properties of NOAA, and predisposing risk factors, such as stratum corneum disruption due to occupational co-exposure to chemicals, and the presence of occupational skin diseases. Attention should be given to: (1) Metal NOAA, since the potential release of ions may induce local skin effects (e.g. irritation and contact dermatitis) and absorption of toxic or sensitizing metals; (2) NOAA with metal catalytic residue, since potential release of ions may also induce local skin effects and absorption of toxic metals; (3) rigid NOAA smaller than 45nm that can penetrate and permeate the skin; (4) non rigid or flexible NOAA, where due to their flexibility liposomes and micelles can penetrate and permeate the intact skin; (5) impaired skin condition of exposed workers. Furthermore, we outline possible situations where health surveillance could be appropriate where there is NOAA occupational skin exposures, e.g. when working with nanoparticles made of sensitizer metals, NOAA containing sensitizer impurities, and/or in occupations with a high prevalence of disrupted skin barrier integrity. The paper furthermore recommends a stepwise approach to evaluate risk related to NOAA to be applied in occupational exposure and risk assessment, and discusses implications related to health surveillance, labelling, and risk communication.

  18. Occupational dermal exposure to nanoparticles and nano-enabled products: Part I-Factors affecting skin absorption.

    PubMed

    Larese Filon, Francesca; Bello, Dhimiter; Cherrie, John W; Sleeuwenhoek, Anne; Spaan, Suzanne; Brouwer, Derk H

    2016-08-01

    The paper reviews and critically assesses the evidence on the relevance of various skin uptake pathways for engineered nanoparticles, nano-objects, their agglomerates and aggregates (NOAA). It focuses especially in occupational settings, in the context of nanotoxicology, risk assessment, occupational medicine, medical/epidemiological surveillance efforts, and the development of relevant exposure assessment strategies. Skin uptake of nanoparticles is presented in the context of local and systemic health effects, especially contact dermatitis, skin barrier integrity, physico-chemical properties of NOAA, and predisposing risk factors, such as stratum corneum disruption due to occupational co-exposure to chemicals, and the presence of occupational skin diseases. Attention should be given to: (1) Metal NOAA, since the potential release of ions may induce local skin effects (e.g. irritation and contact dermatitis) and absorption of toxic or sensitizing metals; (2) NOAA with metal catalytic residue, since potential release of ions may also induce local skin effects and absorption of toxic metals; (3) rigid NOAA smaller than 45nm that can penetrate and permeate the skin; (4) non rigid or flexible NOAA, where due to their flexibility liposomes and micelles can penetrate and permeate the intact skin; (5) impaired skin condition of exposed workers. Furthermore, we outline possible situations where health surveillance could be appropriate where there is NOAA occupational skin exposures, e.g. when working with nanoparticles made of sensitizer metals, NOAA containing sensitizer impurities, and/or in occupations with a high prevalence of disrupted skin barrier integrity. The paper furthermore recommends a stepwise approach to evaluate risk related to NOAA to be applied in occupational exposure and risk assessment, and discusses implications related to health surveillance, labelling, and risk communication. PMID:27289581

  19. Communication: Does a single CH3CN molecule attached to Ru(bipy)3(2+) affect its absorption spectrum?

    PubMed

    Stockett, M H; Brøndsted Nielsen, S

    2015-05-01

    Tris(bipyridine)ruthenium(II) (Ru(bipy)3 (2+)) is a prototypical transition metal coordination complex whose photophysical properties have attracted considerable attention. A much debated issue is whether the metal-to-ligand charge transfer (MLCT) transition that accounts for the complex's beautiful red color is fully delocalized across all three bipyridine ligands or located on just one ligand. Here, we show based on gas-phase action spectroscopy that attachment of a single acetonitrile molecule does not change the absorption spectrum from that of the bare ions, which is indicative of a delocalized state. However, the gas-phase spectra of the bare and one solvent molecule complexes are significantly blueshifted relative to that obtained in bulk acetonitrile, which suggests that in solution the polarizability of many solvent molecules working together can localize the MLCT state. Our data clearly show that more than one solvent molecule is needed to break the symmetry of the MLCT excited state and reproduce its solution-phase characteristics. PMID:25956080

  20. Communication: Does a single CH3CN molecule attached to Ru(bipy)32+ affect its absorption spectrum?

    NASA Astrophysics Data System (ADS)

    Stockett, M. H.; Brøndsted Nielsen, S.

    2015-05-01

    Tris(bipyridine)ruthenium(II) (Ru(bipy)32+) is a prototypical transition metal coordination complex whose photophysical properties have attracted considerable attention. A much debated issue is whether the metal-to-ligand charge transfer (MLCT) transition that accounts for the complex's beautiful red color is fully delocalized across all three bipyridine ligands or located on just one ligand. Here, we show based on gas-phase action spectroscopy that attachment of a single acetonitrile molecule does not change the absorption spectrum from that of the bare ions, which is indicative of a delocalized state. However, the gas-phase spectra of the bare and one solvent molecule complexes are significantly blueshifted relative to that obtained in bulk acetonitrile, which suggests that in solution the polarizability of many solvent molecules working together can localize the MLCT state. Our data clearly show that more than one solvent molecule is needed to break the symmetry of the MLCT excited state and reproduce its solution-phase characteristics.

  1. How various drugs affect anxiety-related behavior in male and female rats prenatally exposed to methamphetamine.

    PubMed

    Macúchová, E; Ševčíková, M; Hrebíčková, I; Nohejlová, K; Šlamberová, R

    2016-06-01

    Different forms of anxiety-related behavior have been reported after a single drug use of many abused substances, however, less is known about how males and females are affected differently from exposure to various drugs. Furthermore, chronic prenatal methamphetamine (MA) exposure was shown to predispose the animal to an increased sensitivity to drugs administrated in adulthood. Using the Elevated plus-maze test (EPM), the first aim of the present study was to examine how male and female rats are affected by acute drug treatment with subcutaneously (s.c.) administrated (a) MA (1mg/kg); (b) drugs with a similar mechanism of action to MA: amphetamine (AMP, 1mg/kg), cocaine (COC, 5mg/kg), 3,4-methylenedioxymethamphetamine (MDMA, 5mg/kg); and (c) drugs with different mechanisms of action: morphine (MOR, 5mg/kg), and Δ 9-tetrahydrocannabinol (THC, 2mg/kg). The second aim was to determine if prenatally MA-exposed (5mg/kg) animals show an increased sensitivity to adult drug treatment. The parameters analyzed were divided into two categories: anxiety-related behavior and anxiety-unrelated/exploratory behavior. Our results showed in female rats a decreased percentage of the time spent in the closed arms (CA) after MA, and an increased percentage of the time spent in the open arms (OA) after MA, AMP, and COC treatment, indicating an anxiolytic-like effect. In females, MDMA and THC treatment increased the percentage of the time spent in the CA. An increased percentage of the time spent in the CA was also seen after MOR treatment in females as well as in males, indicating an anxiogenic-like effect. As far as the interaction between prenatal MA exposure and adult drug treatment is concerned, there was no effect found. In conclusion, it seems that: (a) in some cases female rats are more vulnerable to acute drug treatment, in terms of either anxiogenic- or anxiolytic-like effects; (b) prenatal MA exposure does not sensitize animals to the anxiety-related effects of any of the

  2. Influence of particle design on oral absorption of poorly water-soluble drug in a silica particle-supercritical fluid system.

    PubMed

    Miura, Hiroshi; Kanebako, Makoto; Shirai, Hiroyuki; Nakao, Hiroshi; Inagi, Toshio; Terada, Katsuhide

    2011-01-01

    The physicochemical characteristics and oral absorption of a poorly water-soluble drug, K-832, adsorbed onto porous silica (Sylysia 350), were compared with those of K-832 adsorbed onto non-porous silica (Aerosil 200). K-832 and silica were treated with supercritical CO(2) (scCO(2)) to produce K-832-Sylysia 350 and K-832-Aerosil 200 formulations. Scanning electron microscopy, polarizing microscopy, powder X-ray diffraction, and differential scanning calorimetry results suggested that K-832 mainly existed in an amorphous state in both formulations. The specific surface area of both formulations was much larger than that of pure K-832 crystals. The dissolution rate of K-832 from both formulations was considerably greater than that from corresponding physical mixtures due to rapid wetting of the hydrophilic carrier surfaces and amorphous state, the dissolution from the K-832-Sylysia 350 formulation being the fastest. In vivo absorption tests on the two formulations indicated no significant differences in their peak concentration (C(max)) and the area under their plasma concentration-time curve (AUC), while the concentrations of K-832 in the K-832-Sylysia 350 formulation were significantly higher than those in the K-832-Aerosil 200 formulation 1 h and 1.5 h after administration of these formulations (p<0.05). This could be attributed to the different dispersion states of K-832 in the formulations due to their different three-dimensional structures (porous and non-porous). In physical stability tests, the amorphous drugs in both formulations were stable at room temperature for at least 14 months. Thus, the absorption of poorly water-soluble drugs could be greatly improved by adsorption onto porous silica using scCO(2).

  3. Competency to be resentenced and the Rockefeller Drug Law reform act: how does it affect the mentally Ill?

    PubMed

    Ford, Elizabeth; Winkler, Barry; Barber-Rioja, Virginia; Dell'anno, Christina; Cohen, Shelly

    2009-01-01

    Many of the mentally ill prisoners in this country have been convicted of drug crimes. New York State's Rockefeller Drug Laws from the 1970s established harsh sentences for drug crimes to quell a perceived epidemic. These laws were reformed in 2004 to allow the option of resentencing, with the possibility of lighter sentences. However, there is no formal mechanism in New York for a postconviction hearing for competency to be resentenced, thus affecting the severely mentally ill who were sentenced under the old Rockefeller laws. The purpose of this article is to highlight the psychiatric and legal difficulties that can arise without an option for a resentencing competency hearing and to argue that despite the low number of inmates to whom this would apply, there is an important duty to ensure due process to the mentally ill.

  4. Intradermal Tests for Diagnosis of Drug Allergy are not Affected by a Topical Anesthetic Patch.

    PubMed

    Couto, Mariana; Silva, Diana; Ferreira, Ana; Cernadas, Josefina R

    2014-09-01

    The use of topical anesthesia to perform intradermal tests (IDTs) for drug allergy diagnosis was never investigated. We aimed to determine the effects of a topical anesthetic patch containing prilocaine-lidocaine on wheal size of IDT with drugs. Patients who had positive IDT as part of their investigation process of suspected drug hypersensitivity were selected. IDT were performed according to guidelines. Anesthetic patch (AP) was placed and the same prior positive IDT, as well as positive histamine skin prick test (SPT) and negative (saline IDT) controls, were performed in the anesthetized area. Patients with negative IDT were also included to check for false positives with AP. Increase in wheals after 20 minutes both with and without AP was recorded and compared. 45 IDT were performed (36 patients), of which 37 have been previously positive (14 antibiotics, 10 general anesthetics, 6 non-steroidal anti-inflammatory drugs, 3 iodinated contrasts, 3 anti-Hi-histamines and 1 ranitidine). Mean histamine SPT size without the AP was 4.7 mm [95%CI (4.4-5.1]), and 4.6 mm [95%CI(4.2-5.0)] with anesthesia. Mean wheal increase in IDT for drugs without the anesthesia was 4.5 mm [95%CI(3.3-5.7)] and with anesthesia was 4.3 mm [95%CI(2.8-5.8)]. No statistical significant differences were observed between skin tests with or without AP for histamine SPT (P=0.089), IDT with saline (P=0.750), and IDT with drugs (P=0.995). None of the patients with negative IDT showed positivity with the AP, or vice-versa. The use of an AP containing prilocaine-lidocaine does not interfere with IDT to diagnose drug allergy, and no false positive tests were found. PMID:25229004

  5. Helicobacter pylori infection and drugs malabsorption.

    PubMed

    Lahner, Edith; Virili, Camilla; Santaguida, Maria Giulia; Annibale, Bruno; Centanni, Marco

    2014-08-14

    Drug absorption represents an important factor affecting the efficacy of oral drug treatment. Gastric secretion and motility seem to be critical for drug absorption. A causal relationship between impaired absorption of orally administered drugs and Helicobacter pylori (H. pylori) infection has been proposed. Associations have been reported between poor bioavailability of l-thyroxine and l-dopa and H. pylori infection. According to the Maastricht Florence Consensus Report on the management of H. pylori infection, H. pylori treatment improves the bioavailability of both these drugs, whereas the direct clinical benefits to patients still await to be established. Less strong seems the association between H. pylori infection and other drugs malabsorption, such as delavirdine and ketoconazole. The exact mechanisms forming the basis of the relationship between H. pylori infection and impaired drugs absorption and/or bioavailability are not fully elucidated. H. pylori infection may trigger a chronic inflammation of the gastric mucosa, and impaired gastric acid secretion often follows. The reduction of acid secretion closely relates with the wideness and the severity of the damage and may affect drug absorption. This minireview focuses on the evidence of H. pylori infection associated with impaired drug absorption.

  6. Two-dimensional transport analysis of transdermal drug absorption with a non-perfect sink boundary condition at the skin-capillary interface.

    PubMed

    Simon, Laurent; Ospina, Juan

    2013-07-01

    A transient percutaneous drug absorption model was solved in two dimensions. Clearance of the topically-applied pharmaceutical occured at the skin-capillary boundary. Timolol penetration profiles in the dermal tissue were produced revealing concentration gradients in the directions normal and parallel to the skin surface. Ninety-eight percent of the steady-state flux was reached after 85 h or four time constants. The analytical solution procedure agreed with published results. As the clearance rate increased relative to diffusion, the delivery rate and amount of drug absorbed into the bloodstream increased while the time to reach the equilibrium flux decreased. Researchers can apply the closed-form expressions to simulate the process, estimate key parameters and design devices that meet specific performance requirements.

  7. Genetic diversity of Plasmodium falciparum parasites from Kenya is not affected by antifolate drug selection.

    PubMed

    Nzila, A M; Mberu, E K; Nduati, E; Ross, A; Watkins, W M; Sibley, C H

    2002-11-01

    The genotypes of merozoite surface protein-1, merozoite surface protein-2 and glutamine rich protein are frequently used to distinguish recrudescence from reinfection when parasitaemia reappears after antimalarial drug treatment. However, none of the previous reports has clearly assessed the change of genetic diversity following drug treatment. In the present study, we have assessed the impact of pyrimethamine/sulfadoxine and chlorproguanil/dapsone on the genetic diversity of isolates and the multiplicity of infection in patient isolates from Kilifi, Kenya. We have analysed the length polymorphism of merozoite surface protein-1, merozoite surface protein-2 and glutamine rich protein and the data clearly show that treatment with pyrimethamine/sulfadoxine and chlorproguanil/dapsone did not change the multiplicity of infection found in patients, in contrast to the selection that these drugs exert on the genes encoded by the target enzymes. In addition, we report that children of less than 2 years tend to have fewer numbers of clones per isolate when compared with older children. Overall, this study shows that the selection for genes that confer drug resistance is not a factor in reducing the genetic diversity of parasite clones in a patient. PMID:12392912

  8. Identifying the Needs of Drug-Affected Children: Public Policy Issues. OSAP Prevention Monograph-11.

    ERIC Educational Resources Information Center

    Alcohol, Drug Abuse, and Mental Health Administration (DHHS/PHS), Rockville, MD. Office for Substance Abuse Prevention.

    This monograph explores the research findings and experiential knowledge base on toddlers and preschool-age children who were prenatally exposed to alcohol and other drugs. It is designed to influence public policy relating to the needs and early intervention plans for this population, from the medical, child welfare, psychosocial, developmental,…

  9. Parameters affecting drug release from inert matrices. 1: Monte Carlo simulation.

    PubMed

    Villalobos, Rafael; Viquez, Hugo; Hernández, Beatriz; Ganem, Adriana; Melgoza, Luz María; Young, Paul M

    2012-01-01

    This study investigates the use of Monte Carlo simulation for the determination of release properties from cubic inert matrices. Specifically, the study has focused on factors including porosity, surface area and tortuosity. The release platform was formed by simulating matrices with different ratios of drug and excipient, which undergo drug release in a uni-directional (two-face) or omni-directional (six-face) process. Upon completion of each simulation the matrix 'carcass' was examined and porosity and tortuosity of the medium evaluated. The tortuosity of the medium was evaluated directly by a blind random walk algorithm. These parameters as well as the release profile were then studied with respect to common mathematical models describing drug diffusion (the square-root, power and Weibull models). It was found that, depending on their composition, the matrices systems were either homogeneous or heterogeneous in nature. Furthermore, it was found that the physical parameters could be successfully fitted to the a and b constants of the Weibull model. This approach allows the prediction of drug release from an inert matrix system with the knowledge of a few physical parameters.

  10. Maternal Drug Use during Pregnancy: Are Preterm and Full-Term Infants Affected Differently?

    ERIC Educational Resources Information Center

    Brown, Josephine V.; Bakeman, Roger; Coles, Claire D.; Sexson, William R.; Demi, Alice S.

    1998-01-01

    Examined effects of prenatal drug exposure on infants born preterm and full-term to African American mothers. Found more extreme fetal growth deficits in later-born infants, and more extreme irritability increases in earlier-born infants. Gestation length did not moderate cardiorespiratory reactivity effects. Exposure effects occurred for…

  11. Combining in vitro and in silico methods for better prediction of surfactant effects on the absorption of poorly water soluble drugs-a fenofibrate case example.

    PubMed

    Berthelsen, Ragna; Sjögren, Erik; Jacobsen, Jette; Kristensen, Jakob; Holm, René; Abrahamsson, Bertil; Müllertz, Anette

    2014-10-01

    The aim of this study was to develop a sensitive and discriminative in vitro-in silico model able to simulate the in vivo performance of three fenofibrate immediate release formulations containing different surfactants. In addition, the study was designed to investigate the effect of dissolution volume when predicting the oral bioavailability of the formulations. In vitro dissolution studies were carried out using the USP apparatus 2 or a mini paddle assembly, containing 1000 mL or 100mL fasted state biorelevant medium, respectively. In silico simulations of small intestinal absorption were performed using the GI-Sim absorption model. All simulation runs were performed twice adopting either a total small intestinal volume of 533 mL or 105 mL, in order to examine the implication of free luminal water volumes for the in silico predictions. For the tested formulations, the use of a small biorelevant dissolution volume was critical for in vitro-in silico prediction of drug absorption. Good predictions, demonstrating rank order in vivo-in vitro-in silico correlations for Cmax, were obtained with in silico predictions utilizing a 105 mL estimate for the human intestinal water content combined with solubility and dissolution data performed in a mini paddle apparatus with 100mL fasted state simulated media.

  12. Determination of drug absorption rate in time-variant disposition by direct deconvolution using beta clearance correction and end-constrained non-parametric regression.

    PubMed

    Neelakantan, S; Veng-Pedersen, P

    2005-11-01

    A novel numerical deconvolution method is presented that enables the estimation of drug absorption rates under time-variant disposition conditions. The method involves two components. (1) A disposition decomposition-recomposition (DDR) enabling exact changes in the unit impulse response (UIR) to be constructed based on centrally based clearance changes iteratively determined. (2) A non-parametric, end-constrained cubic spline (ECS) input response function estimated by cross-validation. The proposed DDR-ECS method compensates for disposition changes between the test and the reference administrations by using a "beta" clearance correction based on DDR analysis. The representation of the input response by the ECS method takes into consideration the complex absorption process and also ensures physiologically realistic approximations of the response. The stability of the new method to noisy data was evaluated by comprehensive simulations that considered different UIRs, various input functions, clearance changes and a novel scaling of the input function that includes the "flip-flop" absorption phenomena. The simulated input response was also analysed by two other methods and all three methods were compared for their relative performances. The DDR-ECS method provides better estimation of the input profile under significant clearance changes but tends to overestimate the input when there were only small changes in the clearance.

  13. Did FDA Decisionmaking Affect Anti-Psychotic Drug Prescribing in Children?: A Time-Trend Analysis

    PubMed Central

    Wang, Bo; Franklin, Jessica M.; Eddings, Wesley; Landon, Joan; Kesselheim, Aaron S.

    2016-01-01

    Background Following Food and Drug Administration (FDA) approval, many drugs are prescribed for non-FDA-approved (“off-label”) uses. If substantial evidence supports the efficacy and safety of off-label indications, manufacturers can pursue formal FDA approval through supplemental new drug applications (sNDAs). We evaluated the effect of FDA determinations on pediatric sNDAs for antipsychotic drugs on prescribing of these products in children. Methods Retrospective, segmented time-series analysis using new prescription claims during 2003–2012 for three atypical antipsychotics (olanzapine, quetiapine, ziprasidone). FDA approved the sNDAs for pediatric use of olanzapine and quetiapine in December 2009, but did not approve the sNDA for pediatric use of ziprasidone. Results During the months before FDA approval of its pediatric sNDA, new prescriptions of olanzapine decreased for both children and adults. After FDA approval, the increase in prescribing trends was similar for both age groups (P = 0.47 for schizophrenia and bipolar disorder; P = 0.37 for other indications). Comparable decreases in use of quetiapine were observed between pediatrics and adults following FDA approval of its pediatric sNDA (P = 0.88; P = 0.63). Prescribing of ziprasidone decreased similarly for pediatric and adult patients after FDA non-approval of its pediatric sNDA (P = 0.61; P = 0.79). Conclusions The FDA’s sNDA determinations relating to use of antipsychotics in children did not result in changes in use that favored the approved sNDAs and disfavored the unapproved sNDA. Improved communication may help translate the agency’s expert judgments to clinical practice. PMID:27032095

  14. Seizure Clustering during Drug Treatment Affects Seizure Outcome and Mortality of Childhood-Onset Epilepsy

    ERIC Educational Resources Information Center

    Sillanpaa, Matti; Schmidt, Dieter

    2008-01-01

    To provide evidence of whether seizure clustering is associated with drug resistance and increased mortality in childhood-onset epilepsy, a prospective, long-term population-based study was performed. One hundred and twenty patients who had been followed since disease onset (average age 37.0 years, SD 7.1, median 40.0, range 11-42; incident cases)…

  15. Promoter strength of folic acid synthesis genes affects sulfa drug resistance in Saccharomyces cerevisiae.

    PubMed

    Iliades, Peter; Berglez, Janette; Meshnick, Steven; Macreadie, Ian

    2003-01-01

    The enzyme dihydropteroate synthase (DHPS) is an important target for sulfa drugs in both prokaryotic and eukaryotic microbes. However, the understanding of DHPS function and the action of antifolates in eukaryotes has been limited due to technical difficulties and the complexity of DHPS being a part of a bifunctional or trifunctional protein that comprises the upstream enzymes involved in folic acid synthesis (FAS). Here, yeast strains have been constructed to study the effects of FOL1 expression on growth and sulfa drug resistance. A DHPS knockout yeast strain was complemented by yeast vectors expressing the FOL1 gene under the control of promoters of different strengths. An inverse relationship was observed between the growth rate of the strains and FOL1 expression levels. The use of stronger promoters to drive FOL1 expression led to increased sulfamethoxazole resistance when para-aminobenzoic acid (pABA) levels were elevated. However, high FOL1 expression levels resulted in increased susceptibility to sulfamethoxazole in pABA free media. These data suggest that up-regulation of FOL1 expression can lead to sulfa drug resistance in Saccharomyces cerevisiae.

  16. Decreased Core Crystallinity Facilitated Drug Loading in Polymeric Micelles without Affecting Their Biological Performances.

    PubMed

    Gou, Jingxin; Feng, Shuangshuang; Xu, Helin; Fang, Guihua; Chao, Yanhui; Zhang, Yu; Xu, Hui; Tang, Xing

    2015-09-14

    Cargo-loading capacity of polymeric micelles could be improved by reducing the core crystallinity and the improvement in the amount of loaded cargo was cargo-polymer affinity dependent. The effect of medium chain triglyceride (MCT) in inhibiting PCL crystallization was confirmed by DSC and polarized microscope. When incorporating MCT into polymeric micelles, the maximum drug loading of disulfiram (DSF), cabazitaxel (CTX), and TM-2 (a taxane derivative) increased from 2.61 ± 0.100%, 13.5 ± 0.316%, and 20.9 ± 1.57% to 8.34 ± 0.197%, 21.7 ± 0.951%, and 28.0 ± 1.47%, respectively. Moreover, the prepared oil-containing micelles (OCMs) showed well-controlled particle size, good stability, and decreased drug release rate. MCT incorporation showed little influence on the performances of micelles in cell studies or pharmacokinetics. These results indicated that MCT incorporation could be a core construction module applied in the delivery of hydrophobic drugs. PMID:26314832

  17. Applying Biopharmaceutical Classification System (BCS) Criteria to Predict Oral Absorption of Drugs in Dogs: Challenges and Pitfalls.

    PubMed

    Papich, Mark G; Martinez, Marilyn N

    2015-07-01

    The Biopharmaceutical Classification System (BCS) has been a prognostic tool for assessing the potential effects of formulation on the human drug oral bioavailability. When used in conjunction with in vitro dissolution tests, the BCS can support the prediction of in vivo product performance and the development of mechanistic models that support formulation assessments through the generation of "what if" scenarios. To date, the applicability of existing human BCS criteria has not been evaluated in dogs, thereby limiting its use in canine drug development. Therefore, we examined 50 drugs for which absolute bioavailability (F) was available both in dogs and humans. The drugs were also evaluated for any potential association between solubility (calculated from the dose number, Do) or lipophilicity (LogP) and F in dogs. In humans, solubility is determined in 250 mL of fluid. However, the appropriate volume for classifying drug solubility in dogs has not been established. In this analysis, the estimated volume of a water flush administered to fasted dogs (6 mL) and a volume of 250 mL scaled to a Beagle dog (35 mL) were examined. In addition, in humans, a Do value greater than 1.0 is used to define a compound as highly soluble and a LogP value greater than 1.72 as high permeability. These same criteria were applied for defining highly soluble and highly permeable in dogs. Whether using 35 or 6 mL to determine Do, the canine solubility classification remained unchanged for all but seven compounds. There were no clear associations between a drug's F in dogs and humans or between the canine value of F and either its human BCS classification, its LogP value, or the canine Do estimate. There was a tendency for those drugs with canine values of F equal to or greater than 80% to have LogP values equal to or greater than 1.0. Exceptions to this observation tended to be those compounds known to be absorbed via mechanisms other than passive diffusion (e.g., via transporters or

  18. Identification of Genes Affecting the Toxicity of Anti-Cancer Drug Bortezomib by Genome-Wide Screening in S. pombe

    PubMed Central

    Takeda, Kojiro; Mori, Ayaka; Yanagida, Mitsuhiro

    2011-01-01

    Bortezomib/PS-341/Velcade, a proteasome inhibitor, is widely used to treat multiple myeloma. While several mechanisms of the cytotoxicity of the drug were proposed, the actual mechanism remains elusive. We aimed to identify genes affecting the cytotoxicity of Bortezomib in the fission yeast S.pombe as the drug inhibits this organism's cell division cycle like proteasome mutants. Among the 2815 genes screened (covering 56% of total ORFs), 19 genes, whose deletions induce strong synthetic lethality with Bortezomib, were identified. The products of the 19 genes included four ubiquitin enzymes and one nuclear proteasome factor, and 13 of them are conserved in humans. Our results will provide useful information for understanding the actions of Bortezomib within cells. PMID:21760946

  19. Modafinil does not affect serotonin efflux from rat frontal cortex synaptosomes: comparison with known serotonergic drugs.

    PubMed

    Ferraro, L; Tanganelli, S; Fuxe, K; Bebe, B W; Tomasini, M C; Rambert, F A; Antonelli, T

    2001-03-16

    Modafinil did not affect spontaneous and K(+)-evoked [3H]5-HT efflux from cortical synaptosomes while it increased K(+)-evoked tritium efflux from cortical slices, an action that became stronger in the presence of paroxetine. In contrast, DL-fenfluramine and fluoxetine were able to enhance spontaneous and/or K(+)-evoked tritium efflux from synaptosomes and slices. These results suggest that modafinil does not affect 5-HT transmission from cortical synaptosomes and that its 5-HT releasing action is different from that of DL-fenfluramine and fluoxetine.

  20. High prevalence of potential drug interactions affecting mycophenolic acid pharmacokinetics in nonmyeloablative hematopoietic stem cell transplant recipients

    PubMed Central

    Jaklič, Alenka; Collins, Carol J.; Mrhar, Aleš; Sorror, Mohamed L.; Sandmaier, Brenda M.; Bemer, Meagan J.; Locatelli, Igor; McCune, Jeannine S.

    2013-01-01

    Objective: Mycophenolic acid (MPA) exposure is associated with clinical outcomes in hematopoietic cell transplant (HCT) recipients. Various drug interaction studies, predominantly in healthy volunteers or solid organ transplant recipients, have identified medications which impact MPA pharmacokinetics. Recipients of nonmyeloablative HCT, however, have an increased burden of comorbidities, potentially increasing the number of concomitant medications and potential drug interactions (PDI) affecting MPA exposure. Thus, we sought to be the first to characterize these PDI in nonmyeloablative HCT recipients. Materials and methods: We compiled PDI affecting MPA pharmacokinetics and characterized the prevalence of PDI in nonmyeloablative HCT recipients. A comprehensive literature evaluation of four databases and PubMed was conducted to identify medications with PDI affecting MPA pharmacokinetics. Subsequently, a retrospective medication review was conducted to characterize the cumulative PDI burden, defined as the number of PDI for an individual patient over the first 21 days after allogeneic graft infusion, in 84 nonmyeloablative HCT recipients. Results: Of the 187 concomitant medications, 11 (5.9%) had a PDI affecting MPA pharmacokinetics. 87% of 84 patients had one PDI, with a median cumulative PDI burden of 2 (range 0 – 4). The most common PDI, in descending order, were cyclosporine, omeprazole and pantoprazole. Conclusion: Only a minority of medications (5.9%) have a PDI affecting MPA pharmacokinetics. However, the majority of nonmyeloablative HCT recipients had a PDI, with cyclosporine and the proton pump inhibitors being the most common. A better understanding of PDI and their management should lead to safer medication regimens for nonmyeloablative HCT recipients. PMID:23782584

  1. Negative Affect and HIV Risk in Alcohol and Other Drug (AOD) Abusing Adolescent Offenders

    ERIC Educational Resources Information Center

    Lucenko, Barbara A.; Malow, Robert M.; Sanchez-Martinez, Mario; Jennings, Terri; Devieux, Jessy G.

    2003-01-01

    Various depressive symptoms have been linked to elevated levels of HIV risk across diverse adult populations in multiple studies. However, this link has been examined in a much more limited manner among adolescents, despite an exceedingly heightened risk of both HIV and negative affect in this age group. To address the current lack of clinically…

  2. Drug membrane transporters and CYP3A4 are affected by hypericin, hyperforin or aristoforin in colon adenocarcinoma cells.

    PubMed

    Šemeláková, M; Jendželovský, R; Fedoročko, P

    2016-07-01

    Our previous results have shown that the combination of hypericin-mediated photodynamic therapy (HY-PDT) at sub-optimal dose with hyperforin (HP) (compounds of Hypericum sp.), or its stable derivative aristoforin (AR) stimulates generation of reactive oxygen species (ROS) leading to antitumour activity. This enhanced oxidative stress evoked the need for an explanation for HY accumulation in colon cancer cells pretreated with HP or AR. Generally, the therapeutic efficacy of chemotherapeutics is limited by drug resistance related to the overexpression of drug efflux transporters in tumour cells. Therefore, the impact of non-activated hypericin (HY), HY-PDT, HP and AR on cell membrane transporter systems (Multidrug resistance-associated protein 1-MRP1/ABCC1, Multidrug resistance-associated protein 2-MRP2/ABCC2, Breast cancer resistance protein - BCRP/ABCG2, P-glycoprotein-P-gp/ABCC1) and cytochrome P450 3A4 (CYP3A4) was evaluated. The different effects of the three compounds on their expression, protein level and activity was determined under specific PDT light (T0+, T6+) or dark conditions (T0- T6-). We found that HP or AR treatment affected the protein levels of MRP2 and P-gp, whereas HP decreased MRP2 and P-gp expression mostly in the T0+ and T6+ conditions, while AR decreased MRP2 in T0- and T6+. Moreover, HY-PDT treatment induced the expression of MRP1. Our data demonstrate that HP or AR treatment in light or dark PDT conditions had an inhibitory effect on the activity of individual membrane transport proteins and significantly decreased CYP3A4 activity in HT-29 cells. We found that HP or AR significantly affected intracellular accumulation of HY in HT-29 colon adenocarcinoma cells. These results suggest that HY, HP and AR might affect the efficiency of anti-cancer drugs, through interaction with membrane transporters and CYP3A4. PMID:27261575

  3. Penetration Enhancer-Containing Vesicles: Does the Penetration Enhancer Structure Affect Topical Drug Delivery?

    PubMed

    Caddeo, Carla; Manconi, Maria; Sinico, Chiara; Valenti, Donatella; Celia, Christian; Monduzzi, Maura; Fadda, Anna Maria

    2015-01-01

    The aim of this study was to elucidate the influence of the edge activator structure on the properties of novel deformable liposomes, Penetration Enhancer-containing Vesicles (PEVs), capable of delivering drugs to the skin. The PEVs were prepared by testing five different amphiphilic penetration enhancers as edge activators in the bilayer composition, together with soy phosphatidylcholine and oleic acid. The penetration enhancers contained the same lipophilic tail (one or more C8-C10 carbon chains) and different hydrophilic heads. Conventional phospholipid liposomes were prepared and used as a control. Lidocaine was chosen as a model drug. Liquid and gelified PEVs were obtained, depending on the penetration enhancer used. The vesicular systems were characterized by measuring size distribution, zeta potential, incorporation efficiency, and monitoring these parameters over 90 days. Accelerated ageing tests were also performed to check the stability of the dispersions. The effects of the different nature of the edge activator on the features of the obtained PEVs were assessed by TEM, SAXS and WAXS, rheological and deformability studies. Higher interactions of the most lipophilic penetration enhancers with the lipid bilayers and a consequent higher stability and elasticity of the obtained PEVs were observed. In vitro experiments through pig skin confirmed the superior potential as carriers for lidocaine of the PEVs prepared with the most lipophilic penetration enhancers, even in comparison with commercial EMLA cream.

  4. How Drug Shortages Affect Clinical Care: The Case of the Surgical Anesthetic Propofol

    PubMed Central

    Romito, Bryan; Stone, Jonathan; Ning, Ning; Yin, Chen; Llano, Ernesto M.; Liu, Jing; Somanath, Keerthan; Lee, Christopher T.

    2015-01-01

    Background: Periodic drug shortages have become a reality in clinical practice. In 2010, in the context of a nationwide drug shortage, our hospital experienced an abrupt 3-month shortage of the surgical anesthetic propofol. The purpose of this retrospective study was to survey the clinical impact of the abrupt propofol shortage at our hospital and to survey for any change in perioperative mortality. Methods: A retrospective before-and-after analysis, comparing May through July 2010 (group A, prior to the propofol shortage) to August through October 2010 (group B, during the propofol shortage). Results: In May through July 2010, before the propofol shortage, a majority of patients (80%) received propofol (group A, n = 2,830). In August through October 2010, during the propofol shortage, a majority of patients (81%) received etomidate (group B, n = 3,066). We observed that net usage of etomidate increased by more than 600% in our hospital. Baseline health characteristics and type of surgery were similar between groups A and B. Thirty-day and 2-year mortality were similar between groups A and B. The reported causes and frequency of mortality in groups A and B were also similar. Conclusion: The propofol shortage led to an increased usage of etomidate by more than 600%. In spite of that, we did not detect an increase in mortality associated with the increased use of etomidate during a 3-month propofol shortage. PMID:26912921

  5. Evaluation of neurotoxic and neuroprotective pathways affected by antiepileptic drugs in cultured hippocampal neurons.

    PubMed

    Morte, Maria I; Carreira, Bruno P; Falcão, Maria J; Ambrósio, António F; Soares-da-Silva, Patrício; Araújo, Inês M; Carvalho, Caetana M

    2013-12-01

    In this study we evaluated the neurotoxicity of eslicarbazepine acetate (ESL), and of its in vivo metabolites eslicarbazepine (S-Lic) and R-licarbazepine (R-Lic), as compared to the structurally-related compounds carbamazepine (CBZ) and oxcarbazepine (OXC), in an in vitro model of cultured rat hippocampal neurons. The non-related antiepileptic drugs (AEDs) lamotrigine (LTG) and sodium valproate (VPA) were also studied. We assessed whether AEDs modulate pro-survival/pro-apoptotic pathways, such as extracellular-regulated kinase (ERK1/2), Akt and stress activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK). We found that neither ESL nor its metabolites, CBZ or LTG, up to 0.3mM, for 24h of exposure, decreased cell viability. OXC was the most toxic drug decreasing cell viability in a concentration-dependent manner, leading to activation of caspase-3 and PARP cleavage. VPA caused the appearance of the apoptotic markers, but did not alter cell viability. ESL, S-Lic and OXC decreased the levels of phospho-ERK1/2 and of phospho-Akt, when compared to basal levels, whereas CBZ decreased phospho-SAPK/JNK and phospho-Akt levels. LTG and VPA increased the phosphorylation levels of SAPK/JNK. These results suggest that ESL and its main metabolite S-Lic, as well as CBZ, LTG and VPA, are less toxic to hippocampal neurons than OXC, which was the most toxic agent.

  6. The antiepileptic drug diphenylhydantoin affects the structure of the human erythrocyte membrane.

    PubMed

    Suwalsky, Mario; Mennickent, Sigrid; Norris, Beryl; Villena, Fernando; Cuevas, Francisco; Sotomayor, Carlos P

    2004-01-01

    Phenytoin (diphenylhydantoin) is an antiepileptic agent effective against all types of partial and tonic-clonic seizures. Phenytoin limits the repetitive firing of action potentials evoked by a sustained depolarization of mouse spinal cord neurons maintained in vitro. This effect is mediated by a slowing of the rate of recovery of voltage activated Na+ channels from inactivation. For this reasons it was thought of interest to study the binding affinities of phenytoin with cell membranes and their perturbing effects upon membrane structures. The effects of phenytoin on the human erythrocyte membrane and molecular models have been investigated in the present work. This report presents the following evidence that phenytoin interacts with cell membranes: a) X-ray diffraction and fluorescence spectroscopy of phospholipid bilayers showed that phenytoin perturbed a class of lipids found in the outer moiety of cell membranes; b) in isolated unsealed human erythrocyte membranes (IUM) the drug induced a disordering effect on the polar head groups and acyl chains of the erythrocyte membrane lipid bilayer; c) in scanning electron microscopy (SEM) studies on human erythrocytes the formation of echinocytes was observed, due to the insertion of phenytoin in the outer monolayer of the red cell membrane. This is the first time that an effect of phenytoin on the red cell shape is described. However, the effects of the drug were observed at concentrations higher than those currently found in plasma when phenytoin is therapeutically administered. PMID:18998414

  7. Do nonsteroidal anti-inflammatory drugs affect the outcome of arthroscopic Bankart repair?

    PubMed

    Blomquist, J; Solheim, E; Liavaag, S; Baste, V; Havelin, L I

    2014-12-01

    To achieve pain control after arthroscopic shoulder surgery, nonsteroidal anti-inflammatory drugs (NSAIDs) are a complement to other analgesics. However, experimental studies have raised concerns that these drugs may have a detrimental effect on soft tissue-to-bone healing and, thus, have a negative effect on the outcome. We wanted to investigate if there are any differences in the clinical outcome after the arthroscopic Bankart procedure for patients who received NSAIDs prescription compared with those who did not. 477 patients with a primary arthroscopic Bankart procedure were identified in the Norwegian shoulder instability register and included in the study. 32.5% received prescription of NSAIDs post-operatively. 370 (78%) of the patients answered a follow-up questionnaire containing the Western Ontario Shoulder Instability index (WOSI). Mean follow-up was 21 months. WOSI at follow-up were 75% in the NSAID group and 74% in the control group. 12% of the patients in the NSAID group and 14% in the control group reported recurrence of instability. The reoperation rate was 5% in both groups. There were no statistically significant differences between the groups. Prescription of short-term post-operative NSAID treatment in the post-operative period did not influence on the functional outcome after arthroscopic Bankart procedures. PMID:24750379

  8. [Viewpoint on the methodology of drug trials affecting cognition of elderly patients].

    PubMed

    Allain, H; Bernard, P M; Dartigues, J F; Dérouesné, C; Dubois, B; Hugonot, L; Laurent, B; Léger, J M; Malauzat, D; Michel, B

    1994-01-01

    Clinical trials for cognitive disorders in the elderly require specific methodological guidelines. They must take into account the psychosocial dimension of the patient and his family and must be based on serious neurobiologic knowledge. In degenerative dementias the progress of research concern genetics, molecular intercellular recognition and astrocytic cells. Biology of cognition like hippocampal long term potentiation provides good pharmacologic basis for trials. In normal brain aging several ways must be developed: aminergic systems, free radicals, excitotoxic amino-acid, nerves growth factors. Clinical trials bring informations for pharmacology and epidemiology. Cholinergic neurons are the main pharmacologic target but there are many other ones: GABA-ergic system, Tau protein, amyloid. A rigourous selection of patients allows to precise the nosology of illness responsible of cognitive disorders and to point-out early clinical signs that represent a more sensitive target. Diagnostic criteria are useful in Alzheimer's disease, memory impairment, vascular dementias and other dementias. Evaluation of stage and evolution of dementia, comorbidity, limits of age and caregiver are practical problems. The effects of drugs used to treat cognitive functions are subtle so it is necessary to detect them to choose the best tests in function of each trial. Laboratory investigations can be used to evaluate the response to drug administration. Ethical point of view is represented by the fact that old people with cognitive impairment must not be away from therapeutic progress. In this field we must consider carefully the consequences of cognitive impairment on patient judgment and consent to clinical trial. Legal problems are regulated by supranational rules and French directives of Huriet law.

  9. Do thickening properties of locust bean gum affect the amount of calcium, iron and zinc available for absorption from infant formula? In vitro studies.

    PubMed

    Bosscher, D; Van Caillie-Bertrand, M; Deelstra, H

    2003-07-01

    Locust bean gum acts as a milk thickener in infant formula because of its high apparent viscosity. The effects of such thickening agents on metabolic and physiologic responses during infancy have not been clarified sufficiently. Due to the increased volume of the digest and the bulking and trapping effects, digestion and absorption of nutrients may be influenced in presence of locust bean gum. The central question addressed in this paper is whether the thickening properties of locust bean gum affect the availability of calcium, iron, and zinc. Increasing amounts of powdered locust bean gum were homogenised with infant formula and samples were diluted to 0.14, 0.27, 0.42 and 0.71 g/100 ml. Viscosity of the samples was measured by a Carrie-Med CSL100 rheometer. Available amounts of calcium, iron, and zinc were evaluated using a continuous-flow dialysis model with preliminary digestion. Elemental contents of samples and dialysates were analysed with atomic absorption spectrometry. The first set of experiments showed that addition of locust bean gum to infant formulas increased the viscosity of the luminal contents. Correlations between the locust bean gum concentration and the viscosity of the samples before and after gastric or intestinal digestion were highly significant (0.97). In the second set of experiments, the correlations between the locust bean gum concentration and the amounts of calcium trapped by the locust bean gum fraction also showed high significance (0.93). In the third experimental design, again strong correlations were found between the viscosity of the intestinal digest and the amounts of calcium trapped by the fibre fraction (0.90). For iron and zinc, no such relationships were found. From this experimental set-up it appears that locust bean gum influences calcium availability in infant formulas by means of its physical properties to act as thickening agent, rather than its chemical ability to form complexes as demonstrated earlier with respect

  10. Possible interaction of quinolone antibiotics with peptide transporter 1 in oral absorption of peptide-mimetic drugs.

    PubMed

    Arakawa, Hiroshi; Kamioka, Hiroki; Kanagawa, Masahiko; Hatano, Yasuko; Idota, Yoko; Yano, Kentaro; Morimoto, Kaori; Ogihara, Takuo

    2016-01-01

    The study investigated whether quinolone antibiotics inhibit the PEPT1-mediated uptake of its substrates. Among the quinolones examined, lomefloxacin, moxifloxacin (MFLX) and purlifloxacin significantly inhibited the uptake of PEPT1 substrate phenylalanine-Ψ(CN-S)-alanine (Phe-Ψ-Ala) in HeLa/PEPT1 cells to 31.6 ± 1.3%, 27.6 ± 2.9%, 36.8 ± 2.2% and 32.6 ± 1.4%, respectively. Further examination showed that MFLX was an uncompetitive inhibitor, with an IC50 value of 4.29 ± 1.29 mm. In addition, MFLX significantly decreased the cephalexin and valacyclovir uptake in HeLa/PEPT1 cells. In an in vivo study in rats, the maximum plasma concentration (C(max)) of orally administered Phe-Ψ-Ala was significantly decreased in the presence of MFLX (171 ± 1 ng/ml) compared with that in its absence (244 ± 9 ng/ml). The area under the concentration-time curve (AUC) of orally administered Phe-Ψ-Ala in the presence of MFLX (338 ± 50 ng/ml · h) tended to decrease compared with that in its absence (399 ± 75 ng/ml · h). The oral bioavailability of Phe-Ψ-Ala in the presence and absence of MFLX was 41.7 ± 6.2% and 49.2 ± 9.2%, respectively. The results indicate that administration of quinolone antibiotics concomitantly with PEPT1 substrate drugs may potentially result in drug-drug interaction. PMID:26590007

  11. Drugs.

    ERIC Educational Resources Information Center

    Hurst, Hunter, Ed.; And Others

    1984-01-01

    This document contains the third volume of "Today's Delinquent," an annual publication of the National Center for Juvenile Justice. This volume deals with the issue of drugs and includes articles by leading authorities in delinquency and substance abuse who share their views on causes and cures for the drug problem among youth in this country.…

  12. In Situ Perfusion Model in Rat Colon for Drug Absorption Studies: Comparison with Small Intestine and Caco-2 Cell Model.

    PubMed

    Lozoya-Agullo, Isabel; González-Álvarez, Isabel; González-Álvarez, Marta; Merino-Sanjuán, Matilde; Bermejo, Marival

    2015-09-01

    Our aim is to develop and to validate the in situ closed loop perfusion method in rat colon and to compare with small intestine and Caco-2 cell models. Correlations with human oral fraction absorbed (Fa) and human colon fraction absorbed (Fa_colon) were developed to check the applicability of the rat colon model for controlled release (CR) drug screening. Sixteen model drugs were selected and their permeabilities assessed in rat small intestine and colon, and in Caco-2 monolayers. Correlations between colon/intestine/Caco-2 permeabilities versus human Fa and human Fa_colon have been explored to check model predictability and to apply a BCS approach in order to propose a cut off value for CR screening. Rat intestine perfusion with Doluisio's method and single-pass technique provided a similar range of permeabilities demonstrating the possibility of combining data from different laboratories. Rat colon permeability was well correlated with Caco-2 cell-4 days model reflecting a higher paracellular permeability. Rat colon permeabilities were also higher than human colon ones. In spite of the magnitude differences, a good sigmoidal relationship has been shown between rat colon permeabilities and human colon fractions absorbed, indicating that rat colon perfusion can be used for compound classification and screening of CR candidates.

  13. Do nonsteroidal anti-inflammatory drugs affect bone healing? A critical analysis.

    PubMed

    Pountos, Ippokratis; Georgouli, Theodora; Calori, Giorgio M; Giannoudis, Peter V

    2012-01-01

    Nonsteroidal anti-inflammatory drugs (NSAIDs) play an essential part in our approach to control pain in the posttraumatic setting. Over the last decades, several studies suggested that NSAIDs interfere with bone healing while others contradict these findings. Although their analgesic potency is well proven, clinicians remain puzzled over the potential safety issues. We have systematically reviewed the available literature, analyzing and presenting the available in vitro animal and clinical studies on this field. Our comprehensive review reveals the great diversity of the presented data in all groups of studies. Animal and in vitro studies present so conflicting data that even studies with identical parameters have opposing results. Basic science research defining the exact mechanism with which NSAIDs could interfere with bone cells and also the conduction of well-randomized prospective clinical trials are warranted. In the absence of robust clinical or scientific evidence, clinicians should treat NSAIDs as a risk factor for bone healing impairment, and their administration should be avoided in high-risk patients. PMID:22272177

  14. How does family drug treatment court participation affect child welfare outcomes?

    PubMed

    Gifford, Elizabeth Joanne; Eldred, Lindsey Morgan; Vernerey, Allison; Sloan, Frank Allen

    2014-10-01

    Parental substance use is a risk factor for child maltreatment. Family drug treatment courts (FDTCs) have emerged in the United States as a policy option to treat the underlying condition and promote family preservation. This study examines the effectiveness of FDTCs in North Carolina on child welfare outcomes. Data come from North Carolina records from child protection services, court system, and birth records. Three types of parental participation in a FDTC are considered: referral, enrolling, and completing an FDTC. The sample includes 566 children who were placed into foster care and whose parents participated in a FDTC program. Findings indicate that children of parents who were referred but did not enroll or who enrolled but did not complete had longer stays in foster care than children of completers. Reunification rates for children of completers were also higher. Outcomes for children in the referred and enrolled groups did not differ in the multivariate analyses. While effective substance use treatment services for parents may help preserve families, future research should examine factors for improving participation and completion rates as well as factors involved in scaling programs so that more families are served.

  15. Morphine administration or sexual segregation in infancy affect the response to the same drug in adult mice.

    PubMed

    Laviola, G; Terranova, M L; Alleva, E

    1993-01-01

    Several experiments indicate that CNS opioid regulatory systems show a remarkable plasticity during development. The same systems respond to a wide range of environmental stimuli, particularly those which can affect the threshold of pain sensitivity (e.g., Environmentally Induced Analgesia). This paper summarizes a series of studies using outbred CD-1 mice, aimed at assessing: a) morphine effects on pain sensitivity and locomotor activity at two ages during development, namely, before and after weaning, and b) the consequences of such exposure on adult sensitivity to the same drug. The development of hot-plate response consisted mainly of a progressive decrease of latencies and of a parallel reduction of sensitivity to morphine. While morphine depressed activity on day 14, it increased or had apparently no effect on day 21. With respect to carry-over consequences of early drug and test exposure, the animals with a history of testing at the preweanling stage were more sensitive to the depressant effect of morphine (10 mg/kg) than those pretested at a later stage. By contrast, morphine analgesia was attenuated by drug pre-exposure, independently of the age of previous testing. In sum, the age of early exposure and type of early treatment interacted to determine the level of adult pain sensitivity in the no-drug state. Finally, the long-term effects of sexual segregation in infancy on the response to painful stimulation and morphine were assessed. Adult male mice-reared from birth to weaning in litters containing either only male pups (MM), or both male and female pups (MF)--were challenged in a hot-plate test upon morphine or saline injection.(ABSTRACT TRUNCATED AT 250 WORDS)

  16. Probing for affective side effects of drugs used in geriatric practice: use of daily diaries to test for effects of metoclopramide and naproxen.

    PubMed

    Katz, Ira R; Morales, Knashawn; Datto, Catherine; Streim, Joel; Oslin, David; DiFilippo, Suzanne; Have, Thomas Ten

    2005-08-01

    The aim of this study was to develop the use of daily diaries of affects and events as measures of pharmacological effects on affective processes and to apply them to evaluate the possible affective toxicity of metoclopramide and naproxen, two medications commonly used in geriatric practice. In all, 105 adults aged 65 years or older were randomized to receive metoclopramide (up to 40 mg/day), naproxen (up to 1000 mg/day), or placebo under double-blind conditions for a period of 5 weeks. Patients were seen weekly for evaluations of affective and cognitive outcomes as well as safety. In addition, patients kept diaries with daily records of positive and negative affect and reports of significant daily events. Findings included mixed model analyses of drug assignment, time, events, and interactions for both positive affect and days with significant negative affect. Subjects exhibited high levels of adherence in completing daily diaries. Neither the pattern of dropouts nor the weekly assessments demonstrated significant drug effects on mood or affect. However, diary data demonstrated that metoclopramide increased the apparent impact of negative events on both positive and negative affect relative to placebo, and that naproxen increased the apparent impact of positive events on positive affect and, possibly, of negative events on negative affect relative to placebo. The findings confirm the utility of diary methods for studying drug effects on affective processes in normal elderly subjects. They suggest that both metoclopramide and naproxen can affect the associations between daily events and affects. If replicated, they would demonstrate that drug effects can extend beyond the intensity of affect and/or the emergence of full-fledged psychiatric disorders to include moderation of the interactions between daily events and affect.

  17. Herbal drug quality and phytochemical composition of Hypericum perforatum L. affected by ash yellows phytoplasma infection.

    PubMed

    Bruni, Renato; Pellati, Federica; Bellardi, Maria Grazia; Benvenuti, Stefania; Paltrinieri, Samanta; Bertaccini, Assunta; Bianchi, Alberto

    2005-02-23

    Qualitative/quantitative phytochemical variations were observed in dried flowering tops of cultivated Hypericum perforatum L. cv. Zorzi infected by phytoplasmas of the "ash yellows" class, identified by direct and nested polymerase chain reaction (PCR); this is the first report of ribosomial group 16SrVII phytoplasmas in St. John's Wort. Methanolic extracts of healthy and infected plants were separated by reversed phase high-performance liquid chromatography to quantify naphthodianthrones and flavonoids, while essential oils were analyzed by means of gas chromatography (GC)-GC/MS. The affected plants exhibited decreased amounts of rutin (1.96 +/- 0.23 vs 4.96 +/- 0.02 mg/g), hyperoside (2.38 +/- 0.21 vs 3.04 +/- 0.05 mg/g), isoquercitrin (1.47 +/- 0.04 vs 3.50 +/- 0.08 mg/g), amentoflavone (0.12 +/- 0.01 vs 0.39 +/- 0.02 mg/g), and pseudohypericin (1.41 +/- 0.23 vs 2.29 +/- 0.07 mg/g), whereas the chlorogenic acid content was doubled (1.56 +/- 0.11 vs 0.77 +/- 0.02 mg/g). Hypericin, quercitrin, and quercetin contents were not severely affected. The essential oil yield was drastically reduced in infected material (0.11 vs 0.75% in healthy material) and revealed an increased abundance of sesquiterpenes (beta-caryophyllene, delta-elemene, and germacrene D, in particular) and a matching decrease in monoterpene hydrocarbons and aliphatics. The consequences that the phytopathological condition of cultivated H. perforatum plants has on the commercial quality, market value, and therapeutic efficacy are outlined. PMID:15713006

  18. Quinoa extract enriched in 20-hydroxyecdysone affects energy homeostasis and intestinal fat absorption in mice fed a high-fat diet.

    PubMed

    Foucault, Anne-Sophie; Even, Patrick; Lafont, René; Dioh, Waly; Veillet, Stanislas; Tomé, Daniel; Huneau, Jean-François; Hermier, Dominique; Quignard-Boulangé, Annie

    2014-04-10

    In a previous study, we have demonstrated that a supplementation of a high-fat diet with a quinoa extract enriched in 20-hydroxyecdysone (QE) or pure 20-hydroxyecdysone (20E) could prevent the development of obesity. In line with the anti-obesity effect of QE, we used indirect calorimetry to examine the effect of dietary QE and 20E in high-fat fed mice on different components of energy metabolism. Mice were fed a high-fat (HF) diet with or without supplementation by QE or pure 20E for 3 weeks. As compared to mice maintained on a low-fat diet, HF feeding resulted in a marked physiological shift in energy homeostasis, associating a decrease in global energy expenditure (EE) and an increase in lipid utilization as assessed by the lower respiratory quotient (RQ). Supplementation with 20E increased energy expenditure while food intake and activity were not affected. Furthermore QE and 20E promoted a higher rate of glucose oxidation leading to an increased RQ value. In QE and 20E-treated HFD fed mice, there was an increase in fecal lipid excretion without any change in stool amount. Our study indicates that anti-obesity effect of QE can be explained by a global increase in energy expenditure, a shift in glucose metabolism towards oxidation to the detriment of lipogenesis and a decrease in dietary lipid absorption leading to reduced dietary lipid storage in adipose tissue.

  19. Effect of compounds affecting ABCA1 expression and CETP activity on the HDL pathway involved in intestinal absorption of lutein and zeaxanthin.

    PubMed

    Niesor, Eric J; Chaput, Evelyne; Mary, Jean-Luc; Staempfli, Andreas; Topp, Andreas; Stauffer, Andrea; Wang, Haiyan; Durrwell, Alexandre

    2014-12-01

    The antioxidant xanthophylls lutein and zeaxanthin are absorbed from the diet in a process involving lipoprotein formation. Selective mechanisms exist for their intestinal uptake and tissue-selective distribution, but these are poorly understood. We investigated the role of high-density lipoprotein (HDL), apolipoprotein (apo) A1 and ATP-binding cassette transporter (ABC) A1 in intestinal uptake of lutein in a human polarized intestinal cell culture and a hamster model. Animals received dietary lutein and zeaxanthin and either a liver X receptor (LXR) agonist or statin, which up- or down-regulate intestinal ABCA1 expression, respectively. The role of HDL was studied following treatment with the cholesteryl ester transfer protein (CETP) modulator dalcetrapib or the CETP inhibitor anacetrapib. In vitro, intestinal ABCA1 at the basolateral surface of enterocytes transferred lutein and zeaxanthin to apoA1, not to mature HDL. In hamsters, plasma lutein and zeaxanthin levels were markedly increased with the LXR agonist and decreased with simvastatin. Dalcetrapib, but not anacetrapib, increased plasma and liver lutein and zeaxanthin levels. ABCA1 expression and apoA1 acceptor activity are important initial steps in intestinal uptake and maintenance of lutein and zeaxanthin levels by an HDL-dependent pathway. Their absorption may be improved by physiological and pharmacological interventions affecting HDL metabolism.

  20. 'Ecstasy' as a social drug: MDMA preferentially affects responses to emotional stimuli with social content.

    PubMed

    Wardle, Margaret C; Kirkpatrick, Matthew G; de Wit, Harriet

    2014-08-01

    3,4-Methylenedioxymethamphetamine (MDMA, 'ecstasy') is used recreationally to improve mood and sociability, and has generated clinical interest as a possible adjunct to psychotherapy. One way that MDMA may produce positive 'prosocial' effects is by changing responses to emotional stimuli, especially stimuli with social content. Here, we examined for the first time how MDMA affects subjective responses to positive, negative and neutral emotional pictures with and without social content. We hypothesized that MDMA would dose-dependently increase reactivity to positive emotional stimuli and dampen reactivity to negative stimuli, and that these effects would be most pronounced for pictures with people in them. The data were obtained from two studies using similar designs with healthy occasional MDMA users (total N = 101). During each session, participants received MDMA (0, 0.75 and 1.5 mg/kg oral), and then rated their positive and negative responses to standardized positive, negative and neutral pictures with and without social content. MDMA increased positive ratings of positive social pictures, but reduced positive ratings of non-social positive pictures. We speculate this 'socially selective' effect contributes to the prosocial effects of MDMA by increasing the comparative value of social contact and closeness with others. This effect may also contribute to its attractiveness to recreational users.

  1. 'Ecstasy' as a social drug: MDMA preferentially affects responses to emotional stimuli with social content.

    PubMed

    Wardle, Margaret C; Kirkpatrick, Matthew G; de Wit, Harriet

    2014-08-01

    3,4-Methylenedioxymethamphetamine (MDMA, 'ecstasy') is used recreationally to improve mood and sociability, and has generated clinical interest as a possible adjunct to psychotherapy. One way that MDMA may produce positive 'prosocial' effects is by changing responses to emotional stimuli, especially stimuli with social content. Here, we examined for the first time how MDMA affects subjective responses to positive, negative and neutral emotional pictures with and without social content. We hypothesized that MDMA would dose-dependently increase reactivity to positive emotional stimuli and dampen reactivity to negative stimuli, and that these effects would be most pronounced for pictures with people in them. The data were obtained from two studies using similar designs with healthy occasional MDMA users (total N = 101). During each session, participants received MDMA (0, 0.75 and 1.5 mg/kg oral), and then rated their positive and negative responses to standardized positive, negative and neutral pictures with and without social content. MDMA increased positive ratings of positive social pictures, but reduced positive ratings of non-social positive pictures. We speculate this 'socially selective' effect contributes to the prosocial effects of MDMA by increasing the comparative value of social contact and closeness with others. This effect may also contribute to its attractiveness to recreational users. PMID:24682132

  2. How does hospitalization affect continuity of drug therapy: an exploratory study

    PubMed Central

    Blozik, Eva; Signorell, Andri; Reich, Oliver

    2016-01-01

    Introduction Transitions between different levels of health care, such as hospital admission and discharge, pose a significant threat to the quality and continuity of medication therapy. This study aims to explore the role of hospitalization on medication changes as patients are transferred from and back to ambulatory care. Methods Secondary analysis of claims data from Swiss residents with basic health insurance at the Helsana Group was performed. We evaluated medication invoices of patients who were hospitalized in a Swiss private hospital group in the year 2013. Medication changes were defined as discontinuation, new prescription, or change in the Anatomical Therapeutic Chemical (ATC) Classification System level 4, which is equivalent to a change in the chemical/therapeutic/pharmacological subgroup. Multiple Poisson regression analysis was applied to evaluate whether medication change was predicted by socioeconomic or clinical patient characteristics or by a system factor (physician dispensing of medication allowed in canton of residence). Results We investigated a total of 10,123 hospitalized patients, among whom a mean number of 3.85 (median 3.00) changes were identified. Change most frequently affected antihypertensives, analgesics, and antirheumatics. If patients were enrolled in a managed care plan, they were less likely to undergo changes. If a patient resided in a canton, in which physicians were allowed to dispense medication directly, the patient was more likely to experience change. Conclusion There is considerable change in medication when patients shift between ambulatory and inpatient health care levels. This interruption of medication continuity is in part desirable as it responds to clinical needs. However, we hypothesize that there is also a significant proportion of change due to unwarranted factors such as financial incentives for change of products. PMID:27578981

  3. The influence of food on the oral absorption of bevantolol.

    PubMed

    Toothaker, R D; Randinitis, E J; Nelson, C; Kinkel, A W; Goulet, J R

    1987-04-01

    The bioavailability of bevantolol was compared in 12 healthy volunteers given single doses of the drug as the HCl salt after an overnight fast, or 15 minutes before or after a standardized breakfast in a nonblind, randomized crossover design. Bevantolol was rapidly absorbed in all three treatment groups, with maximum concentrations (Cmax) observed at 1.0, 0.9, and 1.8 hours for the fasting, before breakfast, and after breakfast groups, respectively. Time to Cmax was significantly longer than fasting only when bevantolol was given after breakfast. Food ingestion did not significantly affect Cmax, total of absorbed drug, or the drug elimination rate. Since food only slightly decreases the drug absorption rate and has no measurable effect on the extent of drug absorption, the relationship of bevantolol administration to meals is not expected to influence therapeutic efficacy.

  4. X-ray absorption spectroscopy of an investigational anticancer gallium(III) drug: interaction with serum proteins, elemental distribution pattern, and coordination of the compound in tissue.

    PubMed

    Hummer, Alfred A; Bartel, Caroline; Arion, Vladimir B; Jakupec, Michael A; Meyer-Klaucke, Wolfram; Geraki, Tina; Quinn, Paul D; Mijovilovich, Ana; Keppler, Bernhard K; Rompel, Annette

    2012-06-14

    Tris(8-quinolinolato)gallium(III) (1, KP46) is a very promising investigational anticancer drug. Its interaction with serum proteins, elemental distribution, and coordination in tissue were investigated with X-ray absorption (XAS) methods. Model compounds with mixed O, N, and/or S donor atoms are reported. The coordination and structure of 1 in cell culture medium (minimum essential medium, MEM) and fetal calf serum (FCS) were probed by XANES and EXAFS. The interaction of 1 with the serum proteins apotransferrin (apoTf) and human serum albumin (HSA) was addressed as well. By application of micro-XAS to tissue samples from mice treated with 1, the gallium distribution pattern was analyzed and compared to those of physiological trace elements. The complex 1 turned out to be very stable under physiological conditions, in cell culture media and in tissue samples. The coordination environment of the metal center remains intact in the presence of apoTf and HSA. The gallium distribution pattern in tumor and liver tissue revealed high similarities to the distribution patterns of Zn and Fe, minor similarities to Cu and Ni, and no similarity to Ca.

  5. Percutaneous nitroglycerin absorption in rats.

    PubMed

    Horhota, S T; Fung, H L

    1979-05-01

    Percutaneous nitroglycerin absorption was studied in shaved rats by monitoring unchanged plasma drug concentrations for up to 4 hr. Drug absorption from the neat liquid state or from an alcoholic solution was considerably poorer than that from a commercial ointment. This observation was unanticipated since the driving force for percutaneous drug absorption was assumed to be drug thermodynamics. Potential artifacts such as drug volatilization from the skin, reduction of surface area through droplet formation, and vehicle occlusion were investigated, but they did not appear to be responsible for the observed results. Two experimental aqueous nitroglycerin gels were prepared with polyethylene glycol 400. One gel contained just sufficient polyethylene glycol to solubilize the nitroglycerin; the other had excess polyethylene glycol to solubilize nitroglycerin far below saturation. Both gels gave extremely low plasma nitroglycerin levels. The composite data suggested that percutaneous nitroglycerin absorption is highly vehicle dependent and that this dependency cannot be explained by simple consideration of drug thermodynamic activity.

  6. The Fcp1-Wee1-Cdk1 axis affects spindle assembly checkpoint robustness and sensitivity to antimicrotubule cancer drugs.

    PubMed

    Visconti, R; Della Monica, R; Palazzo, L; D'Alessio, F; Raia, M; Improta, S; Villa, M R; Del Vecchio, L; Grieco, D

    2015-09-01

    To grant faithful chromosome segregation, the spindle assembly checkpoint (SAC) delays mitosis exit until mitotic spindle assembly. An exceedingly prolonged mitosis, however, promotes cell death and by this means antimicrotubule cancer drugs (AMCDs), that impair spindle assembly, are believed to kill cancer cells. Despite malformed spindles, cancer cells can, however, slip through SAC, exit mitosis prematurely and resist killing. We show here that the Fcp1 phosphatase and Wee1, the cyclin B-dependent kinase (cdk) 1 inhibitory kinase, play a role for this slippage/resistance mechanism. During AMCD-induced prolonged mitosis, Fcp1-dependent Wee1 reactivation lowered cdk1 activity, weakening SAC-dependent mitotic arrest and leading to mitosis exit and survival. Conversely, genetic or chemical Wee1 inhibition strengthened the SAC, further extended mitosis, reduced antiapoptotic protein Mcl-1 to a minimum and potentiated killing in several, AMCD-treated cancer cell lines and primary human adult lymphoblastic leukemia cells. Thus, the Fcp1-Wee1-Cdk1 (FWC) axis affects SAC robustness and AMCDs sensitivity. PMID:25744022

  7. FBXW7 and USP7 regulate CCDC6 turnover during the cell cycle and affect cancer drugs susceptibility in NSCLC

    PubMed Central

    Merolla, Francesco; Poser, Ina; Visconti, Roberta; Ilardi, Gennaro; Paladino, Simona; Inuzuka, Hiroyuki; Guggino, Gianluca; Monaco, Roberto; Colecchia, David; Monaco, Guglielmo; Cerrato, Aniello; Chiariello, Mario; Denning, Krista; Claudio, Pier Paolo; Staibano, Stefania; Celetti, Angela

    2015-01-01

    CCDC6 gene product is a pro-apoptotic protein substrate of ATM, whose loss or inactivation enhances tumour progression. In primary tumours, the impaired function of CCDC6 protein has been ascribed to CCDC6 rearrangements and to somatic mutations in several neoplasia. Recently, low levels of CCDC6 protein, in NSCLC, have been correlated with tumor prognosis. However, the mechanisms responsible for the variable levels of CCDC6 in primary tumors have not been described yet. We show that CCDC6 turnover is regulated in a cell cycle dependent manner. CCDC6 undergoes a cyclic variation in the phosphorylated status and in protein levels that peak at G2 and decrease in mitosis. The reduced stability of CCDC6 in the M phase is dependent on mitotic kinases and on degron motifs that are present in CCDC6 and direct the recruitment of CCDC6 to the FBXW7 E3 Ubl. The de-ubiquitinase enzyme USP7 appears responsible of the fine tuning of the CCDC6 stability, affecting cells behaviour and drug response. Thus, we propose that the amount of CCDC6 protein in primary tumors, as reported in lung, may depend on the impairment of the CCDC6 turnover due to altered protein-protein interaction and post-translational modifications and may be critical in optimizing personalized therapy. PMID:25885523

  8. FBXW7 and USP7 regulate CCDC6 turnover during the cell cycle and affect cancer drugs susceptibility in NSCLC.

    PubMed

    Morra, Francesco; Luise, Chiara; Merolla, Francesco; Poser, Ina; Visconti, Roberta; Ilardi, Gennaro; Paladino, Simona; Inuzuka, Hiroyuki; Guggino, Gianluca; Monaco, Roberto; Colecchia, David; Monaco, Guglielmo; Cerrato, Aniello; Chiariello, Mario; Denning, Krista; Claudio, Pier Paolo; Staibano, Stefania; Celetti, Angela

    2015-05-20

    CCDC6 gene product is a pro-apoptotic protein substrate of ATM, whose loss or inactivation enhances tumour progression. In primary tumours, the impaired function of CCDC6 protein has been ascribed to CCDC6 rearrangements and to somatic mutations in several neoplasia. Recently, low levels of CCDC6 protein, in NSCLC, have been correlated with tumor prognosis. However, the mechanisms responsible for the variable levels of CCDC6 in primary tumors have not been described yet.We show that CCDC6 turnover is regulated in a cell cycle dependent manner. CCDC6 undergoes a cyclic variation in the phosphorylated status and in protein levels that peak at G2 and decrease in mitosis. The reduced stability of CCDC6 in the M phase is dependent on mitotic kinases and on degron motifs that are present in CCDC6 and direct the recruitment of CCDC6 to the FBXW7 E3 Ubl. The de-ubiquitinase enzyme USP7 appears responsible of the fine tuning of the CCDC6 stability, affecting cells behaviour and drug response.Thus, we propose that the amount of CCDC6 protein in primary tumors, as reported in lung, may depend on the impairment of the CCDC6 turnover due to altered protein-protein interaction and post-translational modifications and may be critical in optimizing personalized therapy.

  9. Troubled families and individualised solutions: an institutional discourse analysis of alcohol and drug treatment practices involving affected others.

    PubMed

    Selbekk, Anne Schanche; Sagvaag, Hildegunn

    2016-09-01

    Research shows that members of the families with patients suffering from alcohol and other drug-related issues (AOD) experience stress and strain. An important question is, what options do AOD treatment have for them when it comes to support? To answer this, we interviewed directors and clinicians from three AOD treatment institutions in Norway. The study revealed that family-oriented practices are gaining ground as a 'going concern'. However, the relative position of family-orientation in the services, is constrained and shaped by three other going concerns related to: (i) discourse on health and illness, emphasising that addiction is an individual medical and psychological phenomenon, rather than a relational one; (ii) discourse on rights and involvement, emphasising the autonomy of the individual patient and their right to define the format of their own treatment; and (iii) discourse on management, emphasising the relationship between cost and benefit, where family-oriented practices are defined as not being cost-effective. All three discourses are connected to underpin the weight placed on individualised practices. Thus, the findings point to a paradox: there is a growing focus on the needs of children and affected family members, while the possibility of performing integrated work on families is limited.

  10. The Fcp1-Wee1-Cdk1 axis affects spindle assembly checkpoint robustness and sensitivity to antimicrotubule cancer drugs.

    PubMed

    Visconti, R; Della Monica, R; Palazzo, L; D'Alessio, F; Raia, M; Improta, S; Villa, M R; Del Vecchio, L; Grieco, D

    2015-09-01

    To grant faithful chromosome segregation, the spindle assembly checkpoint (SAC) delays mitosis exit until mitotic spindle assembly. An exceedingly prolonged mitosis, however, promotes cell death and by this means antimicrotubule cancer drugs (AMCDs), that impair spindle assembly, are believed to kill cancer cells. Despite malformed spindles, cancer cells can, however, slip through SAC, exit mitosis prematurely and resist killing. We show here that the Fcp1 phosphatase and Wee1, the cyclin B-dependent kinase (cdk) 1 inhibitory kinase, play a role for this slippage/resistance mechanism. During AMCD-induced prolonged mitosis, Fcp1-dependent Wee1 reactivation lowered cdk1 activity, weakening SAC-dependent mitotic arrest and leading to mitosis exit and survival. Conversely, genetic or chemical Wee1 inhibition strengthened the SAC, further extended mitosis, reduced antiapoptotic protein Mcl-1 to a minimum and potentiated killing in several, AMCD-treated cancer cell lines and primary human adult lymphoblastic leukemia cells. Thus, the Fcp1-Wee1-Cdk1 (FWC) axis affects SAC robustness and AMCDs sensitivity.

  11. Duration of time that beef cattle are fed a high-grain diet affects the recovery from a bout of ruminal acidosis: short-chain fatty acid and lactate absorption, saliva production, and blood metabolites.

    PubMed

    Schwaiger, T; Beauchemin, K A; Penner, G B

    2013-12-01

    This study was conducted to determine if the duration of time that beef cattle are fed a high-grain diet affects short-chain fatty acid (SCFA) absorption, saliva production, and blood metabolites before, during, and following an induced bout of ruminal acidosis. Sixteen Angus heifers were assigned to 1 of 4 blocks and within block to 1 of 2 treatments designated as long adapted (LA) or short adapted (SA). Long adapted and SA heifers were fed a backgrounding diet [forage:concentrate (F:C) = 60:40] for 33 and 7 d, respectively, and then transitioned over 20 d to a high-grain diet (F:C = 9:91) with the timing of dietary transition staggered such that the LA and SA heifers were fed the high-grain diet for 34 and 8 d, respectively, before inducing ruminal acidosis. Ruminal acidosis was induced by restricting feed to 50% of DMI:BW for 24 h followed by an intraruminal infusion of ground barley at 10% DMI:BW. Heifers were then given their regular diet allocation 1 h after the intraruminal infusion. Data were collected during an 8 d baseline period (BASE), on the day of the acidosis challenge (CHAL), and during 2 consecutive 8 d recovery periods (REC1 and REC2). When pooled across periods, the fractional rates of propionate (42 vs. 34%/h; P = 0.045) and butyrate (45 vs. 36%/h; P = 0.019) absorption, measured using the isolated and washed reticulorumen technique, were greater for LA than SA heifers. Moreover, overall, LA heifers tended to have greater absolute rates of butyrate absorption (94 vs. 79 mmol/h; P = 0.087) and fractional rates of total SCFA absorption (37 vs. 32%/h; P = 0.100). Treatment × period interactions for lactate absorption (P = 0.024) and serum D-lactate concentration (P = 0.003) were detected with LA heifers having greater D-lactate concentrations during CHAL and greater fractional rates of lactate absorption during REC1 than SA. The absolute and fractional absorption of acetate, propionate, and butyrate increased between REC1 and REC2, with

  12. Factors affecting the determination of drugs and endogenous low molecular mass compounds in human serum by micellar electrokinetic capillary chromatography with direct sample injection.

    PubMed

    Schmutz, A; Thormann, W

    1994-01-01

    Factors influencing the establishment of an analytical window in front of the solubilized proteins in micellar electrokinetic capillary chromatography (MECC) with direct serum injection (DSI) are discussed. Both drugs and endogenous low molecular mass compounds eluting within the analytical window are identified concurrently by multi-wavelength absorption detection. Variables such as the concentration of the micelle forming substance, ionic strength, applied voltage, initial sample zone length, capillary length, selected buffer additives, insufficient renewal of the buffer in the anodic buffer vial and sample matrix are shown to impact MECC of endogenous compounds and model drugs, such as antiepileptics. For two drugs eluting within the analytical window, phenobarbital and ethosuximide, serum levels determined by DSI with external calibration are shown to compare well with levels obtained after liquid-liquid extraction and internal calibration (use of an internal standard). In addition, reproducibility of both assays is excellent. The limit of employing DSI is demonstrated with the determination of the hydrophobic drug phenytoin. Using an automated, commercial instrument and naproxen as model drug, high-speed MECC separations of high reproducibility and with a throughput of 12-15 samples per h are presented.

  13. Factors affecting trust in on-line prescription drug information and impact of trust on behavior following exposure to DTC advertising.

    PubMed

    Huh, Jisu; DeLorme, Denise E; Reid, Leonard N

    2005-12-01

    Despite growing concerns about the quality and accuracy of Internet-based prescription drug information, there has been very little empirical research on consumers' perceptions of the trustworthiness of on-line drug information. In this article, we report on a study modeled after that of Menon, Deshpande, Perri, and Zinkhan (2002) in Health Marketing Quarterly that reexamines how key demographic, predispositional, and media factors are associated with consumer trust in on-line prescription drug information and the impact of trust in on-line drug information on ad-promoted behavior following exposure to direct-to-consumer (DTC) advertising. Four major findings are reported: (1) on-line drug information is not highly trusted; (2) trust in on-line drug information is not differentially affected by consumer demographic or predispositional characteristics; (3) trust in the traditional media of DTC advertising is predictive of trust in on-line drug information; and (4) trust in on-line drug information is associated directly with specific types of ad-promoted behavior following exposure to DTC advertising. Implications and recommendations are offered based on the results.

  14. Drug loading and elution from a phosphorylcholine polymer-coated coronary stent does not affect long-term stability of the coating in vivo.

    PubMed

    Lewis, Andrew L; Willis, Sean L; Small, Sharon A; Hunt, Stuart R; O'byrne, Vincent; Stratford, Peter W

    2004-01-01

    A drug eluting coronary stent was developed for use in preclinical and clinical trial evaluation. The stent was coated with a phosphorylcholine (PC)-based polymer coating containing the cell migration inhibitor batimastat. A pharmacokinetic study was conducted in a rabbit iliac model using (14)C-radiolabeled version of the drug; this showed the drug release to be first order with 94% of it being released within 28 days. Unloaded and drug-loaded stents were implanted in a porcine coronary artery model; a number were explanted at 5 days and scanning electron microscopy was used to show that the presence of the drug did not affect the rate of stent endothelialization. The remainder of the stents were removed after 6 months and the stents carefully removed from the arterial tissue. Fourier-transform infrared (FT-IR) spectroscopy (both attenuated total reflectance and microscopic imaging) was used to show the presence of the PC coating on control unloaded, drug-loaded and explanted stents, providing evidence that the coating was still present. This was further confirmed by use of atomic force microscopy (AFM) amplitude-phase, distance (a-p,d) curves which generated the characteristic traces of the PC coating. Further AFM depth-profiling techniques found that the thicknesses of the PC coatings on an control unloaded stent was 252+/-19 nm, on an control batimastat-loaded stent 906+/-224 nm and on an explanted stent 405+/-224 nm. The increase in thickness after the drug-loading process was a consequence of drug incorporation in the film, and the return to the unloaded dimensions for the explanted sample indicative of elution of the drug from the coating. The drug delivery PC coating was therefore found to be stable following elution of the drug and after 6 months implantation in vivo. PMID:15472385

  15. Effect of food intake and co-administration of placebo self-nanoemulsifying drug delivery systems on the absorption of cinnarizine in healthy human volunteers.

    PubMed

    Christiansen, Martin Lau; Holm, Rene; Abrahamsson, Bertil; Jacobsen, Jette; Kristensen, Jakob; Andersen, Jens Rikardt; Müllertz, Anette

    2016-03-10

    Positive food effects may be observed for low aqueous soluble compounds, these effects could potentially be circumvented using lipid based formulations. However, as all compounds are not chemically stable in lipid based systems, alternative dosage regimes could be investigated to evade the stability issue. The two aims for this present study were therefore; i) to investigate if a nutritional drink, Fresubin Energy®, could induce food effect in humans for the poorly soluble compound cinnarizine; and ii) to investigate if co-administration of a self-nano-emulsifying drug delivery systems (SNEDDS) with a conventional cinnarizine tablet could reduce the observed food-effect. A commercial conventional cinnarizine tablet was dosed to 10 healthy volunteers in a cross-over design in both fasted and fed state, with and without co-administration of a SNEDDS, with a one week wash-out period between dosing. The fed state was induced using a nutritional drink (Fresubin Energy®) and gastric emptying was assessed by administration of paracetamol as a marker. The pharmacokinetic analysis showed that the nutritional drink delayed the uptake and increased the fraction of absorbed cinnarizine, indicative of a food effect on the compound. This was in agreement with a previous dog study and indicates that the nutritional drink can be used for inducing the same level of food effect in humans. Though not statistically significant, the co-administration of SNEDDS exhibited a tendency towards a reduction of the observed food effect and an increased absorption of cinnarizine in the fasted state; based upon the individual ratios, which was not reflected in the mean data. However, the co-administration of SNEEDS in the fasted state, also induce a slower gastric emptying rate, which was observed as a delayed tmax for both cinnarizine and paracetamol. PMID:26775868

  16. Study on the interactions of antiemetic drugs and 12-tungstophosphoric acid by absorption and resonance Rayleigh scattering spectra and their analytical applications

    NASA Astrophysics Data System (ADS)

    Wang, Yaqiong; Liu, Shaopu; Liu, Zhongfang; Yang, Jidong; Hu, Xiaoli

    2013-03-01

    In 0.1 mol L-1 HCl medium, antiemetic drugs (ATM), such as granisetron hydrochloride (GS) and tropisetron hydrochloride (TS), reacted with H3PW12O40·nH2O and formed 3:1 ion-association complex of [(ATM)3PW12O40], then self-aggregated into nanoparticles-[(ATM)3PW12O40]n with an average size of 100 nm. The reaction resulted in the enhancement of resonance Rayleigh scattering (RRS) and the absorption spectra. The increments of scattering intensity (ΔIRRS) and the change of absorbance (ΔA) were both directly proportional to the concentrations of ATM in certain ranges. Accordingly, two new RRS and spectrophotometric methods were proposed for ATM detection. The detection limits (3σ) of GS and TS were 3.2 ng mL-1 and 4.0 ng mL-1(RRS method), 112.5 ng mL-1 and 100.0 ng mL-1(spectrophotometric method). These two methods were applied to determine GS in orally disintegrating tablets and the results were in good agreement with the official method. The ground-state geometries and electronic structures of GS and TS were optimized by the hybrid density functional theory (DFT) method and the shape of [(ATM)3PW12O40]n was characterized by atomic force microscopy (AFM). Take the RRS method with higher sensitivity as an example, the reaction mechanism and the reasons for enhancement of scattering were discussed.

  17. Drug absorption and release properties of crosslinked hydrogels based on diepoxy-terminated poly(ethylene glycol)s and aliphatic polyamines--a study on the effect of the gel molecular structure.

    PubMed

    Cursaru, Bogdan; Teodorescu, Mircea; Boscornea, Cristian; Stanescu, Paul O; Stoleriu, Stefania

    2013-04-01

    Crosslinked hydrogels with well-defined chemical structures and characteristics were prepared through the reaction between diepoxy-terminated poly(ethylene glycol)s of various molecular weights and aliphatic polyamines of different hydrocarbon chain length and functionalities, and the influence of some network parameters (molecular weight between crosslinking points, crosslinking degree, hydrophobic character) upon the absorption and release of drugs of different capacity to interact with the polymer chains was comparatively investigated. Diclofenac sodium (DCFNa) and 5-fluorouracil (5FU) were used as model drugs, based on their dissimilar hydrophobic character and ability of DCFNa to form crown ether-like complexes with PEG chains through the sodium cation. The experiments showed that the most important interactions occurring in these systems were mainly the hydrophobic ones and to a lesser extent the complexation of the Na(+) ion by the PEG chains. Both of them were in favor of DCFNa, resulting in a larger incorporation and a slower release of this one in comparison with 5FU. For both drugs, loading was larger for hydrogels with shorter PEG chains and/or crosslinked with amines with longer hydrocarbon chain or higher functionality. Drug release tests showed a lower rate for stronger drug-network interactions in agreement with the absorption experiments. PMID:23827576

  18. Changes of pathological and physiological indicators affecting drug metabolism in rats after acute exposure to high altitude

    PubMed Central

    LI, WENBIN; WANG, RONG; XIE, HUA; ZHANG, JUANHONG; JIA, ZHENGPING

    2015-01-01

    High altitude environments cause the human body to undergo a series of pathological, physiological and biochemical changes, which have a certain effect on drug pharmacokinetics. The objective of the present study was to observe changes in factors affecting pharmacokinetics in rats following acute exposure to high altitude and return to low altitude. A total of 21 male Wistar rats were randomly assigned to three groups. The rats in group A were maintained at low altitude in Shanghai, 55 m above sea level; those in group B were acutely exposed to high altitude in Maqu, Gansu, 4,010 m above sea level; and those in group C were acutely exposed to high altitude and then returned to low altitude. Blood was collected from the orbit for the analysis of significant biochemical indicators and from the abdominal aorta for blood gas analysis. Brain, lung and kidney tissues were removed to observe pathological changes. In group B, the pH, buffer base (BB), base excess (BE), total carbon dioxide content (ctCO2), oxygen saturation of arterial blood (sO2), oxygen tension of arterial blood (pO2), serum sodium (Na+) concentration, lactate dehydrogenase (LDH) activity and total protein (TP) level were significantly reduced, and the carbon dioxide tension of arterial blood (pCO2), serum chloride (Cl−) concentration, serum total bilirubin (TBIL) level and alkaline phosphatase (ALP) activity were significantly increased compared with those in group A (P<0.05). In group C, the pH, BB, BE, sO2, pO2, hemoglobin (Hb) level, serum Na+ concentration, LDH activity and TP level were significantly reduced, and the pCO2, serum Cl− concentration, alanine transaminase activity, TBIL and urea levels were significantly increased (P<0.05) compared with those in group A. The Hb and ALP levels in group C were significantly lower than those in group B (P<0.05); and the TP, TBIL and urea levels in group C were significantly higher than those in group B (P<0.05). Pathological observation revealed that

  19. Changes in ruminal volatile fatty acid production and absorption rate during the dry period and early lactation as affected by rate of increase of concentrate allowance.

    PubMed

    Dieho, K; Dijkstra, J; Schonewille, J T; Bannink, A

    2016-07-01

    The aim of the present experiment was to study changes in volatile fatty acid (VFA) production using an isotope dilution technique, and changes in VFA fractional absorption rate (kaVFA) using a buffer incubation technique (BIT) during the dry period and early lactation, as affected by the postpartum (pp) rate of increase of concentrate allowance. The current results are complementary to previously reported changes on rumen papillae morphology from the same experiment. From 50 d antepartum to 80 d pp, VFA production rate was measured 5 times and kaVFA was measured 10 times in 12 rumen-cannulated Holstein Friesian cows. Cows had free access to a mixed ration, consisting of grass and corn silage, soybean meal, and (dry period only) chopped straw. Treatment consisted of either a rapid (RAP; 1.0 kg of DM/d; n=6) or gradual (GRAD; 0.25 kg of DM/d; n=6) increase of concentrate allowance (up to 10.9 kg of DM/d), starting at 4 d pp, aimed at creating a contrast in rumen-fermentable organic matter intake. For the BIT, rumen contents were evacuated, the rumen washed, and a standardized buffer fluid introduced [120 mM VFA, 60% acetic (Ac), 25% propionic (Pr), and 15% butyric (Bu) acid; pH 5.9 and Co-EDTA as fluid passage marker]. For the isotope dilution technique, a pulse-dose of (13)C-labeled Ac, Pr, and Bu and Co-EDTA as fluid passage marker was infused. The rate of total VFA production was similar between treatments and was 2 times higher during the lactation (114 mol/d) than the dry period (53 mol/d). Although papillae surface area at 16, 30, and 44 d pp was greater in RAP than GRAD, Bu and Ac production at these days did not differ between RAP and GRAD, whereas at 16 d pp RAP produced more Pr than GRAD. These results provide little support for the particular proliferative effects of Bu on papillae surface area. Similar to developments in papillae surface area in the dry period and early lactation, the kaVFA (per hour), measured using the BIT, decreased from 0.45 (Ac), 0

  20. Factors Affecting the Efficacy of Nonsteroidal Anti-inflammatory Drugs in Preventing Post–Endoscopic Retrograde Cholangiopancreatography Pancreatitis

    PubMed Central

    Rustagi, Tarun; Njei, Basile

    2016-01-01

    Objectives To identify the factors affecting the efficacy of nonsteroidal anti-inflammatory drugs (NSAIDs) in preventing post–endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP). Methods We systematically searched databases for relevant studies published from inception to November 2013. Results A meta-analysis of 11 randomized trials (n = 2497) revealed a significant reduction in PEP in patients who received NSAIDs compared with that in patients who received placebo (relative risk [RR], 0.59; 95% confidence interval [CI], 0.41–0.85; P = 0.005). In subgroup analysis by treatment type, indomethacin had no significant effect (RR, 0.66; 95% CI, 0.38–1.15; P = 0.14), whereas other NSAIDs showed significant benefit (RR, 0.51; 95% CI, 0.29–0.91; P = 0.02). Only rectal administration significantly reduced the incidence of PEP (RR, 0.43; 95% CI, 0.32–0.58; P < 0.00001). The risk for PEP was the lowest among patients who received NSAIDs before ERCP (RR, 0.48; 95% CI, 0.29–0.78; P = 0.003). NSAIDs did not significantly reduce the risk of PEP in men (RR, 0.61; 95% CI, 0.34–1.09), patients with sphincter of Oddi dysfunction (RR, 0.98; 95% CI, 0.38–2.54), or patients with pancreatic duct injection (RR, 0.64; 95% CI, 0.35–1.18). Conclusions Rectal administration of NSAIDs (especially diclofenac), before ERCP, seemed to be the most effective strategy for preventing PEP. PMID:26168316

  1. Molecular organization of the antifungal and anticancer drug 2-(2,4-dihydroxyphenylo)-5,6-dichlorobenzothiazole (dHBBT) in solution and in lipid membranes studied by means of electronic absorption spectroscopy.

    PubMed

    Gagoś, Mariusz; Niewiadomy, Andrzej; Gruszecki, Wiesław I

    2004-10-25

    2-(2,4-Dihydroxyphenylo)-5,6-dichlorobenzthiazole (dHBBT) is a new drug from the group of chemical compounds characterized by documented antifungal, antibacterial, cytostatic as well as antitumour activity. Despite general knowledge regarding pharmacological importance of dHBBT its interaction to biomembranes has not been investigated. In this work, we present the electronic absorption spectroscopic study on molecular organization of dHBBT in organic solvents and on its localization and molecular organization within model lipid membranes formed with dipalmitoylphosphatidylcholine (DPPC). The spectroscopic measurements are interpreted within the framework of the exciton splitting theory. It is concluded that complex absorption spectrum of dHBBT both in the organic solvents and incorporated to DPPC represents superposition of two spectral forms: representing monomers and hypsochromically shifted spectrum representing molecular dimers. Analysis of the temperature dependencies of the absorption spectra of dHBBT incorporated to DPPC liposomes suggests localization of the drug in the polar head-group region of the membrane or in the region of the polar-nonpolar interface. Linear dichroism measurements of dHBBT incorporated to DPPC multibilayers reveal roughly vertical orientation of the drug molecules with respect to the plane of the membrane. A model is presented of molecular organization of dHBBT in lipid membranes. Potential effects of dHBBT on membrane physical properties is briefly discussed. PMID:15488713

  2. Drug-mineral interactions

    SciTech Connect

    Kramer, L.

    1986-03-01

    The effect of drugs such as glucocorticoids and thyroid extract on calcium metabolism is unknown. However, several other medications affect the excretion and intestinal absorption of calcium. A controlled study was carried out to investigate these aspects. Urinary calcium was determined for 3 months during the long-term intake of the antituberculous drug isoniazid (INH) and of the antibiotic tetracycline. The effect of the diuretics furosemide and hydrochlorothiazide, of several aluminum-containing antacids, of thyroid extract and of corticosteroids was also studied. Metabolic balances of calcium, phosphorus, magnesium and zinc were determined, as well as the intestinal absorption of calcium using Ca 47. Plasma levels, urinary and fecal excretions of Ca 47 were determined. All drugs tested increased urinary calcium except for the diuretic hydrochlorothiazide. Regarding the effect of corticosteroids: the intestinal absorption of calcium was unchanged after the short-term use and was very high after long-term use. The studies have shown that several commonly used drugs induce an increase in urinary calcium excretion which may contribute to calcium loss, if this increase persists for prolonged periods of time. Urinary excretions of phosphorus, magnesium and zinc increased in some of the studies.

  3. PAN-811 Blocks Chemotherapy Drug-Induced In Vitro Neurotoxicity, While Not Affecting Suppression of Cancer Cell Growth.

    PubMed

    Jiang, Zhi-Gang; Fuller, Steven A; Ghanbari, Hossein A

    2016-01-01

    Chemotherapy often results in cognitive impairment, and no neuroprotective drug is now available. This study aimed to understand underlying neurotoxicological mechanisms of anticancer drugs and to evaluate neuroprotective effects of PAN-811. Primary neurons in different concentrations of antioxidants (AOs) were insulted for 3 days with methotrexate (MTX), 5-fluorouracil (5-FU), or cisplatin (CDDP) in the absence or presence of PAN-811·Cl·H2O. The effect of PAN-811 on the anticancer activity of tested drugs was also examined using mouse and human cancer cells (BNLT3 and H460) to assess any negative interference. Cell membrane integrity, survival, and death and intramitochondrial reactive oxygen species (ROS) were measured. All tested anticancer drugs elicited neurotoxicity only under low levels of AO and elicited a ROS increase. These results suggested that ROS mediates neurotoxicity of tested anticancer drugs. PAN-811 dose-dependently suppressed increased ROS and blocked the neurotoxicity when neurons were insulted with a tested anticancer drug. PAN-811 did not interfere with anticancer activity of anticancer drugs against BNLT3 cells. PAN-811 did not inhibit MTX-induced death of H460 cells but, interestingly, demonstrated a synergistic effect with 5-FU or CDDP in reducing cancer cell viability. Thus, PAN-811 can be a potent drug candidate for chemotherapy-induced cognitive impairment.

  4. PAN-811 Blocks Chemotherapy Drug-Induced In Vitro Neurotoxicity, While Not Affecting Suppression of Cancer Cell Growth.

    PubMed

    Jiang, Zhi-Gang; Fuller, Steven A; Ghanbari, Hossein A

    2016-01-01

    Chemotherapy often results in cognitive impairment, and no neuroprotective drug is now available. This study aimed to understand underlying neurotoxicological mechanisms of anticancer drugs and to evaluate neuroprotective effects of PAN-811. Primary neurons in different concentrations of antioxidants (AOs) were insulted for 3 days with methotrexate (MTX), 5-fluorouracil (5-FU), or cisplatin (CDDP) in the absence or presence of PAN-811·Cl·H2O. The effect of PAN-811 on the anticancer activity of tested drugs was also examined using mouse and human cancer cells (BNLT3 and H460) to assess any negative interference. Cell membrane integrity, survival, and death and intramitochondrial reactive oxygen species (ROS) were measured. All tested anticancer drugs elicited neurotoxicity only under low levels of AO and elicited a ROS increase. These results suggested that ROS mediates neurotoxicity of tested anticancer drugs. PAN-811 dose-dependently suppressed increased ROS and blocked the neurotoxicity when neurons were insulted with a tested anticancer drug. PAN-811 did not interfere with anticancer activity of anticancer drugs against BNLT3 cells. PAN-811 did not inhibit MTX-induced death of H460 cells but, interestingly, demonstrated a synergistic effect with 5-FU or CDDP in reducing cancer cell viability. Thus, PAN-811 can be a potent drug candidate for chemotherapy-induced cognitive impairment. PMID:26640619

  5. PAN-811 Blocks Chemotherapy Drug-Induced In Vitro Neurotoxicity, While Not Affecting Suppression of Cancer Cell Growth

    PubMed Central

    Jiang, Zhi-Gang; Fuller, Steven A.; Ghanbari, Hossein A.

    2016-01-01

    Chemotherapy often results in cognitive impairment, and no neuroprotective drug is now available. This study aimed to understand underlying neurotoxicological mechanisms of anticancer drugs and to evaluate neuroprotective effects of PAN-811. Primary neurons in different concentrations of antioxidants (AOs) were insulted for 3 days with methotrexate (MTX), 5-fluorouracil (5-FU), or cisplatin (CDDP) in the absence or presence of PAN-811·Cl·H2O. The effect of PAN-811 on the anticancer activity of tested drugs was also examined using mouse and human cancer cells (BNLT3 and H460) to assess any negative interference. Cell membrane integrity, survival, and death and intramitochondrial reactive oxygen species (ROS) were measured. All tested anticancer drugs elicited neurotoxicity only under low levels of AO and elicited a ROS increase. These results suggested that ROS mediates neurotoxicity of tested anticancer drugs. PAN-811 dose-dependently suppressed increased ROS and blocked the neurotoxicity when neurons were insulted with a tested anticancer drug. PAN-811 did not interfere with anticancer activity of anticancer drugs against BNLT3 cells. PAN-811 did not inhibit MTX-induced death of H460 cells but, interestingly, demonstrated a synergistic effect with 5-FU or CDDP in reducing cancer cell viability. Thus, PAN-811 can be a potent drug candidate for chemotherapy-induced cognitive impairment. PMID:26640619

  6. Switch-Loop Flexibility Affects Transport of Large Drugs by the Promiscuous AcrB Multidrug Efflux Transporter

    PubMed Central

    Cha, Hi-jea; Müller, Reinke T.

    2014-01-01

    Multidrug efflux transporters recognize a variety of structurally unrelated compounds for which the molecular basis is poorly understood. For the resistance nodulation and cell division (RND) inner membrane component AcrB of the AcrAB-TolC multidrug efflux system from Escherichia coli, drug binding occurs at the access and deep binding pockets. These two binding areas are separated by an 11-amino-acid-residue-containing switch loop whose conformational flexibility is speculated to be essential for drug binding and transport. A G616N substitution in the switch loop has a distinct and local effect on the orientation of the loop and on the ability to transport larger drugs. Here, we report a distinct phenotypical pattern of drug recognition and transport for the G616N variant, indicating that drug substrates with minimal projection areas of >70 Å2 are less well transported than other substrates. PMID:24914123

  7. Drug-drug interactions between clopidogrel and novel cardiovascular drugs.

    PubMed

    Pelliccia, Francesco; Rollini, Fabiana; Marazzi, Giuseppe; Greco, Cesare; Gaudio, Carlo; Angiolillo, Dominick J

    2015-10-15

    The combination of aspirin and the thienopyridine clopidogrel is a cornerstone in the prevention of atherothrombotic events. These two agents act in concert to ameliorate the prothrombotic processes stimulated by plaque rupture and vessel injury complicating cardiovascular disease. Guidelines recommend the use of clopidogrel in patients with acute coronary syndromes and in those undergoing percutaneous coronary intervention, and the drug remains the most utilized P2Y12 receptor inhibitor despite the fact that newer antiplatelet agents are now available. In recent years, numerous studies have shown inconsistency in the efficacy of clopidogrel to prevent atherothrombotic events. Studies of platelet function testing have shown variability in the response to clopidogrel. One of the major reason for this phenomenon lies in the interaction between clopidogrel and other drugs that may affect clopidogrel absorption, metabolism, and ultimately its antiplatelet action. Importantly, these drug-drug interactions have prognostic implications, since patients with high on-treatment platelet reactivity associated with reduced clopidogrel metabolism have an increased risk of ischemia. Previous systematic reviews have focused on drug-drug interactions between clopidogrel and specific pharmacologic classes, such as proton pump inhibitors, calcium channel blockers, and statins. However, more recent pieces of scientific evidence show that clopidogrel may also interact with newer drugs that are now available for the treatment of cardiovascular patients. Accordingly, the aim of this review is to highlight and discuss recent data on drug-drug interactions between clopidogrel and third-generation proton pump inhibitors, pantoprazole and lansoprazole, statins, pitavastatin, and antianginal drug, ranolazine. PMID:26341013

  8. Direct and long-lasting effects elicited by repeated drug administration on 50-kHz ultrasonic vocalizations are regulated differently: implications for the study of the affective properties of drugs of abuse.

    PubMed

    Simola, Nicola; Frau, Lucia; Plumitallo, Antonio; Morelli, Micaela

    2014-03-01

    Several studies suggest that 50-kHz ultrasonic vocalizations (USVs) may indicate a positive affective state in rats, and these vocalizations are increasingly being used to investigate the properties of psychoactive drugs. Previous studies, however, have focused on dopaminergic psychostimulants and morphine, whereas little is known about how other drugs modulate 50-kHz USVs. To further elucidate the neuropharmacology of 50-kHz USVs, the present study characterized the direct and long-lasting effects of different drugs of abuse, by measuring the number of 50-kHz USVs and their 'trill' subtype emitted by adult male rats. Rats received repeated administrations of amphetamine (2 mg/kg, i.p.), 3,4-methylenedioxymethamphetamine (MDMA, 7.5 mg/kg, i.p.), morphine (7.5 mg/kg, s.c.), or nicotine (0.4 mg/kg, s.c.), on either consecutive or alternate days (five administrations in total) in a novel environment. Seven days later, rats were re-exposed to the drug-paired environment, subjected to USVs recording, and then challenged with the same drug. Finally, 7 d after the challenge, rats were repeatedly exposed to the drug-paired environment and vocalizations were measured. Amphetamine was the only drug to stimulate 50-kHz USVs and 'trill' subtype emission during administration and challenge. Conversely, all rats emitted 50-kHz USVs when re-exposed to the test cage, and this effect was most marked in morphine-treated rats, and less evident in nicotine-treated rats. This study demonstrates that the direct and long-lasting effects of drugs on 50-kHz USVs are regulated differently, providing a better understanding of the usefulness of these vocalizations in the study of psychoactive drugs.

  9. Direct and long-lasting effects elicited by repeated drug administration on 50-kHz ultrasonic vocalizations are regulated differently: implications for the study of the affective properties of drugs of abuse.

    PubMed

    Simola, Nicola; Frau, Lucia; Plumitallo, Antonio; Morelli, Micaela

    2014-03-01

    Several studies suggest that 50-kHz ultrasonic vocalizations (USVs) may indicate a positive affective state in rats, and these vocalizations are increasingly being used to investigate the properties of psychoactive drugs. Previous studies, however, have focused on dopaminergic psychostimulants and morphine, whereas little is known about how other drugs modulate 50-kHz USVs. To further elucidate the neuropharmacology of 50-kHz USVs, the present study characterized the direct and long-lasting effects of different drugs of abuse, by measuring the number of 50-kHz USVs and their 'trill' subtype emitted by adult male rats. Rats received repeated administrations of amphetamine (2 mg/kg, i.p.), 3,4-methylenedioxymethamphetamine (MDMA, 7.5 mg/kg, i.p.), morphine (7.5 mg/kg, s.c.), or nicotine (0.4 mg/kg, s.c.), on either consecutive or alternate days (five administrations in total) in a novel environment. Seven days later, rats were re-exposed to the drug-paired environment, subjected to USVs recording, and then challenged with the same drug. Finally, 7 d after the challenge, rats were repeatedly exposed to the drug-paired environment and vocalizations were measured. Amphetamine was the only drug to stimulate 50-kHz USVs and 'trill' subtype emission during administration and challenge. Conversely, all rats emitted 50-kHz USVs when re-exposed to the test cage, and this effect was most marked in morphine-treated rats, and less evident in nicotine-treated rats. This study demonstrates that the direct and long-lasting effects of drugs on 50-kHz USVs are regulated differently, providing a better understanding of the usefulness of these vocalizations in the study of psychoactive drugs. PMID:24138707

  10. An overview of ABC and SLC drug transporter gene regulation.

    PubMed

    Chen, Qiu-Xia; Hu, Hai-Hong; Zhou, Quan; Yu, Ai-Ming; Zeng, Su

    2013-02-01

    Membrane transporters play a significant role in drug absorption, distribution and excretion, and they consequently affect the pharmacokinetics, efficacy and safety of a drug. Under certain circumstances, such as pathological processes or exposure to certain substances, the expression of drug transporters is modified in cells. Change in transporter expression and function may affect cellular drug disposition resulting in different drug responses. This raises a number of questions such as which drugs are likely to modulate the expression of drug transporters, what factors support this process, and which transporters are influenced in a particular situation. In this paper, we summarize recent findings to find an answer to these questions. Particularly, we present an overview of the transcription factors involved in the regulation of a given drug transporter, the signaling transduction pathways that contribute to drug transporter gene expression, and xenobiotics and endobiotics that initiate the processes.

  11. [Alleviated affect of exogenous CaCl2 on the growth, antioxidative enzyme activities and cadmium absorption efficiency of Wedelia trilobata hairy roots under cadmium stress].

    PubMed

    Shi, Heping; Wang, Yunling; Tsang, PoKeung Eric; Chan, LeeWah Andrew

    2012-06-01

    In order to study the physiological mechanism of exogenous calcium on the toxicity of heavy metal cadmium (Cd) to Wedelia trilobata hairy roots, the effects of Cd alone, and in combination with different concentrations of Ca on growth, contents of soluble protein and malondialdehyde (MDA), activities of superoxide dismutase (SOD) and peroxidase (POD), Cd2+ absorption in W. trilobata hairy roots were investigated. Cd concentrations lower than 50 micromol/L enhanced the growth of hairy roots, while concentrations higher than 100 micromol/L inhibited growth, making the branched roots short and small, and also turning the root tips brown, even black. In comparison with the control (0 micromol/L Cd), the soluble protein content in hairy roots was found to increase when cultured with 10-50 micromol/L Cd, and decrease when exposed to a cadmium concentration higher than 100 micromol/L Cd. In addition, the activities of POD and SOD activity and MDA content were significantly higher than the control. Compared to the control (hairy roots cultured without 10-30 mmol/L Ca), 100 micromol/L Cd or 300 micromol/L Cd in combination with 10-30 mmol/L Ca resulted in increased growth, causing the main root and secondary roots thicker and also an increase in soluble protein content. On the contrary, MDA content and POD and SOD activities decreased. Quantitative analysis by Atomic Absorption Spectrophotometry showed that W. trilobata hairy roots can absorb and adsorb heavy metal Cd in the ionic form of Cd2+. The maximum content of Cd2+ absorbed by the hairy roots was obtained with a concentration 100 micromol/L Cd2+ while that of Cd2+ adsorbed by hairy roots was achieved with a concentration of 300 micromol/L Cd2+. The exogenous addition of 10-30 mmol/L Ca2+ was found to reduce the absorption, adsorption of Cd2+ and the toxicity of Cd significantly. This reduction in toxicity was caused by the reduction in the absorption of Cd and decreasing the lipid peroxidation through regulating the

  12. [Importance of drug interactions with smoking in modern drug research].

    PubMed

    Laki, Szilvia; Kalapos-Kovács, Bernadett; Antal, István; Klebovich, Imre

    2013-01-01

    Drug interaction is a process during which a drug's fate in the body or its pharmacological properties are altered by an influencing factor. The extent of the drug interaction's effect can vary. The interaction could result from the modulation by another drug, food, alcohol, caffeine, narcotics, a drug influencing absorption or smoking. Moreover, transporter interactions with smoking could also have a major impact on many drug's efficacy. Clinically relevant drug interactions with smoking were classified in terms of their effect: pharmacokinetic, pharmacodynamic and transporter interactions. Policyclic aromatic carbohydrates, found in cigarette smoke, have enzyme inducing properties. The interaction affects mainly the hepatic isoenzyme CYP1A2. Interactions caused by smoking have an effect on all drugs being substrates of and therefore metabolised by CYP1A2. Pharmacokinetic alteration can also occur during the absorption, distribution and elimination process. The pharmacodynamic interactions are mainly caused by the effects of nicotine, a cigarette smoke component. Through interactions, smoking could also modify the activity of transporter proteins, altering this way the ADME properties of many drugs. Since smoking is one of the deadliest artefact in the history of human civilisation, identifying drug interactions with smoking is the physician's and pharmacist's major responsibility and task. Moreover, it is necessary to identify the patient's smoking habits during a medical treatment. This review aims to investigate the main types of drug interactions (PK/PD), identify factors influencing the activity of CYP enzymes and transporters, and also summarize the mechanisms of the most important drug interactions with smoking and their clinically relevant consequences (Table II-VI.). Drugs, with effects somehow altered by smoking-interactions, have been studied. PMID:24575657

  13. Prevalence of hospitalized live births affected by alcohol and drugs and parturient women diagnosed with substance abuse at liveborn delivery: United States, 1999-2008.

    PubMed

    Pan, I-Jen; Yi, Hsiao-ye

    2013-05-01

    To describe prevalence trends in hospitalized live births affected by placental transmission of alcohol and drugs, as well as prevalence trends among parturient women hospitalized for liveborn delivery and diagnosed with substance abuse problems in the United States from 1999 to 2008. Comparison of the two sets of trends helps determine whether the observed changes in neonatal problems over time were caused by shifts in maternal substance abuse problems. This study independently identified hospitalized live births and maternal live born deliveries from discharge records in the Nationwide Inpatient Sample, one of the largest hospital administrative databases. Substance-related diagnosis codes on the records were used to identify live births affected by alcohol and drugs and parturient women with substance abuse problems. The analysis calculated prevalence differences and percentage changes over the 10 years, with Loess curves fitted to 10-year prevalence estimates to depict trend patterns. Linear and quadratic trends in prevalence were simultaneously tested using logistic regression analyses. The study also examined data on costs, primary expected payer, and length of hospital stays. From 1999 to 2008, prevalence increased for narcotic- and hallucinogen-affected live births and neonatal drug withdrawal syndrome but decreased for alcohol- and cocaine-affected live births. Maternal substance abuse at delivery showed similar trends, but prevalence of alcohol abuse remained relatively stable. Substance-affected live births required longer hospital stays and higher medical expenses, mostly billable to Medicaid. The findings highlight the urgent need for behavioral intervention and early treatment for substance-abusing pregnant women to reduce the number of substance-affected live births.

  14. Emerging Frontiers in Drug Delivery.

    PubMed

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

    2016-01-27

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

  15. What Affects Reintegration of Female Drug Users after Prison Release? Results of a European Follow-Up Study

    ERIC Educational Resources Information Center

    Zurhold, Heike; Moskalewicz, Jacek; Sanclemente, Cristina; Schmied, Gabriele; Shewan, David; Verthein, Uwe

    2011-01-01

    The main objective of this follow-up study is to explore factors influencing the success or failure of women in reintegrating after their release from prison. Female drug users in five European cities were tracked after being released from prison. Out of 234 female prisoners contacted in prisons, 59 were included in the follow-up study. Structured…

  16. Communication: Does a single CH{sub 3}CN molecule attached to Ru(bipy){sub 3}{sup 2+} affect its absorption spectrum?

    SciTech Connect

    Stockett, M. H.; Brøndsted Nielsen, S.

    2015-05-07

    Tris(bipyridine)ruthenium(II) (Ru(bipy){sub 3}{sup 2+}) is a prototypical transition metal coordination complex whose photophysical properties have attracted considerable attention. A much debated issue is whether the metal-to-ligand charge transfer (MLCT) transition that accounts for the complex’s beautiful red color is fully delocalized across all three bipyridine ligands or located on just one ligand. Here, we show based on gas-phase action spectroscopy that attachment of a single acetonitrile molecule does not change the absorption spectrum from that of the bare ions, which is indicative of a delocalized state. However, the gas-phase spectra of the bare and one solvent molecule complexes are significantly blueshifted relative to that obtained in bulk acetonitrile, which suggests that in solution the polarizability of many solvent molecules working together can localize the MLCT state. Our data clearly show that more than one solvent molecule is needed to break the symmetry of the MLCT excited state and reproduce its solution-phase characteristics.

  17. Multi-drugs resistant acne rosacea in a child affected by Ataxia-Telangiectasia: successful treatment with Isotretinoin.

    PubMed

    Cantarutti, Nicoletta; Claps, Alessia; Angelino, Giulia; Chessa, Luciana; Callea, Francesco; El Hachem, May; Diociaiuti, Andrea; Finocchi, Andrea

    2015-03-28

    Ataxia-Telangiectasia is a rare multisystem autosomal recessive disorder [OMIM 208900], caused by mutations in Ataxia-Telangiectasia Mutated gene. It is characterized by neurological, immunological and cutaneous involvement. Granulomas have been previously reported in Ataxia-Telangiectasia patients, even if acne rosacea has not been described.We report a case of a young Ataxia-Telangiectasia patient with a severe immunological and neurological involvement, who developed granulomatous skin lesions diagnosed by skin biopsy as acne rosacea. Considering the severe clinical picture and the lack of improvement to multiple topic and systemic therapies, treatment with Isotretinoin was started and the skin lesions disappeared after five months. However the therapy was stopped due to drug-hepatotoxicity.Systemic treatment with Isotretinoin should be carefully considered in patient with Ataxia-Telangiectasia for the treatment of multi-drug resistant acne rosacea, however its toxicity may limit long-term use and the risk/benefit ratio of the treatment should be evaluated.

  18. Identification of residues in ABCG2 affecting protein trafficking and drug transport, using co-evolutionary analysis of ABCG sequences

    PubMed Central

    Haider, Ameena J.; Cox, Megan H.; Jones, Natalie; Goode, Alice J.; Bridge, Katherine S.; Wong, Kelvin; Briggs, Deborah; Kerr, Ian D.

    2015-01-01

    ABCG2 is an ABC (ATP-binding cassette) transporter with a physiological role in urate transport in the kidney and is also implicated in multi-drug efflux from a number of organs in the body. The trafficking of the protein and the mechanism by which it recognizes and transports diverse drugs are important areas of research. In the current study, we have made a series of single amino acid mutations in ABCG2 on the basis of sequence analysis. Mutant isoforms were characterized for cell surface expression and function. One mutant (I573A) showed disrupted glycosylation and reduced trafficking kinetics. In contrast with many ABC transporter folding mutations which appear to be ‘rescued’ by chemical chaperones or low temperature incubation, the I573A mutation was not enriched at the cell surface by either treatment, with the majority of the protein being retained in the endoplasmic reticulum (ER). Two other mutations (P485A and M549A) showed distinct effects on transport of ABCG2 substrates reinforcing the role of TM helix 3 in drug recognition and transport and indicating the presence of intracellular coupling regions in ABCG2. PMID:26294421

  19. Impaired thyroid function provoked by neonatal treatment with drugs affecting the maturation of monoaminergic and opioidergic neurons.

    PubMed

    Mess, B; Rúzsás, C; Hayashi, S

    1989-09-01

    The aim of the present work was to study the basal secretion rate and the reactivity of the TSH-thyroid axis in adult rats neonatally exposed to drugs influencing monoaminergic and opioidergic neurons. The early postnatal administration of drugs antagonistic with the dopaminergic or serotoninergic neurons resulted in a persistent higher rate of basal secretion of TSH, while the administration of drugs synergistic with the monoaminergic neuron systems was weakly influential in this respect. The exposure to opioids in the perinatal period resulted in a permanent reduction of serum TSH levels which was even more pronounced when the exposure to morphine was advanced to the fetal period of life. These data raise the possibility that the permanent TSH depressing effect of perinatal administration of opioids is due to their effect exerted on the maturation of the monoaminergic neurons. From the other hand, our results lead to assume that there is a perinatal critical period in the maturation of monoaminergic neurons regulating TSH secretion in the adult age. In accordance with this assumption, the data obtained in rats bearing perinatal neurotoxic destruction of catecholaminergic neurons contribute to the concept that the disturbed maturation of monoaminergic neurons in the supposed critical period of development might lead to permanent deficiency also in the reactivity of the TSH-thyroid axis.

  20. Glucose Absorption by the Bacillary Band of Trichuris muris

    PubMed Central

    Hansen, Michael; Nejsum, Peter; Mejer, Helena; Denwood, Matthew; Thamsborg, Stig M.

    2016-01-01

    Background A common characteristic of Trichuris spp. infections in humans and animals is the variable but low efficacy of single-dose benzimidazoles currently used in mass drug administration programmes against human trichuriasis. The bacillary band, a specialised morphological structure of Trichuris spp., as well as the unique partly intracellular habitat of adult Trichuris spp. may affect drug absorption and perhaps contribute to the low drug accumulation in the worm. However, the exact function of the bacillary band is still unknown. Methodology We studied the dependency of adult Trichuris muris on glucose and/or amino acids for survival in vitro and the absorptive function of the bacillary band. The viability of the worms was evaluated using a motility scale from 0 to 3, and the colorimetric assay Alamar Blue was utilised to measure the metabolic activity. The absorptive function of the bacillary band in living worms was explored using a fluorescent glucose analogue (6-NBDG) and confocal microscopy. To study the absorptive function of the bacillary band in relation to 6-NBDG, the oral uptake was minimised or excluded by sealing the oral cavity with glue and agarose. Principal Findings Glucose had a positive effect on both the motility (p < 0.001) and metabolic activity (p < 0.001) of T. muris in vitro, whereas this was not the case for amino acids. The 6-NBDG was observed in the pores of the bacillary band and within the stichocytes of the living worms, independent of oral sealing. Conclusions/Significance Trichuris muris is dependent on glucose for viability in vitro, and the bacillary band has an absorptive function in relation to 6-NBDG, which accumulates within the stichocytes. The absorptive function of the bacillary band calls for an exploration of its possible role in the uptake of anthelmintics, and as a potential anthelmintic target relevant for future drug development. PMID:27588682

  1. Decellularized skeletal muscle as an in vitro model for studying drug-extracellular matrix interactions

    PubMed Central

    Wassenaar, Jean W.; Boss, Gerry R.; Christman, Karen L.

    2015-01-01

    Several factors can affect drug absorption after intramuscular (IM) injection: drug solubility, drug transport across cell membranes, and drug metabolism at the injection site. We found that potential interactions between the drug and the extracellular matrix (ECM) at the injection site can also affect the rate of absorption post-injection. Using decellularized skeletal muscle, we developed a simple method to model drug absorption after IM injection, and showed that the nature of the drug-ECM interaction could be investigated by adding compounds that alter binding. We validated the model using the vitamin B12 analog cobinamide with different bound ligands. Cobinamide is being developed as an IM injectable treatment for cyanide poisoning, and we found that the in vitro binding data correlated with previously published in vivo drug absorption in animals. Commercially available ECM products, such as collagen and GelTrex, did not recapitulate drug binding behavior. While decellularized ECM has been widely studied in fields such as tissue engineering, this work establishes a novel use of skeletal muscle ECM as a potential in vitro model to study drug-ECM interactions during drug development. PMID:26125502

  2. Cholesterol Absorption and Metabolism.

    PubMed

    Howles, Philip N

    2016-01-01

    Inhibitors of cholesterol absorption have been sought for decades as a means to treat and prevent cardiovascular diseases (CVDs) associated with hypercholesterolemia. Ezetimibe is the one clear success story in this regard, and other compounds with similar efficacy continue to be sought. In the last decade, the laboratory mouse, with all its genetic power, has become the premier experimental model for discovering the mechanisms underlying cholesterol absorption and has become a critical tool for preclinical testing of potential pharmaceutical entities. This chapter briefly reviews the history of cholesterol absorption research and the various gene candidates that have come under consideration as drug targets. The most common and versatile method of measuring cholesterol absorption is described in detail along with important considerations when interpreting results, and an alternative method is also presented. In recent years, reverse cholesterol transport (RCT) has become an area of intense new interest for drug discovery since this process is now considered another key to reducing CVD risk. The ultimate measure of RCT is sterol excretion and a detailed description is given for measuring neutral and acidic fecal sterols and interpreting the results. PMID:27150091

  3. Is drug discontinuation risk of adalimumab compared with etanercept affected by concomitant methotrexate dose in patients with rheumatoid arthritis?

    PubMed Central

    Chen, Hsin-Hua; Chen, Der-Yuan; Chen, Yi-Ming; Tang, Chao-Hsiun

    2016-01-01

    Objective To compare drug discontinuation risk between adalimumab (ADA) and etanercept (ETN) treatment among anti-tumor necrosis factor (anti-TNF)-naïve rheumatoid arthritis (RA) patients, in particular the influence of concomitant dose of methotrexate (MTX). Methods This retrospective nationwide population-based cohort study identified 4,592 anti-TNF-naïve RA patients in whom ETN (n=2,609) or ADA (n=1,983) was initiated using National Health Insurance claims data. After adjustment for prior medication, concomitant medication, and baseline demographic data, the relative risk of drug discontinuation in ADA users compared with ETN users was quantified by calculating adjusted hazard ratios (aHRs) with 95% confidence intervals (CIs) using Cox proportional hazard regression analyses, stratified by the follow-up time (≤1 year, >1 year) and/or concomitant MTX dose (≤10 mg/wk, >10 mg/wk). Results ADA users had a higher risk of drug discontinuation compared with ETN users during the first year of follow-up (aHR, 1.13; 95% CI, 1.01–1.27), but not during all treatment periods (aHR, 1.06; 95% CI, 0.98–1.16) or after 1 year (aHR, 0.99; 95% CI, 0.87–1.13). However, ADA users had a significantly higher risk of drug discontinuation compared with ETN users among patients on concomitant MTX >10 mg/wk during all treatment periods (aHR, 1.27; 95% CI, 1.10–1.47), during the first year of follow-up (aHR, 1.48; 95% CI, 1.22–1.78), or after 1 year (aHR, 1.42; 95% CI, 1.06–1.90), but not among patients on concomitant MTX 0–10 mg/wk. Conclusion This population-based cohort study demonstrated a modification effect of concomitant MTX dose on the relative risk of anti-TNF discontinuation for ADA compared with ETN among anti-TNF-naïve RA patients. However, the lack of exact cause of anti-TNF discontinuation limited causal inference of such a concomitant MTX dose-related modification effect. PMID:26917952

  4. Analytical method development for powder characterization: Visualization of the critical drug loading affecting the processability of a formulation for direct compression.

    PubMed

    Hirschberg, Cosima; Sun, Changquan Calvin; Rantanen, Jukka

    2016-09-01

    Characterization of particulate systems (powders) is one of the remaining scientific challenges. Evaluation of powder behaviour is often empirical and the decision-making processes are experience-based. There is a need for development of analytical instrumentation enabling more fundamental understanding of powder behaviour. Flowability and tabletability, two key factors in commercial scale manufacturing of tablets with direct compression (DC) approach, were analysed for formulations containing increasing amounts of several model active pharmaceutical ingredients (APIs). Flowability was investigated using a ring shear tester and tablets were prepared at four different compression pressures using a single punch tablet press. Thereby, a material sparing screening approach was developed to estimate the influence of APIs on behaviour of a given DC formulation. Additionally, this approach is useful for estimating the low threshold amount of API (wt%), at which the properties of an API start affecting the powder behaviour of a given formulation (API-excipient mixture). This threshold will be referred to as critical drug loading. The flowability of microcrystalline cellulose (reference grade pH 102) was used as a threshold for adequate flowability of model formulations. The threshold for tablet tensile strength was set to 2MPa. Simultaneous visual presentation of both- flowability and tabletability were used for a fast evaluation of manufacturability of a given formulation. The results confirmed that flowability is more sensitive to drug loading than tabletability, and that the critical drug loading for a DC formulation is strongly affected by particulate properties of API. For example, decreasing the particle size of paracetamol led to rapid decrease in flowability index, whereas the tabletability was not affected. PMID:27368089

  5. Factors affecting the development of adverse drug reactions to β-blockers in hospitalized cardiac patient population

    PubMed Central

    Mugoša, Snežana; Djordjević, Nataša; Djukanović, Nina; Protić, Dragana; Bukumirić, Zoran; Radosavljević, Ivan; Bošković, Aneta; Todorović, Zoran

    2016-01-01

    The aim of the present study was to undertake a study on the prevalence of cytochrome P450 2D6 (CYP2D6) poor metabolizer alleles (*3, *4, *5, and *6) on a Montenegrin population and its impact on developing adverse drug reactions (ADRs) of β-blockers in a hospitalized cardiac patient population. A prospective study was conducted in the Cardiology Center of the Clinical Center of Montenegro and included 138 patients who had received any β-blocker in their therapy. ADRs were collected using a specially designed questionnaire, based on the symptom list and any signs that could point to eventual ADRs. Data from patients’ medical charts, laboratory tests, and other available parameters were observed and combined with the data from the questionnaire. ADRs to β-blockers were observed in 15 (10.9%) patients. There was a statistically significant difference in the frequency of ADRs in relation to genetically determined enzymatic activity (P<0.001), with ADRs’ occurrence significantly correlating with slower CYP2D6 metabolism. Our study showed that the adverse reactions to β-blockers could be predicted by the length of hospitalization, CYP2D6 poor metabolizer phenotype, and the concomitant use of other CYP2D6-metabolizing drugs. Therefore, in hospitalized patients with polypharmacy CYP2D6 genotyping might be useful in detecting those at risk of ADRs. PMID:27536078

  6. The CYP3A4 inhibitor intraconazole does not affect the pharmacokinetics of a new calcium-sensitizing drug levosimendan.

    PubMed

    Antila, S; Honkanen, T; Lehtonen, L; Neuvonen, P J

    1998-08-01

    Itraconazole is a potent inhibitor of CYP3A4 isoenzyme and it can cause clinically significant interactions with some other drugs. Levosimendan is a new calcium-sensitizing drug intended for congestive heart failure. We aimed to study possible interactions of itraconazole with levosimendan in healthy volunteers. Twelve healthy male volunteers were included into a randomized, double-blind, two-phase crossover study. A wash-out period of 4 weeks was held between the phases. The subjects were given orally itraconazole 200 mg or placebo daily for 5 days. On the fifth day, they received a single oral dose of 2 mg of levosimendan. Levosimendan plasma concentrations were determined up to 12 hours and ECG, heart rate, and blood pressure followed-up to 8 hours after intake of levosimendan. Itraconazole had no significant effects on the pharmacokinetic parameters of levosimendan. Neither were there any differences in heart rate, PQ-, QTc- or QRS intervals between the placebo and itraconazole phases. The systolic blood pressure was decreased slightly more (p < 0.05) during the itraconazole phase than during the placebo phase. In conclusion, because the potent CYP3A4 inhibitor itraconazole had no significant pharmacokinetic interaction with levosimendan, interactions with CYP3A4 inhibitor, and oral levosimendan are unlikely.

  7. Metabolic fate (absorption, β-oxidation and deposition) of long-chain n-3 fatty acids is affected by sex and by the oil source (krill oil or fish oil) in the rat.

    PubMed

    Ghasemifard, Samaneh; Hermon, Karen; Turchini, Giovanni M; Sinclair, Andrew J

    2015-09-14

    The effects of krill oil as an alternative source of n-3 long-chain PUFA have been investigated recently. There are conflicting results from the few available studies comparing fish oil and krill oil. The aim of this study was to compare the bioavailability and metabolic fate (absorption, β-oxidation and tissue deposition) of n-3 fatty acids originating from krill oil (phospholipid-rich) or fish oil (TAG-rich) in rats of both sexes using the whole-body fatty acid balance method. Sprague-Dawley rats (thirty-six male, thirty-six female) were randomly assigned to be fed either a krill oil diet (EPA+DHA+DPA=1·38 mg/g of diet) or a fish oil diet (EPA+DHA+DPA=1·61 mg/g of diet) to constant ration for 6 weeks. The faeces, whole body and individual tissues were analysed for fatty acid content. Absorption of fatty acids was significantly greater in female rats and was only minimally affected by the oil type. It was estimated that most of EPA (>90 %) and more than half of DHA (>60 %) were β-oxidised in both diet groups. Most of the DPA was β-oxidised (57 and 67 % for female and male rats, respectively) in the fish oil group; however, for the krill oil group, the majority of DPA was deposited (82-83 %). There was a significantly greater deposition of DPA and DHA in rats fed krill oil compared with those fed fish oil, not due to a difference in bioavailability (absorption) but rather due to a difference in metabolic fate (anabolism v. catabolism).

  8. Luteolin induces apoptosis in multidrug resistant cancer cells without affecting the drug transporter function: involvement of cell line-specific apoptotic mechanisms

    PubMed Central

    Rao, Prema S.; Satelli, Arun; Moridani, Majid; Jenkins, Marjorie; Rao, U. Subrahmanyeswara

    2011-01-01

    Bioflavonoids are of considerable interest to human health as these serve as antioxidant and anticancer agents. Although epidemiological and experimental studies suggest that luteolin, a natural bioflavonoid, exhibits chemopreventive properties, its effectiveness as an antiproliferative agent against multidrug resistant (MDR) cancers is unclear. We thus assessed the antiproliferative effects of luteolin and associated molecular mechanisms using two MDR cancer cell lines that express high levels of P-glycoprotein and ABCG2. In this paper, we demonstrate that luteolin induces apoptosis in P-glycoprotein- and ABCG2-expressing MDR cancer cells without affecting the transport functions of these drug transporters. Analysis of various proliferative signaling pathways indicated that luteolin-induced apoptosis involves reactive oxygen species generation, DNA damage, activation of ATR→Chk2→p53 signaling pathway, inhibition of NF-kB signaling pathway, activation of p38 pathway and depletion of anti-apoptotic proteins. Importantly, use of luteolin in these analyses also identified specific molecular characteristics of NCI-ADR/RES and MCF-7/MitoR cells that highlight their different tissue origins. These results suggest that luteolin possesses therapeutic potential to control the proliferation of MDR cancers without affecting the physiological function of drug transporters in the body tissues. PMID:21792893

  9. Effect of lapatinib on oral digoxin absorption in patients.

    PubMed

    Koch, Kevin M; Smith, Deborah A; Botbyl, Jeff; Arya, Nikita; Briley, Linda P; Cartee, Leanne; White, Jane Holshouser; Beyer, Jennifer; Dar, Mohammed M; Chung, Hyun Choel; Chu, Quincy; Bang, Yung-Jue

    2015-11-01

    The potential for an interaction between lapatinib and absorption of the P-glycoprotein (ABCB1) substrate digoxin at a therapeutic dose in breast cancer patients was characterized. Seventeen women with HER2-positive metastatic breast cancer received a single oral 0.5-mg dose of digoxin on days 1 and 9 and oral lapatinib 1500 mg once daily on days 2 through 9. Digoxin pharmacokinetic parameters were determined on day 1 (digoxin administration alone) and on day 9 (coadministration of lapatinib and digoxin), and parameters were compared to determine the effects of lapatinib on digoxin absorption. Concomitant medications that could affect ABCB1 were accounted for. Lapatinib 1500 mg/day increased digoxin absorption approximately 80%, implicating lapatinib inhibition of intestinal ABCB1-mediated efflux. In summary, coadministration of lapatinib with narrow therapeutic index drugs that are substrates of ABCB1 should be undertaken with caution and dose adjustment should be considered. PMID:27137717

  10. Delamanid Coadministered with Antiretroviral Drugs or Antituberculosis Drugs Shows No Clinically Relevant Drug-Drug Interactions in Healthy Subjects

    PubMed Central

    Wells, Charles; Petersen, Carolyn; Paccaly, Anne; Shoaf, Susan E.; Patil, Shiva; Geiter, Lawrence

    2016-01-01

    Delamanid is a medicinal product approved for treatment of multidrug-resistant tuberculosis. Three studies were conducted to evaluate the potential drug-drug interactions between delamanid and antiretroviral drugs, including ritonavir, a strong inhibitor of CYP3A4, and selected anti-TB drugs, including rifampin, a strong inducer of cytochrome P450 (CYP) isozymes. Multiple-dose studies were conducted in parallel groups of healthy subjects. Plasma samples were analyzed for delamanid, delamanid metabolite, and coadministered drug concentrations, and pharmacokinetic (PK) parameters were determined. The magnitude of the interaction was assessed by the ratio of the geometric means and 90% confidence intervals. Coadministration of delamanid with tenofovir or efavirenz did not affect the PK characteristics of delamanid. Coadministration of Kaletra (lopinavir/ritonavir) with delamanid resulted in an approximately 25% higher delamanid area under the concentration-time curve from time 0 to the end of the dosing interval (AUCτ). Tenofovir, efavirenz, lopinavir, and ritonavir exposure were not affected by delamanid. Coadministration of delamanid with the TB drugs (ethambutol plus Rifater [rifampin, pyrazinamide, and isoniazid]) resulted in lower delamanid exposures (47 and 42% for the AUCτ and Cmax [maximum concentration of a drug in plasma] values, respectively), as well as decreased exposure of three primary metabolites (approximately 30 to 50% lower AUCτ values). Delamanid did not affect rifampin, pyrazinamide, and isoniazid exposure; the ethambutol AUCτ and Cmax values were about 25% higher with delamanid coadministration. The lack of clinically significant drug-drug interactions between delamanid and selected antiretroviral agents (including the strong CYP inhibitor ritonavir) and a combination of anti-TB drugs was demonstrated. Although there was a decrease in the delamanid concentrations when coadministered with ethambutol plus Rifater, this is likely related to

  11. Effect of drugs affecting microtubular assembly on microtubules, phospholipid synthesis and physiological indices (signalling, growth, motility and phagocytosis) in Tetrahymena pyriformis.

    PubMed

    Kovács, P; Csaba, G

    2006-01-01

    Structural changes of microtubules, incorporation of radioactively labelled components into phospholipids, cell motility, growth and phagocytosis were studied under the effect of four drugs affecting microtubular assembly: colchicine, nocodazole, vinblastine and taxol. Although the first three agents influence microtubules in the direction of depolymerization and the fourth stabilizes them, their effects on the structure of microtubules cannot be explained by this. Using confocal microscopy after an acetylated anti-tubulin label, in nocodazole- and colchicine-treated cells, the basal body cages disappear and longitudinal microtubules (LM) became thinner without changing transversal microtubules (TM). After taxol treatment LM also became thinner, however TM disappeared. Under the effect of vinblastine TM became thinner, without influencing LM. These drugs influence the incorporation of components ([(3)H]-serine, [(3)H]-palmitic acid and (32)P) into phospholipids, however their effect is equivocal and cannot be consequently coupled with the effect on the microtubules. Nocodazole, vinblastine and taxol significantly reduced the cell's motility, however colchicine did so to a lesser degree. Vinblastine and nocodazole totally inhibited, and taxol significantly decreased cell growth, while colchicine in a lower concentration increased the multiplication of cells. Phagocytosis was not significantly influenced after 1 min, but after 5 min all the agents studied (except colchicine) significantly inhibited phagocytosis. After 15 and 30 min each molecule caused highly significant inhibition. The experiments demonstrate that drugs affecting microtubular assembly dynamics influence differently the diverse (longitudinal, transversal etc.) microtubular systems of Tetrahymena and also differently influence microtubule-dependent physiological processes. The latter are more dependent on microtubular dynamics than are changes in phospholipid signalling.

  12. Alcohol effects on drug-nutrient interactions.

    PubMed

    Seitz, H K

    1985-01-01

    The interaction of ethanol with drugs and xenobiotics is complex because ethanol can affect any of the following steps; absorption, plasma protein binding, hepatic blood flow, distribution, hepatic uptake of drugs, and phase I and II hepatic metabolism. The ingestion of ethanol can lead to malabsorption of a variety of nutrients and can modify the absorption of various drugs. High concentrations of ethanol in conjunction with aspirin causes gastric mucosal damage. The principal effect of acute ethanol ingestion on drug metabolism is inhibition of microsomal drug metabolism. The synergistic effects of ethanol on central nervous system depressants can be explained by this mechanism. In contrast, chronic ethanol consumption increases mixed function oxidation and drug metabolism. The cross tolerance between ethanol and sedatives in chronic alcoholics may be due to this effect of alcohol. In addition, enhanced production of hepatotoxic products from certain drugs and xenobiotics and an increased activation of procarcinogens to carcinogens can result from this microsomal induction. The increased susceptibility to hepatotoxins and the enhanced carcinogenesis in the alcoholic may be explained by this fact. Other effects of the interaction between drugs and ethanol are the result of changes in organ susceptibility, best demonstrated for the central nervous system. Subsequently, the presence of liver disease has a great effect on drug metabolism in alcoholics.

  13. Absorption, Distribution, Metabolism, Excretion, and Toxicity Evaluation in Drug Discovery. 14. Prediction of Human Pregnane X Receptor Activators by Using Naive Bayesian Classification Technique.

    PubMed

    Shi, Huali; Tian, Sheng; Li, Youyong; Li, Dan; Yu, Huidong; Zhen, Xuechu; Hou, Tingjun

    2015-01-20

    The activation of pregnane X receptor (PXR), a member of the nuclear receptor (NR) superfamily, can mediate potential drug-drug interactions, and therefore, prediction of PXR activation is of great importance for evaluating drug metabolism and toxicity. In this study, based on 532 structurally diverse compounds, we present a comprehensive analysis with the aim to build accurate classification models for distinguishing PXR activators from nonactivators by using a naive Bayesian classification technique. First, the distributions of eight important molecular physicochemical properties of PXR activators versus nonactivators were compared, illustrating that the hydrophobicity-related molecular descriptors (AlogP and log D) show slightly better capability to discriminate PXR activators from nonactivators than the others. Then, based on molecular physicochemical properties, VolSurf descriptors, and molecular fingerprints, naive Bayesian classifiers were developed to separate PXR activators from nonactivators. The results demonstrate that the introduction of molecular fingerprints is quite essential to enhance the prediction accuracy of the classifiers. The best Bayesian classifier based on the 21 physicochemical properties, VolSurf descriptors, and LCFC_10 fingerprints descriptors yields a prediction accuracy of 92.7% for the training set based on leave-one-out (LOO) cross-validation and of 85.2% for the test set. Moreover, by exploring the important structural fragments derived from the best Bayesian classifier, we observed that flexibility is an important structural pattern for PXR activation. In addition, chemical compounds containing more halogen atoms, unsaturated alkanes chains relevant to π-π stacking, and fewer nitrogen atoms tend to be PXR activators. We believe that the naive Bayesian classifier can be used as a reliable virtual screening tool to predict PXR activation in the drug design and discovery pipeline.

  14. Physiological and pathophysiological factors affecting the expression and activity of the drug transporter MRP2 in intestine. Impact on its function as membrane barrier.

    PubMed

    Arana, Maite R; Tocchetti, Guillermo N; Rigalli, Juan P; Mottino, Aldo D; Villanueva, Silvina S M

    2016-07-01

    The gastrointestinal epithelium functions as a selective barrier to absorb nutrients, electrolytes and water, but at the same time restricts the passage into the systemic circulation of intraluminal potentially toxic compounds. This epithelium maintains its selective barrier function through the presence of very selective and complex intercellular junctions and the ability of the absorptive cells to reject those compounds. Accordingly, the enterocytes metabolize orally incorporated xenobiotics and secrete the hydrophilic metabolites back into the intestinal lumen through specific transporters localized apically. In the recent decades, there has been increasing recognition of the existence of the intestinal cellular barrier. In the present review we focus on the role of the multidrug resistance-associated protein 2 (MRP2, ABCC2) in the apical membrane of the enterocytes, as an important component of this intestinal barrier, as well as on its regulation. We provide a detailed compilation of significant contributions demonstrating that MRP2 expression and function vary under relevant physiological and pathophysiological conditions. Because MRP2 activity modulates the availability and pharmacokinetics of many therapeutic drugs administered orally, their therapeutic efficacy and safety may vary as well. PMID:27109321

  15. On the positive and negative affective responses to cocaine and their relation to drug self-administration in rats

    PubMed Central

    Ettenberg, Aaron; Fomenko, Vira; Kaganovsky, Konstantin; Shelton, Kerisa; Wenzel, Jennifer M.

    2015-01-01

    Rationale Acute cocaine administration produces an initial rewarding state followed by a dysphoric/anxiogenic “crash”. Objective To determine whether individual differences in the relative value of cocaine’s positive and negative effects would account for variations in subsequent drug self-administration. Methods The dual actions of cocaine were assessed using a conditioned place test (where animals formed preferences for environments paired with the immediate rewarding effects of 1.0 mg/kg i.v. cocaine or aversions of environments associated with the anxiogenic effects present 15 min post-injection) and a runway test (where animals developed approach-avoidance “retreat” behaviors about entering a goal-box associated with cocaine delivery). Ranked scores from these two tests were then correlated with each other and with the escalation in the operant responding of the same subjects observed over 10 days of 1- or 6-h/day access to i.v. (0.4 mg/inj) cocaine self-administration. Results a) larger place preferences were associated with faster runway start latencies (rs=−0.64), but not with retreat frequency or run times; b) larger place aversions predicted slower runway start times (rs=0.62) and increased run times (rs=0.65) and retreats (rs=0.62); c) response escalation was observed in both the 1-h and 6-h self-administration groups and was associated with increased CPPs (rs=0.58) but not CPAs, as well as with faster run times (rs=−0.60). Conclusions Together, these data suggest that animals exhibiting a greater positive than negative response to acute (single daily injections of) cocaine are at the greatest risk for subsequent escalated cocaine self-administration, a presumed indicator of cocaine addiction. PMID:25662610

  16. Segmental dependent transport of low permeability compounds along the small intestine due to P-glycoprotein: the role of efflux transport in the oral absorption of BCS class III drugs.

    PubMed

    Dahan, Arik; Amidon, Gordon L

    2009-01-01

    The purpose of this study was to investigate the role of P-gp efflux in the in vivo intestinal absorption process of BCS class III P-gp substrates, i.e. high-solubility low-permeability drugs. The in vivo permeability of two H (2)-antagonists, cimetidine and famotidine, was determined by the single-pass intestinal perfusion model in different regions of the rat small intestine, in the presence or absence of the P-gp inhibitor verapamil. The apical to basolateral (AP-BL) and the BL-AP transport of the compounds in the presence or absence of various efflux transporters inhibitors (verapamil, erythromycin, quinidine, MK-571 and fumitremorgin C) was investigated across Caco-2 cell monolayers. P-gp expression levels in the different intestinal segments were confirmed by immunoblotting. Cimetidine and famotidine exhibited segmental dependent permeability through the gut wall, with decreased P(eff) in the distal ileum in comparison to the proximal regions of the intestine. Coperfusion of verapamil with the drugs significantly increased the permeability in the ileum, while no significant change in the jejunal permeability was observed. Both drugs exhibited significantly greater BL-AP than AP-BL Caco-2 permeability, indicative of net mucosal secretion. Concentration dependent decrease of this secretion was obtained by the P-gp inhibitors verapamil, erythromycin and quinidine, while no effect was evident by the MRP2 inhibitor MK-571 and the BCRP inhibitor FTC, indicating that P-gp is the transporter mediates the intestinal efflux of cimetidine and famotidine. P-gp levels throughout the intestine were inversely related to the in vivo permeability of the drugs from the different segments. The data demonstrate that for these high-solubility low-permeability P-gp substrates, P-gp limits in vivo intestinal absorption in the distal segments of the small intestine; however P-gp plays a minimal role in the proximal intestinal segments due to significant lower P-gp expression levels

  17. THE ABSORPTION OF ADRENALIN

    PubMed Central

    Lyon, D. Murray

    1923-01-01

    1. Adrenalin solution given subcutaneously is usually rapidly absorbed, probably by lymphatic channels. 2. The speed of this process may be influenced by the circulation rate. 3. The relative amounts of adrenalin at any moment unabsorbed at the site of inoculation, carried in the circulating fluids, and taken up by the reacting tissues can be calculated from figures extracted from the curve of the blood pressure changes. The relative rates of transference of adrenalin into the blood and from the circulation into the tissues can also be estimated. 4. When absorption takes place rapidly a large quantity of the drug comes into action at once and the maximum occurs early, the curve of blood pressure reaches a considerable height, and subsides quickly. When absorption is slow the apex appears later and does not reach so high a level. 5. The response to adrenalin bears a logarithmic relationship to the dose employed and a method of allowing for this is indicated. PMID:19868816

  18. Variables that affect the mechanism of drug release from osmotic pumps coated with acrylate/methacrylate copolymer latexes.

    PubMed

    Jensen, J L; Appel, L E; Clair, J H; Zentner, G M

    1995-05-01

    The feasibility of using modified Eudragit acrylic latexes as microporous coatings for osmotic devices was investigated. Potassium chloride tablets were coated with mixtures of Eudragit RS30D and RL30D acrylic latexes that also contained a plasticizer (triethyl citrate or acetyl tributyl citrate) and a pore-forming agent (urea). A 2(5-1) fractional factorial experimental design was employed to determine the effect of five formulation variables (RS30D:RL30D polymer ratio plasticizer type, plasticizer level, urea level, and cure) on the in vitro release rate of KCl in deionized water (di water), lag time, and coat burst strength. The RS30D:RL30D polymer ratio had the greatest effect on the release rate, and both lag time and burst strength were most affected by the urea level. Statistical optimization was performed, and a coat formulation with predicted desirable in vitro performance was prepared and tested. The in vitro release rate (di water), lag time, and coat burst strength agreed well with the prediction. Dissolutions were also performed in phosphate buffered saline (PBS; pH 7.4); several formulations released markedly slower in PBS than in di water. This discrepancy was dependent on the type of plasticizer and the amount of pore former. Only those coat formulations containing acetyl tributyl citrate as the plasticizer and a 100% urea [(g urea/g polymer solids) x 100] level exhibited similar release rates in di water and PBS. The mechanism of release from these devices was primarily osmotic, whereas the release from devices coated with a formulation containing triethyl citrate and 50% urea was not dependent on the osmotic pressure difference. Devices with an osmotic release mechanism behaved similarly in vivo and in vitro.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7658339

  19. Variables that affect the mechanism of drug release from osmotic pumps coated with acrylate/methacrylate copolymer latexes.

    PubMed

    Jensen, J L; Appel, L E; Clair, J H; Zentner, G M

    1995-05-01

    The feasibility of using modified Eudragit acrylic latexes as microporous coatings for osmotic devices was investigated. Potassium chloride tablets were coated with mixtures of Eudragit RS30D and RL30D acrylic latexes that also contained a plasticizer (triethyl citrate or acetyl tributyl citrate) and a pore-forming agent (urea). A 2(5-1) fractional factorial experimental design was employed to determine the effect of five formulation variables (RS30D:RL30D polymer ratio plasticizer type, plasticizer level, urea level, and cure) on the in vitro release rate of KCl in deionized water (di water), lag time, and coat burst strength. The RS30D:RL30D polymer ratio had the greatest effect on the release rate, and both lag time and burst strength were most affected by the urea level. Statistical optimization was performed, and a coat formulation with predicted desirable in vitro performance was prepared and tested. The in vitro release rate (di water), lag time, and coat burst strength agreed well with the prediction. Dissolutions were also performed in phosphate buffered saline (PBS; pH 7.4); several formulations released markedly slower in PBS than in di water. This discrepancy was dependent on the type of plasticizer and the amount of pore former. Only those coat formulations containing acetyl tributyl citrate as the plasticizer and a 100% urea [(g urea/g polymer solids) x 100] level exhibited similar release rates in di water and PBS. The mechanism of release from these devices was primarily osmotic, whereas the release from devices coated with a formulation containing triethyl citrate and 50% urea was not dependent on the osmotic pressure difference. Devices with an osmotic release mechanism behaved similarly in vivo and in vitro.(ABSTRACT TRUNCATED AT 250 WORDS)

  20. Effect of medium-chain glycerides (MGK) on the intestinal absorption and the hepatobiliary transport of bromthymol blue.

    PubMed

    Higaki, K; Kishimoto, I; Komatsu, H; Hashida, M; Sezaki, H

    1986-06-01

    The effect of medium chain glyceride (MGK) emulsion on the intestinal absorption and the biliary excretion of bromthymol blue (BTB) was investigated in rats. Extensive tissue accumulation of BTB was reduced when BTB was administered with MGK emulsion formulation. HCO-100, an emulsifier, was also important for the decrease in the tissue accumulation of BTB. The ratios of absorption percent to tissue accumulation percent and to free fraction, not contained in the droplet of emulsion, in MGK emulsion were much greater than that of the control. Pretreatment with BTB-free emulsion reduced BTB absorption under the control, although tissue accumulation was not affected. The absorption appeared to decrease with increase in the time of pretreatment. The effect of leaving treatment after pretreatment on the absorption of BTB was also investigated. With the increase in leaving time after pretreatment, reduced absorption tended to resume to the level of control. The change in monocaprylate content from 54 to 60% in MGK made a difference in BTB absorption and it was suggested that monocaprylate content in MGK was one of the significant factors of MGK emulsion on drug absorption. Bile recovery study was simultaneously carried out with an in situ recirculation experiment. The recovery of BTB into bile tended to decrease. The ratio of recovery percent of BTB into bile to the absorption percent of BTB also decreased extensively, which is possibly another effect of MGK on drug disposition. PMID:3761141

  1. Pollution-induced community tolerance to non-steroidal anti-inflammatory drugs (NSAIDs) in fluvial biofilm communities affected by WWTP effluents.

    PubMed

    Corcoll, Natàlia; Acuña, Vicenç; Barceló, Damià; Casellas, Maria; Guasch, Helena; Huerta, Belinda; Petrovic, Mira; Ponsatí, Lidia; Rodríguez-Mozaz, Sara; Sabater, Sergi

    2014-10-01

    We assessed the tolerance acquired by stream biofilms to two non-steroidal anti-inflammatory-drugs (NSAIDs), ibuprofen and diclofenac. Biofilms came from a stream system receiving the effluent of a wastewater treatment plant (WWTP). The response of biofilms from a non-polluted site (upstream the WWTP) was compared to that of others downstream with relevant and decreasing levels of NSAIDs. Experiments performed in the laboratory following the pollution-induced community tolerance (PICT) approach determined that both algae and microbial communities from biofilms of the sites exposed at the highest concentrations of ibuprofen and diclofenac acquired tolerance to the mixture of these NSAIDs occurring at the sites. It was also observed that the chronic pollution by the WWTP effluent affected the microbial metabolic profile, as well as the structure of the algal community. The low (at ng L(-1) level) but chronic inputs of pharmaceuticals to the river ecosystem result in tolerant communities of lower diversity and altered microbial metabolism.

  2. Resting-state cerebellar-cerebral networks are differently affected in first-episode, drug-naive schizophrenia patients and unaffected siblings.

    PubMed

    Guo, Wenbin; Liu, Feng; Chen, Jindong; Wu, Renrong; Zhang, Zhikun; Yu, Miaoyu; Xiao, Changqing; Zhao, Jingping

    2015-11-26

    Dysconnectivity hypothesis posits that schizophrenia is a disorder with dysconnectivity of the cortico-cerebellar-thalamic-cortical circuit (CCTCC). However, it remains unclear to the changes of the cerebral connectivity with the cerebellum in schizophrenia patients and unaffected siblings. Forty-nine patients with first-episode, drug-naive schizophrenia patients, 46 unaffected siblings of schizophrenia patients and 46 healthy controls participated in the study. Seed-based resting-state functional connectivity approach was employed to analyze the data. Compared with the controls, the patients and the siblings share increased default-mode network (DMN) seed - right Crus II connectivity. The patients have decreased right dorsal attention network (DAN) seed - bilateral cerebellum 4,5 connectivity relative to the controls. By contrast, the siblings exhibit increased FC between the right DAN seed and the right cerebellum 6 and right cerebellum 4,5 compared to the controls. No other abnormal connectivities (executive control network and salience network) are observed in the patients/siblings relative to the controls. There are no correlations between abnormal cerebellar-cerebral connectivities and clinical variables. Cerebellar-cerebral connectivity of brain networks within the cerebellum are differently affected in first-episode, drug-naive schizophrenia patients and unaffected siblings. Increased DMN connectivity with the cerebellum may serve as potential endophenotype for schizophrenia.

  3. Resting-state cerebellar-cerebral networks are differently affected in first-episode, drug-naive schizophrenia patients and unaffected siblings

    PubMed Central

    Guo, Wenbin; Liu, Feng; Chen, Jindong; Wu, Renrong; Zhang, Zhikun; Yu, Miaoyu; Xiao, Changqing; Zhao, Jingping

    2015-01-01

    Dysconnectivity hypothesis posits that schizophrenia is a disorder with dysconnectivity of the cortico-cerebellar-thalamic-cortical circuit (CCTCC). However, it remains unclear to the changes of the cerebral connectivity with the cerebellum in schizophrenia patients and unaffected siblings. Forty-nine patients with first-episode, drug-naive schizophrenia patients, 46 unaffected siblings of schizophrenia patients and 46 healthy controls participated in the study. Seed-based resting-state functional connectivity approach was employed to analyze the data. Compared with the controls, the patients and the siblings share increased default-mode network (DMN) seed – right Crus II connectivity. The patients have decreased right dorsal attention network (DAN) seed – bilateral cerebellum 4,5 connectivity relative to the controls. By contrast, the siblings exhibit increased FC between the right DAN seed and the right cerebellum 6 and right cerebellum 4,5 compared to the controls. No other abnormal connectivities (executive control network and salience network) are observed in the patients/siblings relative to the controls. There are no correlations between abnormal cerebellar-cerebral connectivities and clinical variables. Cerebellar-cerebral connectivity of brain networks within the cerebellum are differently affected in first-episode, drug-naive schizophrenia patients and unaffected siblings. Increased DMN connectivity with the cerebellum may serve as potential endophenotype for schizophrenia. PMID:26608842

  4. Clinically significant drug interactions.

    PubMed

    Ament, P W; Bertolino, J G; Liszewski, J L

    2000-03-15

    A large number of drugs are introduced every year, and new interactions between medications are increasingly reported. Consequently, it is no longer practical for physicians to rely on memory alone to avoid potential drug interactions. Multiple drug regimens carry the risk of adverse interactions. Precipitant drugs modify the object drug's absorption, distribution, metabolism, excretion or actual clinical effect. Nonsteroidal anti-inflammatory drugs, antibiotics and, in particular, rifampin are common precipitant drugs prescribed in primary care practice. Drugs with a narrow therapeutic range or low therapeutic index are more likely to be the objects for serious drug interactions. Object drugs in common use include warfarin, fluoroquinolones, antiepileptic drugs, oral contraceptives, cisapride and 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors. Many other drugs, act as precipitants or objects, and a number of drugs act as both. Regularly updated manuals of drug interactions and CD-ROM-formatted programs are useful office references. PMID:10750880

  5. [Study on intestinal absorption features of oligosaccharides in Morinda officinalis How. with sigle-pass perfusion].

    PubMed

    Deng, Shao-Dong; Zhang, Peng; Lin, Li; Xiao, Feng-Xia; Lin, Jing-Ran

    2015-01-01

    To study the in situ intestinal absorption of five oligosaccharides contained in Morinda officinalis How. (sucrose, kestose, nystose, 1F-Fructofuranosyinystose and Bajijiasu). The absorption of the five oligosaccharides in small intestine (duodenum, jejunum and ileum) and colon of rats and their contents were investigated by using in situ single-pass perfusion model and HPLC-ELSD. The effects of drug concentration, pH in perfusate and P-glycoprotein inhibitor on the intestinal absorption were investigated to define the intestinal absorption mechanism of the five oligosaccharides in rats. According to the results, all of the five oligosaccharides were absorbed in the whole intestine, and their absorption rates were affected by the pH of the perfusion solution, drug concentration and intestinal segments. Verapamil Hydrochloride could significantly increase the absorptive amount of sucrose and Bajijiasu, suggesting sucrose and Bajijiasu are P-gp's substrate. The five oligosaccharides are absorbed mainly through passive diffusion in the intestinal segments, without saturated absorption. They are absorbed well in all intestines and mainly in duodenum and jejunum.

  6. Exploring food effects on indinavir absorption with human intestinal fluids in the mouse intestine.

    PubMed

    Holmstock, Nico; De Bruyn, Tom; Bevernage, Jan; Annaert, Pieter; Mols, Raf; Tack, Jan; Augustijns, Patrick

    2013-04-11

    Food can have a significant impact on the pharmacokinetics of orally administered drugs, as it may affect drug solubility as well as permeability. Since fed state conditions cannot easily be implemented in the presently available permeability tools, including the frequently used Caco-2 system, exploring food effects during drug development can be quite challenging. In this study, we investigated the effect of fasted and fed state conditions on the intestinal absorption of the HIV protease inhibitor indinavir using simulated and human intestinal fluids in the in situ intestinal perfusion technique in mice. Although the solubility of indinavir was 6-fold higher in fed state human intestinal fluids (FeHIF) as compared to fasted state HIF (FaHIF), the intestinal permeation of indinavir was 22-fold lower in FeHIF as compared to FaHIF. Dialysis experiments showed that only a small fraction of indinavir is accessible for absorption in FeHIF due to micellar entrapment, possibly explaining its low intestinal permeation. The presence of ritonavir, a known P-gp inhibitor, increased the intestinal permeation of indinavir by 2-fold in FaHIF, while there was no increase when using FeHIF. These data confirm that drug-food interactions form a complex interplay between solubility and permeability effects. The use of HIF in in situ intestinal perfusions holds great promise for biorelevant absorption evaluation as it allows to directly explore this complex solubility/permeability interplay on drug absorption.

  7. Phenoxyethanol absorption by polyvinyl chloride.

    PubMed

    Lee, M G

    1984-12-01

    Phenoxyethanol was found to be absorbed by polyvinyl chloride administration sets during continuous irrigation therapy. Depending upon the conditions of administration up to 20% loss of potency could occur. Absorption of the drug by the rigid plastic luer-lock fitting of the set caused softening and decreased rigidity of the plastic.

  8. ABSORPTION ANALYZER

    DOEpatents

    Brooksbank, W.A. Jr.; Leddicotte, G.W.; Strain, J.E.; Hendon, H.H. Jr.

    1961-11-14

    A means was developed for continuously computing and indicating the isotopic assay of a process solution and for automatically controlling the process output of isotope separation equipment to provide a continuous output of the desired isotopic ratio. A counter tube is surrounded with a sample to be analyzed so that the tube is exactly in the center of the sample. A source of fast neutrons is provided and is spaced from the sample. The neutrons from the source are thermalized by causing them to pass through a neutron moderator, and the neutrons are allowed to diffuse radially through the sample to actuate the counter. A reference counter in a known sample of pure solvent is also actuated by the thermal neutrons from the neutron source. The number of neutrons which actuate the detectors is a function of a concentration of the elements in solution and their neutron absorption cross sections. The pulses produced by the detectors responsive to each neu tron passing therethrough are amplified and counted. The respective times required to accumulate a selected number of counts are measured by associated timing devices. The concentration of a particular element in solution may be determined by utilizing the following relation: T2/Ti = BCR, where B is a constant proportional to the absorption cross sections, T2 is the time of count collection for the unknown solution, Ti is the time of count collection for the pure solvent, R is the isotopic ratlo, and C is the molar concentration of the element to be determined. Knowing the slope constant B for any element and when the chemical concentration is known, the isotopic concentration may be readily determined, and conversely when the isotopic ratio is known, the chemical concentrations may be determined. (AEC)

  9. Drug Affected Babies: A Bibliography.

    ERIC Educational Resources Information Center

    Portland Public Schools, OR. Dept. of Research, Evaluation, and Testing.

    This 42-item annotated bibliography, represents a comprehensive effort to gather information on the educational problems of infant children of substance-abusing parents. Extensive searches were conducted in databases in the fields of education, medicine, social sciences, and the humanities. In particular, studies on the problems of "crack babies"…

  10. Interactions between antiepileptic drugs, and between antiepileptic drugs and other drugs.

    PubMed

    Zaccara, Gaetano; Perucca, Emilio

    2014-12-01

    Interactions between antiepileptic drugs, or between antiepileptic drugs and other drugs, can be pharmacokinetic or pharmacodynamic in nature. Pharmacokinetic interactions involve changes in absorption, distribution or elimination, whereas pharmacodynamic interactions involve synergism and antagonism at the site of action. Most clinically important interactions of antiepileptic drugs result from induction or inhibition of drug metabolism. Carbamazepine, phenytoin, phenobarbital and primidone are strong inducers of cytochrome P450 and glucuronizing enzymes (as well as P-glycoprotein) and can reduce the efficacy of co-administered medications such as oral anticoagulants, calcium antagonists, steroids, antimicrobial and antineoplastic drugs through this mechanism. Oxcarbazepine, eslicarbazepine acetate, felbamate, rufinamide, topiramate (at doses ≥ 200 mg/day) and perampanel (at doses ≥ 8 mg/day) have weaker inducing properties, and a lower propensity to cause interactions mediated by enzyme induction. Unlike enzyme induction, enzyme inhibition results in decreased metabolic clearance of the affected drug, the serum concentration of which may increase leading to toxic effects. Examples of important interactions mediated by enzyme inhibition include the increase in the serum concentration of phenobarbital and lamotrigine caused by valproic acid. There are also interactions whereby other drugs induce or inhibit the metabolism of antiepileptic drugs, examples being the increase in serum carbamazepine concentration by erythromycin, and the decrease in serum lamotrigine concentration by oestrogen-containing contraceptives. Pharmacodynamic interactions between antiepileptic drugs may also be clinically important. These interactions can have potentially beneficial effects, such as the therapeutic synergism of valproic acid combined with lamotrigine, or adverse effects, such as the reciprocal potentiation of neurotoxicity observed in patients treated with a combination of

  11. Prescription Drugs

    MedlinePlus

    ... body, especially in brain areas involved in the perception of pain and pleasure. Prescription stimulants , such as ... of drug that causes changes in your mood, perceptions, and behavior can affect judgment and willingness to ...

  12. Serum Immunoglobulin G Levels to Porphyromonas gingivalis Peptidylarginine Deiminase Affect Clinical Response to Biological Disease-Modifying Antirheumatic Drug in Rheumatoid Arthritis

    PubMed Central

    Kobayashi, Tetsuo; Ito, Satoshi; Kobayashi, Daisuke; Shimada, Atsushi; Narita, Ichiei; Murasawa, Akira; Nakazono, Kiyoshi; Yoshie, Hiromasa

    2016-01-01

    Objectives To determine whether serum immunity to Porphyromonas gingivalis peptidylarginine deiminase (PPAD) affects the clinical response to biological disease-modifying antirheumatic drug (bDMARD) in patients with rheumatoid arthritis (RA). Methods In a retrospective study, rheumatologic and periodontal conditions of 60 patients with RA who had been treated with conventional synthetic DMARD were evaluated before (baseline) and after 3 and 6 months of bDMARD therapy. After serum levels of anti-PPAD immunoglobulin G (IgG) were determined at baseline, the patients were respectively divided into two groups for high and low anti-PPAD IgG titers according to the median measurements. Genotypes at 8 functional single nucleotide polymorphisms (SNPs) related to RA were also determined. Results After 3 and 6 months of therapy, patients with low anti-PPAD IgG titers showed a significantly greater decrease in changes in the Disease Activity Score including 28 joints using C-reactive protein (DAS28-CRP) (P = 0.04 for both) and anti-cyclic citrullinated peptide (CCP) IgG levels (P = 0.03 and P = 0.04) than patients with high anti-PPAD IgG titers, although these parameter values were comparable at baseline. The anti-PPAD IgG titers were significantly positively correlated with changes in the DAS28-CRP (P = 0.01 for both) and the anti-CCP IgG levels (P = 0.02 for both) from baseline to 3 and 6 months later. A multiple regression analysis revealed a significantly positive association between the anti-PPAD IgG titers and changes in the DAS28-CRP after 6 months of bDMARD therapy (P = 0.006), after adjusting for age, gender, smoking, periodontal condition, and RA-related SNPs. Conclusion The serum IgG levels to PPAD affect the clinical response to bDMARD in patients with RA. PMID:27111223

  13. New Approaches for Working with Children and Families Involved in Family Treatment Drug Courts: Findings from the Children Affected by Methamphetamine Program.

    PubMed

    Rodi, Michael S; Killian, Colleen M; Breitenbucher, Philip; Young, Nancy K; Amatetti, Sharon; Bermejo, Russ; Hall, Erin

    2015-01-01

    This is a descriptive study of the Children Affected by Methamphetamine (CAM) grant program, a federally funded effort to improve outcomes through the addition of targeted interventions for 1,940 families, including 2,596 adults and 4,245 children involved in 12 diverse Family Treatment Drug Courts (FTDCs) located across six U.S. states. The majority were children of parents with a primary methamphetamine use disorder. Findings reflect grantees' reporting on 18 performance indicators of child safety and permanency, adult recovery, and family well-being. Additional information gleaned from grantees' biannual reports provides insights about program implementation. Results, drawn from this large and complex dataset, indicate that comprehensively addressing families' needs is associated with better outcomes than those experienced by similarly situated families in grantees' communities and the nation overall. In addition to describing common program components and outcomes, this article presents important lessons learned about implementing evidence-based children's services in the FTDC context, as well as future directions for research and evaluation in this arena. PMID:26827483

  14. Transport of gemifloxacin, a 4th generation quinolone antibiotic, in the Caco-2 and engineered MDCKII cells, and potential involvement of efflux transporters in the intestinal absorption of the drug.

    PubMed

    Jin, Hyo-Eon; Song, Boran; Kim, Sang-Bum; Shim, Won-Sik; Kim, Dae-Duk; Chong, Saeho; Chung, Suk-Jae; Shim, Chang-Koo

    2013-04-01

    The oral (po) bioavailability of gemifloxacin mesylate in rats and its possible association with efflux transporters was investigated. The apparent permeabilities (Papp) of gemifloxacin across the Caco-2 cell monolayer were 1.20 ± 0.09 × 10(-5) cm/s for apical to basal (absorptive) transport, and 2.13 ± 0.6 × 10(-5) cm/s for basal to apical (secretory) transport for a 5-500 μM concentration range, suggesting the involvement of a carrier-mediated efflux in the secretory transport. The secretory transport in Caco-2 cells was significantly decreased by MRP2 (MK571) and BCRP (Ko143) inhibitors. The secretory transport was distinct in MDCKII/P-gp, MDCKII/MRP2 and MDCKII/BCRP cells, and the affinity was highest for MRP2, followed by BCRP and P-gp. The efflux was significantly decreased by verapamil and Ko143, but not significantly by MK571. The comparative po bioavailability in rats was increased by the preadministration of Ko143 (four-fold), MK571 (two-fold) and verapamil (two-fold). Efflux transporters appeared to significantly limit the bioavailability of gemifloxacin in rats, suggesting their possible contribution to the low bioavailability of the drug in the human (70%).

  15. Effective absorption in cladding-pumped fibers

    NASA Astrophysics Data System (ADS)

    Zervas, Michalis N.; Marshall, Andy; Kim, Jaesun

    2011-02-01

    We investigate experimentally and theoretically the wavelength dependence of the pump absorption along Yb3+-doped fibers, for cladding-pumped single as well as coupled multimode (GTWaveTM) fibers. We show that significant spectral absorption distortions occur along the length with the 976nm absorption peak affected the most. We have developed a novel theoretical approach, based on coupled mode theory, to explain the observed effects. We have also investigated the mode mixing requirements in order to improve the absorption spectral distribution along the increase the overall absorption efficiency and discuss the implications on fiber laser performance.

  16. MicroRNAs as regulators of drug transporters, drug-metabolizing enzymes, and tight junctions: implication for intestinal barrier function.

    PubMed

    Ikemura, Kenji; Iwamoto, Takuya; Okuda, Masahiro

    2014-08-01

    Drug transporters, drug-metabolizing enzymes, and tight junctions in the small intestine function as an absorption barrier and sometimes as a facilitator of orally administered drugs. The expression of these proteins often fluctuates and thereby causes individual pharmacokinetic variability. MicroRNAs (miRNAs), which are small non-coding RNAs, have recently emerged as a new class of gene regulator. MiRNAs post-transcriptionally regulate gene expression by binding to target mRNA to suppress its translation or regulate its degradation. They have been shown to be key regulators of proteins associated with pharmacokinetics. Moreover, the role of miRNAs on the expression of some proteins expressed in the small intestine has recently been clarified. In this review, we summarize current knowledge regarding the role of miRNAs in the regulation of drug transporters, drug-metabolizing enzymes, and tight junctions as well as its implication for intestinal barrier function. MiRNAs play vital roles in the differentiation, architecture, and barrier function of intestinal epithelial cells, and directly and/or indirectly regulate the expression and function of proteins associated with drug absorption in intestinal epithelial cells. Moreover, the variation of miRNA expression caused by pathological and physiological conditions as well as genetic factors should affect the expression of these proteins. Therefore, miRNAs could be significant factors affecting inter- and intra-individual variations in the pharmacokinetics and intestinal absorption of drugs. Overall, miRNAs could be promising targets for personalized pharmacotherapy or other attractive therapies through intestinal absorption of drugs.

  17. The Interactions of P-Glycoprotein with Antimalarial Drugs, Including Substrate Affinity, Inhibition and Regulation.

    PubMed

    Senarathna, S M D K Ganga; Page-Sharp, Madhu; Crowe, Andrew

    2016-01-01

    The combination of passive drug permeability, affinity for uptake and efflux transporters as well as gastrointestinal metabolism defines net drug absorption. Efflux mechanisms are often overlooked when examining the absorption phase of drug bioavailability. Knowing the affinity of antimalarials for efflux transporters such as P-glycoprotein (P-gp) may assist in the determination of drug absorption and pharmacokinetic drug interactions during oral absorption in drug combination therapies. Concurrent administration of P-gp inhibitors and P-gp substrate drugs may also result in alterations in the bioavailability of some antimalarials. In-vitro Caco-2 cell monolayers were used here as a model for potential drug absorption related problems and P-gp mediated transport of drugs. Artemisone had the highest permeability at around 50 x 10(-6) cm/sec, followed by amodiaquine around 20 x 10(-6) cm/sec; both mefloquine and artesunate were around 10 x 10(-6) cm/sec. Methylene blue was between 2 and 6 x 10(-6) cm/sec depending on the direction of transport. This 3 fold difference was able to be halved by use of P-gp inhibition. MRP inhibition also assisted the consolidation of the methylene blue transport. Mefloquine was shown to be a P-gp inhibitor affecting our P-gp substrate, Rhodamine 123, although none of the other drugs impacted upon rhodamine123 transport rates. In conclusion, mefloquine is a P-gp inhibitor and methylene blue is a partial substrate; methylene blue may have increased absorption if co-administered with such P-gp inhibitors. An upregulation of P-gp was observed when artemisone and dihydroartemisinin were co-incubated with mefloquine and amodiaquine. PMID:27045516

  18. The Interactions of P-Glycoprotein with Antimalarial Drugs, Including Substrate Affinity, Inhibition and Regulation.

    PubMed

    Senarathna, S M D K Ganga; Page-Sharp, Madhu; Crowe, Andrew

    2016-01-01

    The combination of passive drug permeability, affinity for uptake and efflux transporters as well as gastrointestinal metabolism defines net drug absorption. Efflux mechanisms are often overlooked when examining the absorption phase of drug bioavailability. Knowing the affinity of antimalarials for efflux transporters such as P-glycoprotein (P-gp) may assist in the determination of drug absorption and pharmacokinetic drug interactions during oral absorption in drug combination therapies. Concurrent administration of P-gp inhibitors and P-gp substrate drugs may also result in alterations in the bioavailability of some antimalarials. In-vitro Caco-2 cell monolayers were used here as a model for potential drug absorption related problems and P-gp mediated transport of drugs. Artemisone had the highest permeability at around 50 x 10(-6) cm/sec, followed by amodiaquine around 20 x 10(-6) cm/sec; both mefloquine and artesunate were around 10 x 10(-6) cm/sec. Methylene blue was between 2 and 6 x 10(-6) cm/sec depending on the direction of transport. This 3 fold difference was able to be halved by use of P-gp inhibition. MRP inhibition also assisted the consolidation of the methylene blue transport. Mefloquine was shown to be a P-gp inhibitor affecting our P-gp substrate, Rhodamine 123, although none of the other drugs impacted upon rhodamine123 transport rates. In conclusion, mefloquine is a P-gp inhibitor and methylene blue is a partial substrate; methylene blue may have increased absorption if co-administered with such P-gp inhibitors. An upregulation of P-gp was observed when artemisone and dihydroartemisinin were co-incubated with mefloquine and amodiaquine.

  19. The Interactions of P-Glycoprotein with Antimalarial Drugs, Including Substrate Affinity, Inhibition and Regulation

    PubMed Central

    Senarathna, S M D K Ganga; Page-Sharp, Madhu; Crowe, Andrew

    2016-01-01

    The combination of passive drug permeability, affinity for uptake and efflux transporters as well as gastrointestinal metabolism defines net drug absorption. Efflux mechanisms are often overlooked when examining the absorption phase of drug bioavailability. Knowing the affinity of antimalarials for efflux transporters such as P-glycoprotein (P-gp) may assist in the determination of drug absorption and pharmacokinetic drug interactions during oral absorption in drug combination therapies. Concurrent administration of P-gp inhibitors and P-gp substrate drugs may also result in alterations in the bioavailability of some antimalarials. In-vitro Caco-2 cell monolayers were used here as a model for potential drug absorption related problems and P-gp mediated transport of drugs. Artemisone had the highest permeability at around 50 x 10−6 cm/sec, followed by amodiaquine around 20 x 10−6 cm/sec; both mefloquine and artesunate were around 10 x 10−6 cm/sec. Methylene blue was between 2 and 6 x 10−6 cm/sec depending on the direction of transport. This 3 fold difference was able to be halved by use of P-gp inhibition. MRP inhibition also assisted the consolidation of the methylene blue transport. Mefloquine was shown to be a P-gp inhibitor affecting our P-gp substrate, Rhodamine 123, although none of the other drugs impacted upon rhodamine123 transport rates. In conclusion, mefloquine is a P-gp inhibitor and methylene blue is a partial substrate; methylene blue may have increased absorption if co-administered with such P-gp inhibitors. An upregulation of P-gp was observed when artemisone and dihydroartemisinin were co-incubated with mefloquine and amodiaquine. PMID:27045516

  20. Systems Pharmacology in Small Molecular Drug Discovery.

    PubMed

    Zhou, Wei; Wang, Yonghua; Lu, Aiping; Zhang, Ge

    2016-01-01

    Drug discovery is a risky, costly and time-consuming process depending on multidisciplinary methods to create safe and effective medicines. Although considerable progress has been made by high-throughput screening methods in drug design, the cost of developing contemporary approved drugs did not match that in the past decade. The major reason is the late-stage clinical failures in Phases II and III because of the complicated interactions between drug-specific, human body and environmental aspects affecting the safety and efficacy of a drug. There is a growing hope that systems-level consideration may provide a new perspective to overcome such current difficulties of drug discovery and development. The systems pharmacology method emerged as a holistic approach and has attracted more and more attention recently. The applications of systems pharmacology not only provide the pharmacodynamic evaluation and target identification of drug molecules, but also give a systems-level of understanding the interaction mechanism between drugs and complex disease. Therefore, the present review is an attempt to introduce how holistic systems pharmacology that integrated in silico ADME/T (i.e., absorption, distribution, metabolism, excretion and toxicity), target fishing and network pharmacology facilitates the discovery of small molecular drugs at the system level.

  1. Systems Pharmacology in Small Molecular Drug Discovery

    PubMed Central

    Zhou, Wei; Wang, Yonghua; Lu, Aiping; Zhang, Ge

    2016-01-01

    Drug discovery is a risky, costly and time-consuming process depending on multidisciplinary methods to create safe and effective medicines. Although considerable progress has been made by high-throughput screening methods in drug design, the cost of developing contemporary approved drugs did not match that in the past decade. The major reason is the late-stage clinical failures in Phases II and III because of the complicated interactions between drug-specific, human body and environmental aspects affecting the safety and efficacy of a drug. There is a growing hope that systems-level consideration may provide a new perspective to overcome such current difficulties of drug discovery and development. The systems pharmacology method emerged as a holistic approach and has attracted more and more attention recently. The applications of systems pharmacology not only provide the pharmacodynamic evaluation and target identification of drug molecules, but also give a systems-level of understanding the interaction mechanism between drugs and complex disease. Therefore, the present review is an attempt to introduce how holistic systems pharmacology that integrated in silico ADME/T (i.e., absorption, distribution, metabolism, excretion and toxicity), target fishing and network pharmacology facilitates the discovery of small molecular drugs at the system level. PMID:26901192

  2. Environment-, drug- and stress-induced alterations in body temperature affect the neurotoxicity of substituted amphetamines in the C57BL/6J mouse.

    PubMed

    Miller, D B; O'Callaghan, J P

    1994-08-01

    In the companion paper we demonstrated that d-methamphetamine (d-METH), d-methylenedioxyamphetamine (d-MDA) and d-methylenedioxymethamephetamine (d-MDMA), but not d-fenfluramine (d-FEN), appear to damage dopaminergic projections to the striatum of the mouse. An elevation in core temperature also was associated with exposure to d-METH, d-MDA and d-MDMA, whereas exposure to d-FEN lowered core temperature. Given these findings, we examined the effects of temperature on substituted amphetamine (AMP)-induced neurotoxicity in the C57BL/6J mouse. Levels of striatal dopamine (DA) and glial fibrillary acidic protein (GFAP) were taken as indicators of neurotoxicity. Alterations in ambient temperature, pretreatment with drugs reported to cause hypothermia in the mouse and hypothermia induced by restraint stress were used to affect AMP-induced neurotoxicity. Mice received d-METH (10 mg/kg), d-MDA (20 mg/kg) or d-MDMA (20 mg/kg) every 2 hr for a total of four s.c. injections. All three AMPs increased core temperature and caused large (> 75%) decreases in striatal dopamine and large (> 300%) increases in striatal glial fibrillary acidic protein 72 hr after the last injection. Lowering ambient temperature from 22 degrees C to 15 degrees C blocked (d-MDA and d-MDMA) or severely attenuated (d-METH) these effects. Pretreatment with MK-801 lowered core temperature and blocked AMP-induced neurotoxicity; elevation of ambient temperature during this regimen elevated core temperature and markedly attenuated the neuroprotective effects of MK-801. Pretreatment with MK-801 also lowered core temperature in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice but did not block 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurotoxicity.(ABSTRACT TRUNCATED AT 250 WORDS)

  3. Transcriptome modification of white blood cells after dietary administration of curcumin and non-steroidal anti-inflammatory drug in osteoarthritic affected dogs.

    PubMed

    Colitti, M; Gaspardo, B; Della Pria, A; Scaini, C; Stefanon, Bruno

    2012-06-30

    The dietary effect of non-steroidal anti-inflammatory drug (NSAID) or curcumin on the gene expression of peripheral white blood cells in osteoarthritis (OA) affected dogs was investigated using a 44K oligo microarray. Two groups of OA dogs and one group of healthy dogs (6 dogs each) were clinically evaluated and blood was sampled before (T0) and after 20days (T20) of dietary administration of NSAID (NSAID group) or curcumin (CURCUMIN group). Differentially expressed genes (P<0.05) in comparison to the control group were identified with MeV software and were functional annotated and monitored for signaling pathways and candidate biomarkers using the Ingenuity Pathways Analysis (IPA). After 20days of treatment, the differentially expressed transcripts significantly (P<0.05) decreased from 475 to 173 in NSAID group and from 498 to 141 in CURCUMIN group. Genes involved in "inflammatory response" and in "connective tissue development and function" dramatically decreased at T20. Other genes, included in "cellular movement", "cellular compromise" and "immune cell trafficking", were differentially expressed at T0 but not at T20 in both groups. Specific molecular targets of CURCUMIN, not observed for NSAID, were the IkB up regulation in the "TNRF1 signaling pathway" and IL18 down regulation in the "role of cytokines in mediating communication between immune cells". The activity of CURCUMIN was also evidenced from the inhibition of macrophages proliferation (HBEGF), related to a strong down regulation of TNFα and to activation of fibrinolysis (SERPINE1). The results would suggest that curcumin offers a complementary antinflammatory support for OA treatment in dogs. PMID:22591841

  4. Reactivation of human polyomavirus JC in patients affected by psoriasis vulgaris and psoriatic arthritis and treated with biological drugs: preliminary results.

    PubMed

    Nardis, Chiara; Anzivino, Elena; Bellizzi, Anna; Rodio, Donatella M; De Pità, Ornella; Chiarini, Fernanda; Pietropaolo, Valeria

    2012-12-01

    Psoriasis vulgaris (PsV) and psoriatic arthritis (PSA) are inter-related heritable inflammatory skin diseases. Psoriatic lesions develop as a result of abnormal immune responses, hyperproliferation and altered differentiation of keratinocytes, and a notable subset of psoriatic patients develops PsA, characterized by joints inflammation. Recently, biological drugs were introduced to treat these diseases. However, this therapy has already been associated with the development of serious life-threatening infections, such as the reactivation of human polyomavirus JC (JCV), responsible for the progressive multifocal leukoencephalopathy (PML), a lethal demyelinating disease caused by oligodendrocytes lytic infection. Therefore, the aims of our study were the investigation of the possible JCV reactivation in PsV and PsA patients treated with adalimumab, etanercept, and methotrexate, performing quantitative real-time PCR in sera and skin biopsies at the time of recruitment (T0) and after 3 (T3) and 6 (T6) months of treatment, and the sequencing analysis of the JCV non-coding control region (NCCR). We found JCV DNA in 5/15 PsV patients and in 2/15 PsA patients and JCV NCCR sequence analysis always showed a structure similar to non-pathogenic CY archetype, with random occurrence of a few irrelevant point mutations. Nevertheless the poor number of patients analyzed, our preliminary data can pave the way for taking into account that the follow-up of JCV DNA detection and the JCV NCCR sequence analysis in psoriatic patients may be important to evaluate the risk of PML onset, considering that patients affected by autoimmune diseases and treated with biologics continue to rise. PMID:22422468

  5. Modulation of ganciclovir intestinal absorption in presence of absorption enhancers.

    PubMed

    Shah, Pranav; Jogani, Viral; Mishra, Pushpa; Mishra, Anil Kumar; Bagchi, Tamishraha; Misra, Ambikanandan

    2007-10-01

    The purpose of this investigation was to study the influences of absorption enhancers in increasing oral bioavailability of Ganciclovir (GAN) by assessing the transepithelial permeation across cell monolayers in vitro and bioavailability in rats in vivo. The permeation of GAN across Caco-2 and MDCK cell monolayers in the absence/presence of dimethyl-beta-cyclodextrin (DMbetaCD), chitosan hydrochloride (CH), sodium lauryl sulphate (SLS), and their combinations was studied for a 2-h period. GAN was administered to rats in absence/presence of absorption enhancers and drug contents in plasma were estimated. We found that the apparent permeability coefficient (Papp) of GAN in absence of absorption enhancers (control) were 0.261 +/- 0.072 x 10(-6) and 0.486 +/- 0.063 x 10(-6) cm/s in Caco-2 and MDCK cell monolayers, respectively, whereas in the presence of DMbetaCD, CH, SLS, and their combinations, Papp of GAN increased by 5- to 25-fold and 7- to 33-fold as compared to control in Caco-2 and MDCK cell monolayers, respectively. However, in rats, the maximum enhancement in bioavailability of GAN during coadministration of these absorption enhancers was only fivefold compared to GAN control. To conclude, the absorption enhancers-DMbetaCD, CH, SLS, and their combinations demonstrated significant improvement in transepithelial permeation and bioavailability of GAN.

  6. [Resorption of drugs through the vaginal wall].

    PubMed

    Bourin, M; Guenzet, J; Pradal, G

    1983-01-01

    Drug absorption during vaginal administration. A method is described (systems approach to vaginal delivery of drugs and development of in situ vaginal drug absorption procedure) and is able to show vaginal absorption of drugs. Some drugs are rapidly and largely absorbed through vaginal epithelium: Metronidazole (Flagyl), Prostaglandins, Estrogens, Polyvidone-iodine (Betadine), Chloroquinadol (Gynotherax), d-Methadone, Hexachlorophene (Phisohex et Ultralan), Insulin and Triclosan. Other drugs are poorly absorbed: Amphotericin B (Fungizone, Amphocycline), Econazole (Pevaryl) and Trimethoprim. At least, some drugs are not absorbed: Nystatine (Mycostatine) and Furazolidone (Tricofuron).

  7. “First, do no harm”: legal guidelines for health programmes affecting adolescents aged 10–17 who sell sex or inject drugs

    PubMed Central

    Conner, Brendan

    2015-01-01

    Introduction There is a strong evidence base that the stigma, discrimination and criminalization affecting adolescent key populations (KPs) aged 10–17 is intensified due to domestic and international legal constructs that rely on law-enforcement-based interventions dependent upon arrest, pre-trial detention, incarceration and compulsory “rehabilitation” in institutional placement. While there exists evidence and rights-based technical guidelines for interventions among older cohorts, these guidelines have not yet been embraced by international public health actors for fear that international law applies different standards to adolescents aged 10–17 who engage in behaviours such as selling sex or injecting drugs. Discussion As a matter of international human rights, health, juvenile justice and child protection law, interventions among adolescent KPs aged 10–17 must not involve arrest, prosecution or detention of any kind. It is imperative that interventions not rely on law enforcement, but instead low-threshold, voluntary services, shelter and support, utilizing peer-based outreach as much as possible. These services must be mobile and accessible, and permit alternatives to parental consent for the provision of life-saving support, including HIV testing, treatment and care, needle and syringe programmes, opioid substitution therapy, safe abortions, antiretroviral therapy and gender-affirming care and hormone treatment for transgender adolescents. To ensure enrolment in services, international guidance indicates that informed consent and confidentiality must be ensured, including by waiver of parental consent requirements. To remove the disincentive to health practitioners and researchers to engaging with adolescent KPs aged 10–17 government agencies and ethical review boards are advised to exempt or grant waivers for mandatory reporting. In the event that, in violation of international law and guidance, authorities seek to involuntarily place adolescent

  8. Adverse drug reactions in veterinary patients associated with drug transporters.

    PubMed

    Mealey, Katrina L

    2013-09-01

    For many drugs used in veterinary practice, plasma and tissue concentrations are highly dependent on the activity of drug transporters. This article describes how functional changes in drug transporters, whether mediated by genetic variability or drug-drug interactions, affect drug disposition and, ultimately, drug safety and efficacy in veterinary patients. A greater understanding of species, breed, and individual (genetic) differences in drug transporter function, as well as drug-drug interactions involving drug transporters, will result in improved strategies for drug design and will enable veterinarians to incorporate individualized medicine in their practices.

  9. Adverse drug reactions in veterinary patients associated with drug transporters.

    PubMed

    Mealey, Katrina L

    2013-09-01

    For many drugs used in veterinary practice, plasma and tissue concentrations are highly dependent on the activity of drug transporters. This article describes how functional changes in drug transporters, whether mediated by genetic variability or drug-drug interactions, affect drug disposition and, ultimately, drug safety and efficacy in veterinary patients. A greater understanding of species, breed, and individual (genetic) differences in drug transporter function, as well as drug-drug interactions involving drug transporters, will result in improved strategies for drug design and will enable veterinarians to incorporate individualized medicine in their practices. PMID:23890239

  10. Drugs and Young People

    MedlinePlus

    Drug abuse is a serious public health problem. It affects almost every community and family in some way. Drug abuse in children and teenagers may pose a ... of young people may be more susceptible to drug abuse and addiction than adult brains. Abused drugs ...

  11. “They Don’t Look at What Affects Us”: The Role of Ecodevelopmental Factors on Alcohol and Drug Use among Latinos with Physical Disabilities

    PubMed Central

    Cordova, David; Parra-Cardona, J. Ruben; Blow, Adrian; Johnson, Deborah J.; Prado, Guillermo; Fitzgerald, Hiram E.

    2014-01-01

    Objectives Latinos with disabilities disproportionately report substance use, including binge drinking and drug use. Ecodevelopmental factors, including socioeconomic patterning of poverty, social exclusion and post-colonial racism, have been shown to impact alcohol and drug use. However, this line of research remains under-developed among Latinos with disabilities. The purpose of this study was to obtain rich descriptions of the role of ecodevelopmental factors, including family and community, on alcohol and drug use among Latinos with physical disabilities. Methods We utilized a community-based participatory research design, in conjunction with an innovative methodology referred to as photovoice. Three rounds of photography and focus group interviews were conducted with a total of 17 focus groups. Reflections in each focus group interview were aloud and digitally audiotaped. A total of 28 participants 19–35 years of age (mean age= 27.65, SD= 5.48) participated in each round of photography and focus group interviews. Data analyses followed the tenets of descriptive phenomenology. Results Findings highlight ecodevelopmental family and community risk and protective factors. At the family level, participants reflected on the ways in which family functioning, including family support, communication and cohesion, can serve as risk and promotive factors for alcohol and drug use. Additionally, participants described in detail how experiences of poverty, stigma and discrimination, violence, accessibility to alcohol and drugs, accessibility for persons with disabilities, transportation, community support and cohesion, and access to health and mental health services constitute risk and promotive factors at the community level. Conclusion Findings are suggestive of how ecodevelopmental family and community factors might increase the risk for alcohol and drug use among Latinos with physical disabilities. From this qualitative research, we derive a series of testable

  12. 'They don't look at what affects us': the role of ecodevelopmental factors on alcohol and drug use among Latinos with physical disabilities.

    PubMed

    Cordova, David; Parra-Cardona, Jose Ruben; Blow, Adrian; Johnson, Deborah J; Prado, Guillermo; Fitzgerald, Hiram E

    2015-01-01

    Objectives. Latinos with disabilities disproportionately report substance use, including binge drinking and drug use. Ecodevelopmental factors, including socioeconomic patterning of poverty, social exclusion, and post-colonial racism, have been shown to impact alcohol and drug use. However, this line of research remains underdeveloped among Latinos with disabilities. The purpose of this study was to obtain rich descriptions of the role of ecodevelopmental factors, including family and community, on alcohol and drug use among Latinos with physical disabilities. Methods. We utilized a community-based participatory research design, in conjunction with an innovative methodology referred to as photovoice. Three rounds of photography and focus group interviews were conducted with a total of 17 focus groups. Reflections in each focus group interview were aloud and digitally audiotaped. A total of 28 participants 19-35 years of age (mean age = 27.65, SD = 5.48) participated in each round of photography and focus group interviews. Data analyses followed the tenets of descriptive phenomenology. Results. Findings highlight ecodevelopmental family and community risk and protective factors. At the family level, participants reflected on the ways in which family functioning, including family support, communication, and cohesion, can serve as risk and promotive factors for alcohol and drug use. Additionally, participants described in detail how experiences of poverty, stigma and discrimination, violence, accessibility to alcohol and drugs, accessibility for persons with disabilities, transportation, community support and cohesion, and access to health and mental health services constitute risk and promotive factors at the community level. Conclusion. Findings are suggestive of how ecodevelopmental family and community factors might increase the risk of alcohol and drug use among Latinos with physical disabilities. From this qualitative research, we derive a series of testable

  13. Does the theory-driven program affect the risky behavior of drug injecting users in a healthy city? A quasi-experimental study

    PubMed Central

    Karimy, Mahmood; Abedi, Ahmad Reza; Abredari, Hamid; Taher, Mohammad; Zarei, Fatemeh; Rezaie Shahsavarloo, Zahra

    2016-01-01

    Background: The horror of HIV/AIDS as a non-curable, grueling disease is a destructive issue for every country. Drug use, shared needles and unsafe sex are closely linked to the transmission of HIV/AIDS. Modification or changing unhealthy behavior through educational programs can lead to HIV prevention. The aim of this study was to evaluate the efficiency of theory-based education intervention on HIV prevention transmission in drug addicts. Methods: In this quasi-experimental study, 69 male drug injecting users were entered in to the theory- based educational intervention. Data were collected using a questionnaire, before and 3 months after four sessions (group discussions, lecture, film displaying and role play) of educational intervention. Results: The findings signified that the mean scores of constructs (self-efficacy, susceptibility, severity and benefit) significantly increased after the educational intervention, and the perceived barriers decreased (p< 0.001). Also, the history of HIV testing was reported to be 9% before the intervention, while the rate increased to 88% after the intervention. Conclusion: The present research offers a primary founding for planning and implementing a theory based educational program to prevent HIV/AIDS transmission in drug injecting addicts. This research revealed that health educational intervention improved preventive behaviors and the knowledge of HIV/AIDS participants. PMID:27390684

  14. A Growth Curve Analysis of the Joint Influences of Parenting Affect, Child Characteristics and Deviant Peers on Adolescent Illicit Drug Use

    ERIC Educational Resources Information Center

    Pires, Paulo; Jenkins, Jennifer M.

    2007-01-01

    This study purports that parental rejection and warmth are critical to the development of adolescent drug use, and investigates a model that also considers children's vulnerability and deviant peer affiliations. It tests mediation through the proximal risk factor of deviant peers. Poisson growth curve modeling was used to examine participants from…

  15. Can access limits on sales representatives to physicians affect clinical prescription decisions? A study of recent events with diabetes and lipid drugs.

    PubMed

    Chressanthis, George A; Khedkar, Pratap; Jain, Nitin; Poddar, Prashant; Seiders, Michael G

    2012-07-01

    The authors explored to what extent important medical decisions by practitioners can be influenced by pharmaceutical representatives and, in particular, whether restricting such access could delay appropriate changes in clinical practice. Medical practices were divided into four categories based on the degree of sales representative access to clinicians: very low, low, medium, and high from a database compiled by ZS Associates called AccessMonitor (Evanston, IL) used extensively by many pharmaceutical companies. Clinical decisions of 58,647 to 72,114 physicians were statistically analyzed using prescription data from IMS Health (Danbury, CT) in three critical areas: an innovative drug for type 2 diabetes (sitagliptin), an older diabetes drug with a new Food and Drug Administration-required black box warning for cardiovascular safety (rosiglitazone), and a combination lipid therapy that had reported negative outcomes in a clinical trial (simvastatin+ezetimbe). For the uptake of the new diabetes agent, the authors found that physicians with very low access to representatives had the lowest adoption of this new therapy and took 1.4 and 4.6 times longer to adopt than physicians in the low- and medium-access restriction categories, respectively. In responding to the black box warning for rosiglitazone, the authors found that physicians with very low access were 4.0 times slower to reduce their use of this treatment than those with low access. Likewise, there was significantly less response in terms of changing prescribing to the negative news with the lipid therapy for physicians in more access-restricted offices. Overall, cardiologists were the most responsive to information changes relative to primary care physicians. These findings emphasize that limiting access to pharmaceutical representatives can have the unintended effect of reducing appropriate responses to negative information about drugs just as much as responses to positive information about innovative

  16. Can access limits on sales representatives to physicians affect clinical prescription decisions? A study of recent events with diabetes and lipid drugs.

    PubMed

    Chressanthis, George A; Khedkar, Pratap; Jain, Nitin; Poddar, Prashant; Seiders, Michael G

    2012-07-01

    The authors explored to what extent important medical decisions by practitioners can be influenced by pharmaceutical representatives and, in particular, whether restricting such access could delay appropriate changes in clinical practice. Medical practices were divided into four categories based on the degree of sales representative access to clinicians: very low, low, medium, and high from a database compiled by ZS Associates called AccessMonitor (Evanston, IL) used extensively by many pharmaceutical companies. Clinical decisions of 58,647 to 72,114 physicians were statistically analyzed using prescription data from IMS Health (Danbury, CT) in three critical areas: an innovative drug for type 2 diabetes (sitagliptin), an older diabetes drug with a new Food and Drug Administration-required black box warning for cardiovascular safety (rosiglitazone), and a combination lipid therapy that had reported negative outcomes in a clinical trial (simvastatin+ezetimbe). For the uptake of the new diabetes agent, the authors found that physicians with very low access to representatives had the lowest adoption of this new therapy and took 1.4 and 4.6 times longer to adopt than physicians in the low- and medium-access restriction categories, respectively. In responding to the black box warning for rosiglitazone, the authors found that physicians with very low access were 4.0 times slower to reduce their use of this treatment than those with low access. Likewise, there was significantly less response in terms of changing prescribing to the negative news with the lipid therapy for physicians in more access-restricted offices. Overall, cardiologists were the most responsive to information changes relative to primary care physicians. These findings emphasize that limiting access to pharmaceutical representatives can have the unintended effect of reducing appropriate responses to negative information about drugs just as much as responses to positive information about innovative

  17. Use of PET Imaging to Evaluate Transporter-Mediated Drug-Drug Interactions.

    PubMed

    Langer, Oliver

    2016-07-01

    Several membrane transporters belonging to the adenosine triphosphate-binding cassette (ABC) and solute carrier (SLC) families can transport drugs and drug metabolites and thereby exert an effect on drug absorption, distribution, and excretion, which may potentially lead to transporter-mediated drug-drug interactions (DDIs). Some transporter-mediated DDIs may lead to changes in organ distribution of drugs (eg, brain, liver, kidneys) without affecting plasma concentrations. Positron emission tomography (PET) is a noninvasive imaging method that allows studying of the distribution of radiolabeled drugs to different organs and tissues and is therefore the method of choice to quantitatively assess transporter-mediated DDIs on a tissue level. There are 2 approaches to how PET can be used in transporter-mediated DDI studies. When the drug of interest is a potential perpetrator of DDIs, it may be administered in unlabeled form to assess its influence on tissue distribution of a generic transporter-specific PET tracer (probe substrate). When the drug of interest is a potential victim of DDIs, it may be radiolabeled with carbon-11 or fluorine-18 and used in combination with a prototypical transporter inhibitor (eg, rifampicin). PET has already been used both in preclinical species and in humans to assess the effects of transporter-mediated DDIs on drug disposition in different organ systems, such as brain, liver, and kidneys, for which examples are given in the present review article. Given the growing importance of membrane transporters with respect to drug safety and efficacy, PET is expected to play an increasingly important role in future drug development. PMID:27385172

  18. Does sediment resuspension by storms affect the fate of polychlorobiphenyls (PCBs) in the benthic food chain? Interactions between changes in POM characteristics, adsorption and absorption by the mussel Mytilus galloprovincialis

    NASA Astrophysics Data System (ADS)

    Charles, François; Lopez-Legentil, Susanna; Grémare, Antoine; Michel Amouroux, Jean; Desmalades, Martin; Vétion, Gilles; Escoubeyrou, Karine

    2005-12-01

    Environmental parameters and gross sedimentation rates (GSR) were monitored at a fixed site located in the Bay of Banyuls-sur-Mer (NW Mediterranean), between March 1997 and April 1998, together with the main biochemical characteristics of both sedimenting and sedimented particulate organic matter (POM). Three storms which occurred during this time period resulted in natural sediment resuspension. This is indicated by the corresponding increase in GSR and a decrease in the enzymatically hydrolysable amino acids/totally hydrolysable amino acids ratio (EHAA/THAA), within the sedimenting POM. Only the strongest storm resulted in (1) a transitory increase in fine-grained particles, (2) concomitant increases in organic carbon, carbohydrates, lipids and THAA, and (3) a decrease in the EHAA/THAA ratio in surficial sediments. For most of the assayed parameters, the values recorded after the December 1997 storm corresponded to extremes for the whole period under study. This emphasises the role of storms in controlling the characteristics of sedimented and sedimenting POM. Ten sediment types, with contrasting biochemical characteristics, were selected for experiments; these were based on the results of the monitoring survey and were used during adsorption and absorption experiments involving 14C tetrachlorobiphenyl (TCB). Adsorption rates differed significantly between the sediment types, but did not correlate with any of the assayed biochemical parameters. Absorption efficiency by the mussel Mytilus galloprovincialis also differed between the sediment types; it correlated positively with all the assayed biochemical parameters, except lipids. Comparison between the magnitudes of the increase in GSR, together with the decrease in absorption efficiency during resuspension events, suggests that resuspension tends to enhance the transfer of organic pollutants in the benthic food chain.

  19. Antiretroviral drug levels and interactions affect lipid, lipoprotein and glucose metabolism in HIV-1 seronegative subjects: A pharmacokinetic-pharmacodynamic analysis

    PubMed Central

    Rosenkranz, Susan L.; Yarasheski, Kevin E.; Para, Michael F.; Reichman, Richard C.; Morse, Gene D.

    2007-01-01

    Background: HIV-infected patients treated with antiretroviral medications (ARVs) develop undesirable changes in lipid and glucose metabolism that mimic the metabolic syndrome and may be proatherogenic. Antiretroviral drug levels and their interactions may contribute to these metabolic alterations. Methods: Fifty-six HIV-seronegative adults were enrolled in an open-label, randomized, pharmacokinetic interaction study, and received a non-nucleoside reverse transcriptase inhibitor (efavirenz on days 1-21) plus a protease inhibitor (PI; amprenavir on days 11-21), with a second PI on days 15-21 (saquinavir, nelfinavir, indinavir, or ritonavir). Fasting triglycerides, total, LDL- and HDL-cholesterol, glucose, insulin and C-peptide levels were measured on days 0, 14, 21, and 2-3 weeks after discontinuing drugs. Regression models were used to estimate changes in these parameters and associations between these changes and circulating levels of study drugs. Results: Short-term efavirenz and amprenavir administration significantly increased cholesterol, triglycerides and glucose levels. Addition of a second protease inhibitor further increased triglycerides, total- and LDL-cholesterol levels. Higher amprenavir levels predicted larger increases in triglycerides, total and LDL-cholesterol. Two weeks after all study drugs were stopped, total, LDL- and HDL-cholesterol remained elevated above baseline. Conclusions: ARV regimens that include a non-nucleoside reverse transcriptase inhibitor plus single or boosted PIs are becoming more common, but the pharmacodynamic interactions associated with these regimens can result in persistent, undesirable alterations in serum lipid/lipoprotein levels. Additional pharmacodynamic studies are needed to examine the metabolic effects of ritonavir-boosted regimens, with and without efavirenz. PMID:18007962

  20. Effect of polycarbophil on the absorption of nutrients.

    PubMed

    Yamada, T; Nagata, O; Tamai, I; Tsuji, A

    1996-05-01

    The effects of polycarbophil on the absorption of various nutrients were evaluated by several in situ methods. Polycarbophil reduced the absorption of 3-O-methyl-D-glucose (3-OMG) and L-phenylalanine in the in situ loop and the in situ perfusion methods, but it did not affect the absorption of these nutrients in an open system, the in situ modified loop method, which is closer to physiological conditions. It also did not affect the absorption of vitamin A or phosphatidylcholine-L-alpha-dipalmitoyl in the latter system. These results indicate that the absorption of nutrients is probably not altered by polycarbophil under physiological conditions.

  1. [Drugs affecting the incretin system and renal glucose transport: do they meet the expectations of modern therapy of type 2 diabetes?].

    PubMed

    Gumieniczek, Anna

    2016-05-04

    Agents introduced into therapy of type 2 diabetes in the last few years are still the subject of numerous clinical and experimental studies. Although many studies have been completed, we still do not know all aspects of these drugs' action, especially the long-term effects of their use. Most questionable is their impact on the processes of cell proliferation, on the cardiovascular and immune systems, on lipids and uric acid metabolism. A summary of the most important observations on the use of three groups of new drugs - analogs of glucagon-like peptide 1 (GLP-1), inhibitors of dipeptidyl peptidase IV (DPPIV) and inhibitors of sodium glucose cotransporters (SGLT1 and SGLT2) - has been made, based on a review of the literature over the past five years (2010-2014). The information included in the present review concerns the structure and activity relationship, therapeutic efficacy, side effects and the observed additional therapeutic effects, which can determine new standards in therapy of diabetes and also facilitate the development of better antidiabetic drugs.

  2. [Drugs affecting the incretin system and renal glucose transport: do they meet the expectations of modern therapy of type 2 diabetes?].

    PubMed

    Gumieniczek, Anna

    2016-01-01

    Agents introduced into therapy of type 2 diabetes in the last few years are still the subject of numerous clinical and experimental studies. Although many studies have been completed, we still do not know all aspects of these drugs' action, especially the long-term effects of their use. Most questionable is their impact on the processes of cell proliferation, on the cardiovascular and immune systems, on lipids and uric acid metabolism. A summary of the most important observations on the use of three groups of new drugs - analogs of glucagon-like peptide 1 (GLP-1), inhibitors of dipeptidyl peptidase IV (DPPIV) and inhibitors of sodium glucose cotransporters (SGLT1 and SGLT2) - has been made, based on a review of the literature over the past five years (2010-2014). The information included in the present review concerns the structure and activity relationship, therapeutic efficacy, side effects and the observed additional therapeutic effects, which can determine new standards in therapy of diabetes and also facilitate the development of better antidiabetic drugs. PMID:27180961

  3. [Intestinal absorption kinetics of flurbiprofen in rats].

    PubMed

    Peng, Jun-Jie; Lin, Cong-Cong; Li, Jiang; Zhu, Zhi-Hong; Yang, Xing-Gang; Pan, Wei-San

    2013-03-01

    To study the in situ intestinal absorption kinetics of flrubiprofen in rats, the absorption of flurbiprofen in small intestine (duodenum, jejunum and ileum) and colon of rats was investigated using in situ single-pass perfusion method and the drug content was measured by HPLC. The effects of drug concentration on the intestinal absorption were investigated. The K(a) and P(app) values of flurbiprofen in the small intestine and colon had no significant difference (P > 0.05). Drug concentration (4.0, 10.0 and 16.0 mg x L(-1)) had no significant influence on the K(a) values (P > 0.05). However, when concentration was 4.0 mg x L(-1) and 10.0 mg x L(-1), significant effect on the P(app) values (P < 0.05) was found, but significant effect on the P(app) values was not shown between 10.0 mg x L(-1) and 16.0 mg x L(-1) (P > 0.05). The K(a) and P(app) values of flurbiprofen on the perfusion flow rate had significant difference (P < 0.05). Flurbiprofen could be absorbed at all segments of the intestine in rats and had no special absorption window. The absorption of flurbiprofen complies with the facilitated diffusion in the general intestinal segments, and accompany with the cytopsistransport mechanism probably. The perfusion flow rate had significant effect on the K(a) and P(app).

  4. Glucose-dependent insulinotropic polypeptide regulates dipeptide absorption in mouse jejunum.

    PubMed

    Coon, Steven D; Schwartz, John H; Rajendran, Vazhaikkurichi M; Jepeal, Lisa; Singh, Satish K

    2013-11-15

    Glucose-dependent insulinotropic polypeptide (GIP) secreted from jejunal mucosal K cells augments insulin secretion and plays a critical role in the pathogenesis of obesity and Type 2 diabetes mellitus. In recent studies, we have shown GIP directly activates Na-glucose cotransporter-1 (SGLT1) and enhances glucose absorption in mouse jejunum. It is not known whether GIP would also regulate other intestinal nutrient absorptive processes. The present study investigated the effect of GIP on proton-peptide cotransporter-1 (PepT1) that mediates di- and tripeptide absorption as well as peptidomimetic drugs. Immunohistochemistry studies localized both GIP receptor (GIPR) and PepT1 proteins on the basolateral and apical membranes of normal mouse jejunum, respectively. Anti-GIPR antibody detected 50-, 55-, 65-, and 70-kDa proteins, whereas anti-PepT1 detected a 70-kDa proteins in mucosal homogenates of mouse jejunum. RT-PCR analyses established the expression of GIPR- and PepT1-specific mRNA in mucosal cells of mouse jejunum. Absorption of Gly-Sar (a nondigestible dipeptide) measured under voltage-clamp conditions revealed that the imposed mucosal H(+) gradient-enhanced Gly-Sar absorption as an evidence for the presence of PepT1-mediated H(+):Gly-Sar cotransport on the apical membranes of mouse jejunum. H(+):Gly-Sar absorption was completely inhibited by cephalexin (a competitive inhibitor of PepT1) and was activated by GIP. The GIP-activated Gly-Sar absorption was completely inhibited by RP-cAMP (a cAMP antagonist). In contrast to GIP, the ileal L cell secreting glucagon-like peptide-1 (GLP-1) did not affect the H(+):Gly-Sar absorption in mouse jejunum. We conclude from these observations that GIP, but not GLP-1, directly activates PepT1 activity by a cAMP-dependent signaling pathway in jejunum.

  5. Drugs that suppress TSH or cause central hypothyroidism.

    PubMed

    Haugen, Bryan R

    2009-12-01

    Many different drugs affect thyroid function. Most of these drugs act at the level of the thyroid in patients with normal thyroid function, or at the level of thyroid hormone absorption or metabolism in patients requiring exogenous levothyroxine. A small subset of medications including glucocorticoids, dopamine agonists, somatostatin analogues and rexinoids affect thyroid function through suppression of TSH in the thyrotrope or hypothalamus. Fortunately, most of these medications do not cause clinically evident central hypothyroidism. A newer class of nuclear hormone receptors agonists, called rexinoids, cause clinically significant central hypothyroidism in most patients and dopamine agonists may exacerbate 'hypothyroidism' in patients with non-thyroidal illness. In this review, we explore mechanisms governing TSH suppression of these drugs and the clinical relevance of these effects. PMID:19942154

  6. Uptake Carriers and Oncology Drug Safety

    PubMed Central

    Sprowl, Jason A.

    2014-01-01

    Members of the solute carrier (SLC) family of transporters are responsible for the cellular influx of a broad range of endogenous compounds and xenobiotics in multiple tissues. Many of these transporters are highly expressed in the gastrointestinal tract, liver, and kidney and are considered to be of particular importance in governing drug absorption, elimination, and cellular sensitivity of specific organs to a wide variety of oncology drugs. Although the majority of studies on the interaction of oncology drugs with SLC have been restricted to the use of exploratory in vitro model systems, emerging evidence suggests that several SLCs, including OCT2 and OATP1B1, contribute to clinically important phenotypes associated with those agents. Recent literature has indicated that modulation of SLC activity may result in drug-drug interactions, and genetic polymorphisms in SLC genes have been described that can affect the handling of substrates. Alteration of SLC function by either of these mechanisms has been demonstrated to contribute to interindividual variability in the pharmacokinetics and toxicity associated with several oncology drugs. In this report, we provide an update on this rapidly emerging field. PMID:24378324

  7. Regulatory review time for approval of oncology drugs in Japan between 2001 and 2014. Considerations of changes, factors that affect review time, and difference with the United States.

    PubMed

    Maeda, Hideki; Kurokawa, Tatsuo

    2015-05-01

    In this study, we comprehensively and historically studied the review time of oncology drugs approved by the regulatory authorities in Japan with publicly available information. A total of 120 applications of oncology drugs were approved in Japan between April 2001 and July 2014. The review time peaked with 732.0 days (24.4 months) in 2005, and showed a tendency to decline gradually each year thereafter. After 2012, a significant reduction of the review time was seen in comparison to the median of 13-year median time. In addition, we compared the review time with that in the United States. The median review time lag with the United States was significantly peaked in 2005. After 2005, the review time lag with the FDA has decreased, but lag did not significantly reduce by 2014. We also examined factors influencing the review time in Japan with multiple regression analysis. It was found that the factors related to a use of overseas data and expedited program for accelerating the reviews influenced the direction of shortening the review time. We consider that regulatory authorities in Japan need to keep making efforts to reduce the review time further and eliminate the review time lag with the United States.

  8. Imaging of Drug-induced Complications in the Gastrointestinal System.

    PubMed

    McGettigan, Melissa J; Menias, Christine O; Gao, Zhenqiang J; Mellnick, Vincent M; Hara, Amy K

    2016-01-01

    Drug-induced injury commonly affects the gastrointestinal and hepatobiliary systems because of the mechanisms of absorption and metabolism. In pill esophagitis, injury is frequently related to direct contact with the esophageal mucosa, resulting in small superficial ulcers in the mid esophagus. Nonsteroidal anti-inflammatory drugs can lead to gastrointestinal tract ulcers and small bowel mucosal diaphragms (thin weblike strictures). Injury to the pancreatic and hepatobiliary systems can manifest as pancreatitis, acute or chronic hepatitis, cholestasis, or steatosis and steatohepatitis (which may progress to cirrhosis). Various drugs may also insult the hepatic vasculature, resulting in Budd-Chiari and sinusoidal obstructive syndromes. Focal lesions such as hepatic adenomas may develop after use of oral contraceptives or anabolic steroids. Ultrasonography, computed tomography, and magnetic resonance imaging can aid in diagnosis of drug-induced injuries and often are necessary to exclude other causes. PMID:26761532

  9. Time-dependent oral absorption models

    NASA Technical Reports Server (NTRS)

    Higaki, K.; Yamashita, S.; Amidon, G. L.

    2001-01-01

    The plasma concentration-time profiles following oral administration of drugs are often irregular and cannot be interpreted easily with conventional models based on first- or zero-order absorption kinetics and lag time. Six new models were developed using a time-dependent absorption rate coefficient, ka(t), wherein the time dependency was varied to account for the dynamic processes such as changes in fluid absorption or secretion, in absorption surface area, and in motility with time, in the gastrointestinal tract. In the present study, the plasma concentration profiles of propranolol obtained in human subjects following oral dosing were analyzed using the newly derived models based on mass balance and compared with the conventional models. Nonlinear regression analysis indicated that the conventional compartment model including lag time (CLAG model) could not predict the rapid initial increase in plasma concentration after dosing and the predicted Cmax values were much lower than that observed. On the other hand, all models with the time-dependent absorption rate coefficient, ka(t), were superior to the CLAG model in predicting plasma concentration profiles. Based on Akaike's Information Criterion (AIC), the fluid absorption model without lag time (FA model) exhibited the best overall fit to the data. The two-phase model including lag time, TPLAG model was also found to be a good model judging from the values of sum of squares. This model also described the irregular profiles of plasma concentration with time and frequently predicted Cmax values satisfactorily. A comparison of the absorption rate profiles also suggested that the TPLAG model is better at prediction of irregular absorption kinetics than the FA model. In conclusion, the incorporation of a time-dependent absorption rate coefficient ka(t) allows the prediction of nonlinear absorption characteristics in a more reliable manner.

  10. [A daycare program of animal assisted therapy for affective disorder patients during psychotropic drug therapy: evaluation of the relaxation effect by fNIRS (functional near-infrared spectroscopy)].

    PubMed

    Iwahashi, Kazuhiko; Fukamauchi, Fumihiko; Aoki, Jun; Kurihara, Kouhei; Yoshihara, Eiji; Inoue, Masao; Shibanai, Hiroko; Ishigooka, Jun

    2010-06-01

    During daycare programs of animal assisted therapy (AAT), we collected data on the brain function of two affective disorder patients who received psychotropic drug therapy with fNIRS, after written informed consent was obtained. A male patient at first showed a bloodstream drop, seen in the lower inside part of frontal lobe. In both patients, at least a slight activation of the function of the frontal lobe was seen during the therapy. Therefore, an activation effect of AAT was seen at least objectively by fNIRS.

  11. Can Platforms Affect the Safety and Efficacy of Drug-Eluting Stents in the Era of Biodegradable Polymers?: A Meta-Analysis of 34,850 Randomized Individuals

    PubMed Central

    Zhang, Ming-Duo; Li, Xin-He; Nie, Mao-Xiao; Feng, Ting-Ting; Zhao, Xin; Wang, Lu-Ya; Zhao, Quan-Ming

    2016-01-01

    Objective In the era of bare metal stents (BMSs), alloys have been considered to be better materials for stent design than stainless steel. In the era of biodegradable polymer drug-eluting stents (BP-DESs), the safety and efficacy of BP-DESs with different metal platforms (stainless steel or alloys) have not yet been reported, although their polymers are eventually absorbed, and only the metal platforms remain in the body. This study sought to determine the clinical safety and efficacy of BP-DESs with different platforms compared with other stents (other DESs and BMSs). Methods PubMed, Embase and Clinical Trials.gov were searched for randomized controlled trials (RCTs) that compared BP-DESs with other stents. After performing pooled analysis of BP-DESs and other stents, we performed a subgroup analysis using two classification methods: stent platform and follow-up time. The study characteristics, patient characteristics and clinical outcomes were abstracted. Results Forty RCTs (49 studies) comprising 34,850 patients were included. Biodegradable polymer stainless drug-eluting stents (BP-stainless DESs) were superior to the other stents [mainly stainless drug-eluting stents (DESs)] in terms of pooled definite/probable stent thrombosis (ST) (OR [95% CI] = 0.76[0.61–0.95], p = 0.02), long-term definite/probable ST (OR [95% CI] = 0.73[0.57–0.94], p = 0.01), very late definite/probable ST (OR [95% CI] = 0.56[0.33–0.93], p = 0.03) and long-term definite ST. BP-stainless DESs had lower rates of pooled, mid-term and long-term target vessel revascularization (TVR) and target lesion revascularization (TLR) than the other stainless DESs and BMSs. Furthermore, BP-stainless DESs were associated with lower rates of long-term death than other stainless DESs and lower rates of mid-term myocardial infarction than BMSs. However, only the mid-term and long-term TVR rates were superior in BP-alloy DESs compared with the other stents. Conclusion Our results indirectly suggest that

  12. Sunitinib-ibuprofen drug interaction affects the pharmacokinetics and tissue distribution of sunitinib to brain, liver, and kidney in male and female mice differently.

    PubMed

    Lau, Christine Li Ling; Chan, Sook Tyng; Selvaratanam, Manimegahlai; Khoo, Hui Wen; Lim, Adeline Yi Ling; Modamio, Pilar; Mariño, Eduardo L; Segarra, Ignacio

    2015-08-01

    Tyrosine kinase inhibitor sunitinib (used in GIST, advanced RCC, and pancreatic neuroendocrine tumors) undergoes CYP3A4 metabolism and is an ABCB1B and ABCG2 efflux transporters substrate. We assessed the pharmacokinetic interaction with ibuprofen (an NSAID used by patients with cancer) in Balb/c male and female mice. Mice (study group) were coadministered (30 min apart) 30 mg/kg of ibuprofen and 60 mg/kg of sunitinib PO and compared with the control groups, which received sunitinib alone (60 mg/kg, PO). Sunitinib concentration in plasma, brain, kidney, and liver was measured by HPLC as scheduled and noncompartmental pharmacokinetic parameters estimated. In female control mice, sunitinib AUC0→∞ decreased in plasma (P < 0.05), was higher in liver and brain (P < 0.001), and lower in kidney (P < 0.001) vs. male control mice. After ibuprofen coadministration, female mice showed lower AUC0→∞ in plasma (P < 0.01), brain, liver, and kidney (all P < 0.001). However, in male mice, AUC0→∞ remained unchanged in plasma, increased in liver and kidney, and decreased in brain (all P < 0.001). The tissue-to-plasma AUC0→∞ ratio was similar between male and female control mice, but changed after ibuprofen coadministration: Male mice showed 1.6-fold higher liver-to-plasma ratio (P < 0.001) while remained unchanged in female mice and in kidney (male and female mice) but decreased 55% in brain (P < 0.05). The tissue-to-plasma partial AUC ratio, the drug tissue targeting index, and the tissue-plasma hysteresis-like plots also showed sex-based ibuprofen-sunitinib drug interaction differences. The results illustrate the relevance of this DDI on sunitinib pharmacokinetics and tissue uptake. These may be due to gender-based P450 and efflux/transporters differences.

  13. The miR-27a-calreticulin axis affects drug-induced immunogenic cell death in human colorectal cancer cells

    PubMed Central

    Colangelo, T; Polcaro, G; Ziccardi, P; Muccillo, L; Galgani, M; Pucci, B; Rita Milone, M; Budillon, A; Santopaolo, M; Mazzoccoli, G; Matarese, G; Sabatino, L; Colantuoni, V

    2016-01-01

    Immunogenic cell death (ICD) evoked by chemotherapeutic agents implies emission of selected damage-associated molecular patterns (DAMP) such as cell surface exposure of calreticulin, secretion of ATP and HMGB1. We sought to verify whether miR-27a is implicated in ICD, having demonstrated that it directly targets calreticulin. To this goal, we exposed colorectal cancer cell lines, genetically modified to express high or low miR-27a levels, to two bona fide ICD inducers (mitoxantrone and oxaliplatin). Low miR-27a-expressing cells displayed more ecto-calreticulin on the cell surface and increased ATP and HMGB1 secretion than high miR-27a-expressing ones in time-course experiments upon drug exposure. A calreticulin target protector counteracted the miR-27a effects while specific siRNAs mimicked them, confirming the results reported. In addition, miR-27a negatively influenced the PERK-mediated route and the late PI3K-dependent secretory step of the unfolded protein response to endoplasmic reticulum stress, suggesting that miR-27a modulates the entire ICD program. Interestingly, upon chemotherapeutic exposure, low miR-27a levels associated with an earlier and stronger induction of apoptosis and with morphological and molecular features of autophagy. Remarkably, in ex vivo setting, under the same chemotherapeutic induction, the conditioned media from high miR-27a-expressing cells impeded dendritic cell maturation while increased the secretion of specific cytokines (interleukin (IL)-4, IL-6, IL-8) and negatively influenced CD4+ T-cell interferon γ production and proliferation, all markers of a tumor immunoevasion strategy. In conclusion, we provide the first evidence that miR-27a impairs the cell response to drug-induced ICD through the regulatory axis with calreticulin. PMID:26913599

  14. The miR-27a-calreticulin axis affects drug-induced immunogenic cell death in human colorectal cancer cells.

    PubMed

    Colangelo, T; Polcaro, G; Ziccardi, P; Muccillo, L; Galgani, M; Pucci, B; Milone, M Rita; Budillon, A; Santopaolo, M; Mazzoccoli, G; Matarese, G; Sabatino, L; Colantuoni, V

    2016-01-01

    Immunogenic cell death (ICD) evoked by chemotherapeutic agents implies emission of selected damage-associated molecular patterns (DAMP) such as cell surface exposure of calreticulin, secretion of ATP and HMGB1. We sought to verify whether miR-27a is implicated in ICD, having demonstrated that it directly targets calreticulin. To this goal, we exposed colorectal cancer cell lines, genetically modified to express high or low miR-27a levels, to two bona fide ICD inducers (mitoxantrone and oxaliplatin). Low miR-27a-expressing cells displayed more ecto-calreticulin on the cell surface and increased ATP and HMGB1 secretion than high miR-27a-expressing ones in time-course experiments upon drug exposure. A calreticulin target protector counteracted the miR-27a effects while specific siRNAs mimicked them, confirming the results reported. In addition, miR-27a negatively influenced the PERK-mediated route and the late PI3K-dependent secretory step of the unfolded protein response to endoplasmic reticulum stress, suggesting that miR-27a modulates the entire ICD program. Interestingly, upon chemotherapeutic exposure, low miR-27a levels associated with an earlier and stronger induction of apoptosis and with morphological and molecular features of autophagy. Remarkably, in ex vivo setting, under the same chemotherapeutic induction, the conditioned media from high miR-27a-expressing cells impeded dendritic cell maturation while increased the secretion of specific cytokines (interleukin (IL)-4, IL-6, IL-8) and negatively influenced CD4(+) T-cell interferon γ production and proliferation, all markers of a tumor immunoevasion strategy. In conclusion, we provide the first evidence that miR-27a impairs the cell response to drug-induced ICD through the regulatory axis with calreticulin.

  15. Clinically and pharmacologically relevant interactions of antidiabetic drugs.

    PubMed

    May, Marcus; Schindler, Christoph

    2016-04-01

    Patients with type 2 diabetes mellitus often require multifactorial pharmacological treatment due to different comorbidities. An increasing number of concomitantly taken medications elevate the risk of the patient experiencing adverse drug effects or drug interactions. Drug interactions can be divided into pharmacokinetic and pharmacodynamic interactions affecting cytochrome (CYP) enzymes, absorption properties, transporter activities and receptor affinities. Furthermore, nutrition, herbal supplements, patient's age and gender are of clinical importance. Relevant drug interactions are predominantly related to sulfonylureas, thiazolidinediones and glinides. Although metformin has a very low interaction potential, caution is advised when drugs that impair renal function are used concomitantly. With the exception of saxagliptin, dipeptidyl peptidase-4 (DPP-4) inhibitors also show a low interaction potential, but all drugs affecting the drug transporter P-glycoprotein should be used with caution. Incretin mimetics and sodium-glucose cotransporter-2 (SGLT-2) inhibitors comprise a very low interaction potential and are therefore recommended as an ideal combination partner from the clinical-pharmacologic point of view. PMID:27092232

  16. Clinically and pharmacologically relevant interactions of antidiabetic drugs

    PubMed Central

    May, Marcus; Schindler, Christoph

    2016-01-01

    Patients with type 2 diabetes mellitus often require multifactorial pharmacological treatment due to different comorbidities. An increasing number of concomitantly taken medications elevate the risk of the patient experiencing adverse drug effects or drug interactions. Drug interactions can be divided into pharmacokinetic and pharmacodynamic interactions affecting cytochrome (CYP) enzymes, absorption properties, transporter activities and receptor affinities. Furthermore, nutrition, herbal supplements, patient’s age and gender are of clinical importance. Relevant drug interactions are predominantly related to sulfonylureas, thiazolidinediones and glinides. Although metformin has a very low interaction potential, caution is advised when drugs that impair renal function are used concomitantly. With the exception of saxagliptin, dipeptidyl peptidase-4 (DPP-4) inhibitors also show a low interaction potential, but all drugs affecting the drug transporter P-glycoprotein should be used with caution. Incretin mimetics and sodium–glucose cotransporter-2 (SGLT-2) inhibitors comprise a very low interaction potential and are therefore recommended as an ideal combination partner from the clinical–pharmacologic point of view. PMID:27092232

  17. Exploratory Investigation of the Limiting Steps of Oral Absorption of Fluconazole and Ketoconazole in Children Using an In Silico Pediatric Absorption Model.

    PubMed

    Cristofoletti, Rodrigo; Charoo, Naseem A; Dressman, Jennifer B

    2016-09-01

    Due to the higher total clearance of certain drugs in children than in adults, it is recommended that, in such cases, higher relative doses on a milligram/kilogram basis should be administered to children in order to achieve similar systemic exposure to adults. This is the case for fluconazole and ketoconazole. Even though the lower absorptive surface area and smaller volumes of intestinal fluids in children does not affect fluconazole absorption, cumulative fraction absorbed of ketoconazole seems to be dose dependent. A dose of 200 mg of ketoconazole, which belongs to the class 2a of the Developability Classification System (DCS) in adults, seems to be higher than the maximum absorbable dose in children, and ketoconazole absorption is expected to be solubility limited (i.e., DCS class 2b) in this population, indicating a DCS class migration. Therefore, extrapolating DCS and DCS drug classification from adults to pediatric groups does not seem to be straightforward and the development of specific pediatric classification systems should be a high priority.

  18. Fluid absorption in the isolated midgut of adult female yellow fever mosquitoes (Aedes aegypti).

    PubMed

    Onken, Horst; Moffett, David F

    2015-07-01

    The transepithelial voltage (Vte) and the volume of isolated posterior midguts of adult female yellow fever mosquitoes (Aedes aegypti) were monitored. In all experiments, the initial Vte after filling the midgut was lumen negative, but subsequently became lumen positive at a rate of approximately 1 mV min(-1). Simultaneously, the midgut volume decreased, indicating spontaneous fluid absorption. When the midguts were filled and bathed with mosquito saline, the average rate of fluid absorption was 36.5±3.0 nl min(-1) (N=4, ±s.e.m.). In the presence of theophylline (10 mmol l(-1)), Vte reached significantly higher lumen-positive values, but the rate of fluid absorption was not affected (N=6). In the presence of NaCN (5 mmol l(-1)), Vte remained close to 0 mV (N=4) and fluid absorption was reduced (14.4±1.3 nl min(-1), N=3, ±s.e.m.). When midguts were filled with buffered NaCl (154 mmol l(-1) plus 1 mmol l(-1) HEPES) and bathed in mosquito saline with theophylline, fluid absorption was augmented (50.0±5.8 nl min(-1), N=12, ±s.e.m.). Concanamycin A (10 µmol l(-1)), ouabain (1 mmol l(-1)), and acetazolamide (1 mmol l(-1)) affected Vte in different ways, but all reduced fluid absorption by 60-70% of the value before addition of the drugs.

  19. A national study of clinical and laboratory factors affecting the survival of patients with multiple drug resistant tuberculosis in the UK

    PubMed Central

    Drobniewski, F; Eltringham, I; Graham, C; Magee, J; Smith, E; Watt, B

    2002-01-01

    Background: This study aimed to describe the clinical, microbiological, molecular epidemiology and treatment of multidrug resistant tuberculosis (MDRTB) cases in the UK and to determine factors associated with survival. Methods: Ninety MDRTB cases were identified from 1 January 1996 to 30 June 1997; 69 were DNA fingerprinted. Date of diagnosis was determined and data were collated on key demographic factors, clinical, radiological and treatment details. Variables associated with survival were included in a Cox proportional hazards model. Results: Most of the patients (72.4%) were male, born outside the UK (57.1%), were sputum smear positive (82.2%), and had entered the UK more than 5 years previously (61.9%). Thirty eight of 78 cases (48.7%) had prior TB. Sufficient data on 82 patients were available for survival analysis; 20/27 (74.1%) known to be dead at the end of the observation period had died of tuberculosis. Median survival time overall was 1379 days (95% CI 1336 to 2515) or 3.78 (95% CI 3.66 to 6.89) years (858 days (95% CI 530 to 2515) in immunocompromised individuals (n=32) and 1554 (95% CI 1336 to 2066) days in immunocompetent cases (n=48)). Median survival in patients treated with three drugs to which the bacterium was susceptible on in vitro testing (n=62) was 2066 days (95% CI 1336 to 2515) or 5.66 years, whereas in those not so treated (n=13) survival was 599 days (95% CI 190 to 969) or 1.64 years. Conclusions: Immunocompromised status, failure to culture the bacterium in 30 days or to apply appropriate three drug treatment, and age were significant factors in mortality. An immunocompromised patient was nearly nine times more likely to die, while application of appropriate treatment reduced the risk (risk ratio 0.06). Increasing age was associated with increasing risk of death (risk ratio 2.079; 95% CI 1.269 to 3.402)—that is, for every 10 year increase in age the risk almost doubled. Overall survival was lower than that reported in previous

  20. Absolute bioavailability and effect of formulation change, food, or elevated pH with rabeprazole on cobimetinib absorption in healthy subjects.

    PubMed

    Musib, Luna; Choo, Edna; Deng, Yuzhong; Eppler, Steve; Rooney, Isabelle; Chan, Iris T; Dresser, Mark J

    2013-11-01

    Cobimetinib is a potent and highly selective inhibitor of MEK1/2. Since cobimetinib exhibited absorption variability in cancer patients, a series of single-dose studies in healthy subjects were conducted to determine absolute bioavailability and elucidate potential effects of formulation, food, and elevated gastric pH on cobimetinib bioavailability. Three crossover trials were performed with a 20 mg cobimetinib oral dose: absolute bioavailability using a 2 mg intravenous infusion (n = 13), relative bioavailability of tablets versus capsules and food effect (n = 20), and drug interaction with a proton pump inhibitor (20 mg of rabeprazole daily for 5 days prior to cobimetinib administration; n = 20). Absolute bioavailability of cobimetinib was 46.2% (24.2, CV %), likely due to metabolism rather than incomplete absorption. The mean systemic clearance of cobimetinib was low (11.7 L/h [28.2, CV %]). Administration of cobimetinib tablets with a high-fat meal delayed drug absorption (prolonged tmax) but had no statistically significant effect on cobimetinib exposure (Cmax and AUC0-∞). Tablet and capsule formulations of cobimetinib showed comparable exposures. Cobimetinib exhibited delayed absorption (tmax) in the presence of rabeprazole, with no statistically significant effects on drug exposure (Cmax and AUC0-∞) in the fasted state. In conclusion, cobimetinib oral absorption was not affected by change in formulation, food, or elevated gastric pH.

  1. How Illegal Drug Use, Alcohol Use, Tobacco Use, and Depressive Symptoms Affect Adolescent Suicidal Ideation: A Secondary Analysis of the 2011 Youth Risk Behavior Survey.

    PubMed

    Gart, Rachel; Kelly, Sarah

    2015-08-01

    The purpose of this study was to identify the major risk factors among adolescents who have either contemplated or attempted suicide. Along with successful suicides, suicide attempts and contemplation are coexisting factors that are prominent in the adolescent population and therefore warrant major concern. A secondary data analysis of the Youth Risk Behavior Survey (YRBS) was completed to explore the factors that may influence adolescents' thoughts or actions about suicidal behavior. The YRBS represents high-school students throughout 50 states. Nine questions from the YRBS were used to elicit information about the relationships among the risk factors: (1) Suicidal thoughts and attempts; (2) illegal drug use; (3) alcohol use; (4) tobacco use; and (5) depressive symptoms. Statistically significant relationships among the risk factors were found for adolescents. Adolescents considered suicide (15.8%); attempted suicide at least once (7.8%); were injured while attempting suicide (n = 2.7%). Our findings support the idea that illegal substance use can lead to suicidal thoughts and actions. Depression had a positive relationship with suicidal ideations, supporting similar studies suggesting that depression leads to suicidal action. PMID:26379135

  2. Factors affecting the response to inhibition of drug metabolism by cimetidine--dose response and sensitivity of elderly and induced subjects.

    PubMed Central

    Feely, J; Pereira, L; Guy, E; Hockings, N

    1984-01-01

    The effect of cimetidine on oxidative drug metabolism was characterised using antipyrine clearance in a group of healthy volunteers. In six subjects cimetidine produced a dose dependent reduction of antipyrine clearance: 400 mg/day (16.8 +/- 2.2%, mean +/- s.e. mean), 800 mg/day (26.3 +/- 1.5%) and 1600 mg/day (33.5 +/- 2.4%). The effect of cimetidine (800 mg/day) was of similar magnitude (approximately 25%) in two groups of six young (21-26 years) and six elderly (65-78 years) subjects. The effect of pretreatment begun just 1 h before administration of antipyrine was similar to that of 24 h pretreatment and that reported for chronic cimetidine pretreatment. The percentage reduction in antipyrine clearance produced by cimetidine 800 mg/day was greater (44 +/- 5 vs 24 +/- 3%; P less than 0.05) in six subjects who had been pretreated with the hepatic enzyme inducer rifampicin (600 mg/day for 21 days) than in the control uninduced state. Although cimetidine was capable of rapidly reversing the effect of rifampicin on antipyrine clearance, following withdrawal of both rifampicin and cimetidine there was still evidence of enzyme induction. These results suggest that the effect of cimetidine on oxidative metabolism is dose dependent, is more marked in enzyme induced subjects, is independent of the duration of pretreatment and is of similar magnitude in young and elderly subjects. PMID:6691891

  3. Are major reductions in new HIV infections possible with people who inject drugs? The case for low dead-space syringes in highly affected countries.

    PubMed

    Zule, William A; Cross, Harry E; Stover, John; Pretorius, Carel

    2013-01-01

    Circumstantial evidence from laboratory studies, mathematical models, ecological studies and bio behavioural surveys, suggests that injection-related HIV epidemics may be averted or reversed if people who inject drugs (PWID) switch from using high dead-space to using low dead-space syringes. In laboratory experiments that simulated the injection process and rinsing with water, low dead space syringes retained 1000 times less blood than high dead space syringes. In mathematical models, switching PWID from high dead space to low dead space syringes prevents or reverses injection-related HIV epidemics. No one knows if such an intervention is feasible or what effect it would have on HIV transmission among PWID. Feasibility studies and randomized controlled trials (RCTs) will be needed to answer these questions definitively, but these studies will be very expensive and take years to complete. Rather than waiting for them to be completed, we argue for an approach similar to that used with needle and syringe programs (NSP), which were promoted and implemented before being tested more rigorously. Before implementation, rapid assessments that involve PWID will need to be conducted to ensure buy-in from PWID and other local stakeholders. This commentary summarizes the existing evidence regarding the protective effects of low dead space syringes and estimates potential impacts on HIV transmission; it describes potential barriers to transitioning PWID from high dead space to low dead space needles and syringes; and it presents strategies for overcoming these barriers.

  4. Solar absorption surface panel

    DOEpatents

    Santala, Teuvo J.

    1978-01-01

    A composite metal of aluminum and nickel is used to form an economical solar absorption surface for a collector plate wherein an intermetallic compound of the aluminum and nickel provides a surface morphology with high absorptance and relatively low infrared emittance along with good durability.

  5. Drug hypersensitivity syndrome with significant gastrointestinal involvement.

    PubMed

    Chung, Wan-Ling; Teo, Lynn; Wang, Yi-Shi; Liu, Tsun-Tsien

    2012-11-01

    Drug hypersensitivity syndrome (DHS) is an idiosyncratic systemic reaction to a drug. The clinical presentation of this syndrome comprises a diverse spectrum, ranging from mild to fulminating organ failure. Nonspecific gastrointestinal symptoms are common in DHS, but severe morbidities and mortalities attributed to gut disease in DHS are rarely described. We present a case of DHS with significant gastrointestinal symptoms of prolonged profuse watery diarrhoea and persistent hypokalaemia requiring judicious intravenous water and electrolyte replacement. The symptoms resolved only after the introduction of intravenous hydrocortisone. It is important to consider intravenous corticosteroids if the gastrointestinal system is involved, as accelerated gut motility and mucosal damage would affect absorption of oral medications. Supportive treatment with the monitoring of fluid and electrolytes status and judicious replacement remains fundamental in the management of DHS patients with gut involvement.

  6. Mouse ECG findings in aging, with conduction system affecting drugs and in cardiac pathologies: Development and validation of ECG analysis algorithm in mice.

    PubMed

    Merentie, Mari; Lipponen, Jukka A; Hedman, Marja; Hedman, Antti; Hartikainen, Juha; Huusko, Jenni; Lottonen-Raikaslehto, Line; Parviainen, Viktor; Laidinen, Svetlana; Karjalainen, Pasi A; Ylä-Herttuala, Seppo

    2015-12-01

    Mouse models are extremely important in studying cardiac pathologies and related electrophysiology, but very few mouse ECG analysis programs are readily available. Therefore, a mouse ECG analysis algorithm was developed and validated. Surface ECG (lead II) was acquired during transthoracic echocardiography from C57Bl/6J mice under isoflurane anesthesia. The effect of aging was studied in young (2-3 months), middle-aged (14 months) and old (20-24 months) mice. The ECG changes associated with pharmacological interventions and common cardiac pathologies, that is, acute myocardial infarction (AMI) and progressive left ventricular hypertrophy (LVH), were studied. The ECG raw data were analyzed with an in-house ECG analysis program, modified specially for mouse ECG. Aging led to increases in P-wave duration, atrioventricular conduction time (PQ interval), and intraventricular conduction time (QRS complex width), while the R-wave amplitude decreased. In addition, the prevalence of arrhythmias increased during aging. Anticholinergic atropine shortened PQ time, and beta blocker metoprolol and calcium-channel blocker verapamil increased PQ interval and decreased heart rate. The ECG changes after AMI included early JT elevation, development of Q waves, decreased R-wave amplitude, and later changes in JT/T segment. In progressive LVH model, QRS complex width was increased at 2 and especially 4 weeks timepoint, and also repolarization abnormalities were seen. Aging, drugs, AMI, and LVH led to similar ECG changes in mice as seen in humans, which could be reliably detected with this new algorithm. The developed method will be very useful for studies on cardiovascular diseases in mice.

  7. The VMAT-2 inhibitor tetrabenazine affects effort-related decision making in a progressive ratio/chow feeding choice task: reversal with antidepressant drugs.

    PubMed

    Randall, Patrick A; Lee, Christie A; Nunes, Eric J; Yohn, Samantha E; Nowak, Victoria; Khan, Bilal; Shah, Priya; Pandit, Saagar; Vemuri, V Kiran; Makriyannis, Alex; Baqi, Younis; Müller, Christa E; Correa, Merce; Salamone, John D

    2014-01-01

    Behavioral activation is a fundamental feature of motivation, and organisms frequently make effort-related decisions based upon evaluations of reinforcement value and response costs. Furthermore, people with major depression and other disorders often show anergia, psychomotor retardation, fatigue, and alterations in effort-related decision making. Tasks measuring effort-based decision making can be used as animal models of the motivational symptoms of depression, and the present studies characterized the effort-related effects of the vesicular monoamine transport (VMAT-2) inhibitor tetrabenazine. Tetrabenazine induces depressive symptoms in humans, and also preferentially depletes dopamine (DA). Rats were assessed using a concurrent progressive ratio (PROG)/chow feeding task, in which they can either lever press on a PROG schedule for preferred high-carbohydrate food, or approach and consume a less-preferred lab chow that is freely available in the chamber. Previous work has shown that the DA antagonist haloperidol reduced PROG work output on this task, but did not reduce chow intake, effects that differed substantially from those of reinforcer devaluation or appetite suppressant drugs. The present work demonstrated that tetrabenazine produced an effort-related shift in responding on the PROG/chow procedure, reducing lever presses, highest ratio achieved and time spent responding, but not reducing chow intake. Similar effects were produced by administration of the subtype selective DA antagonists ecopipam (D1) and eticlopride (D2), but not by the cannabinoid CB1 receptor neutral antagonist and putative appetite suppressant AM 4413, which suppressed both lever pressing and chow intake. The adenosine A2A antagonist MSX-3, the antidepressant and catecholamine uptake inhibitor bupropion, and the MAO-B inhibitor deprenyl, all reversed the impairments induced by tetrabenazine. This work demonstrates the potential utility of the PROG/chow procedure as a rodent model of

  8. A population pharmacokinetic model for the complex systemic absorption of ropivacaine after femoral nerve block in patients undergoing knee surgery.

    PubMed

    Gaudreault, François; Drolet, Pierre; Fallaha, Michel; Varin, France

    2012-12-01

    Because of its slow systemic absorption and flip-flop kinetics, ropivacaine's pharmacokinetics after a peripheral nerve block has never been thoroughly characterized. The purpose of this study was to develop a population pharmacokinetic model for ropivacaine after loco-regional administration and to identify patient characteristics that may influence the drug's absorption and disposition. Frequent plasma samples were taken up to 93 h after a 100 mg dose given as femoral block for postoperative analgesia in 15 orthopedic patients. Ropivacaine plasma concentration-time data were analyzed using a nonlinear mixed effects modeling method. A one-compartment model with parallel inverse Gaussian and time-dependent inputs best described ropivacaine plasma concentration-time curves. Ropivacaine systemic absorption was characterized by a rapid phase (mean absorption time of 25 ± 4.8 min) followed by a much slower phase (half-life of 3.9 ± 0.65 h). Interindividual variability (IIV) for these parameters, 58 and 9 %, indicated that the initial absorption phase was more variable. The apparent volume of distribution (V/F = 77.2 ± 11.5 L, IIV = 26 %) was influenced by body weight (Δ 1.49 % per kg change) whereas the absorption rate constant (slower phase) of ropivacaine was affected by age (Δ 2.25 % per year change). No covariate effects were identified for the apparent clearance of the drug (CL/F =10.8 ± 1.0 L/h, 34  IIV = 34 %). These findings support our hypothesis that modeling a complex systemic absorption directly from plasma concentration-time curves exhibiting flip-flop kinetics is possible. Only the age-effect was considered as relevant for possible dosing adjustments.

  9. Polarization control of intermediate state absorption in resonance-mediated multi-photon absorption process

    NASA Astrophysics Data System (ADS)

    Xu, Shuwu; Huang, Yunxia; Yao, Yunhua; Jia, Tianqing; Ding, Jingxin; Zhang, Shian; Sun, Zhenrong

    2015-07-01

    We theoretically and experimentally demonstrate the control of the intermediate state absorption in an (n + m) resonance-mediated multi-photon absorption process by the polarization-modulated femtosecond laser pulse. An analytical solution of the intermediate state absorption in a resonance-mediated multi-photon absorption process is obtained based on the time-dependent perturbation theory. Our theoretical results show that the control efficiency of the intermediate state absorption by the polarization modulation is independent of the laser intensity when the transition from the intermediate state to the final state is coupled by the single-photon absorption, but will be affected by the laser intensity when this transition is coupled by the non-resonant multi-photon absorption. These theoretical results are experimentally confirmed via a two-photon fluorescence control in (2 + 1) resonance-mediated three-photon absorption of Coumarin 480 dye and a single-photon fluorescence control in (1 + 2) resonance-mediated three-photon absorption of IR 125 dye.

  10. Attitudes towards drug legalization among drug users.

    PubMed

    Trevino, Roberto A; Richard, Alan J

    2002-01-01

    Research shows that support for legalization of drugs varies significantly among different sociodemographic and political groups. Yet there is little research examining the degree of support for legalization of drugs among drug users. This paper examines how frequency and type of drug use affect the support for legalization of drugs after adjusting for the effects of political affiliation and sociodemographic characteristics. A sample of 188 drug users and non-drug users were asked whether they would support the legalization of marijuana, cocaine, and heroin. Respondents reported their use of marijuana, crack, cocaine, heroin, speedball, and/or methamphetamines during the previous 30 days. Support for legalization of drugs was analyzed by estimating three separate logistic regressions. The results showed that the support for the legalization of drugs depended on the definition of "drug user" and the type of drug. In general, however, the results showed that marijuana users were more likely to support legalizing marijuana, but they were less likely to support the legalization of cocaine and heroin. On the other hand, users of crack, cocaine, heroin, speedball, and/or methamphetamines were more likely to support legalizing all drugs including cocaine and heroin.

  11. Quasar Absorption Studies

    NASA Technical Reports Server (NTRS)

    Mushotzky, Richard (Technical Monitor); Elvis, Martin

    2004-01-01

    The aim of the proposal is to investigate the absorption properties of a sample of inter-mediate redshift quasars. The main goals of the project are: Measure the redshift and the column density of the X-ray absorbers; test the correlation between absorption and redshift suggested by ROSAT and ASCA data; constrain the absorber ionization status and metallicity; constrain the absorber dust content and composition through the comparison between the amount of X-ray absorption and optical dust extinction. Unanticipated low energy cut-offs where discovered in ROSAT spectra of quasars and confirmed by ASCA, BeppoSAX and Chandra. In most cases it was not possible to constrain adequately the redshift of the absorber from the X-ray data alone. Two possibilities remain open: a) absorption at the quasar redshift; and b) intervening absorption. The evidences in favour of intrinsic absorption are all indirect. Sensitive XMM observations can discriminate between these different scenarios. If the absorption is at the quasar redshift we can study whether the quasar environment evolves with the Cosmic time.

  12. Model predicting impact of complexation with cyclodextrins on oral absorption.

    PubMed

    Gamsiz, Ece D; Thombre, Avinash G; Ahmed, Imran; Carrier, Rebecca L

    2013-09-01

    Significant effort and resource expenditure is dedicated to enabling low-solubility oral drug delivery using solubilization technologies. Cyclodextrins (CD) are cyclic oligosaccharides which form inclusion complexes with many drugs and are often used as solubilizing agents. It is not clear prior to developing a drug delivery device with CD what level of absorption enhancement might be achieved; modeling can provide useful guidance in formulation and minimize resource intensive iterative formulation development. A model was developed to enable quantitative, dynamic prediction of the influence of CD on oral absorption of low solubility drug administered as a pre-formed complex. The predominant effects of CD considered were enhancement of dissolution and slowing of precipitation kinetics, as well as binding of free drug in solution. Simulation results with different parameter values reflective of typical drug and CD properties indicate a potential positive (up to five times increase in drug absorption), negative (up to 50% decrease in absorption) or lack of effect of CD. Comparison of model predictions with in vitro and in vivo experimental results indicate that a systems-based dynamic model incorporating CD complexation and key process kinetics may enable quantitative prediction of impact of CD delivered as a pre-formed complex on drug bioavailability.

  13. Finasteride. Does it affect spermatogenesis and pregnancy?

    PubMed Central

    Pole, M.; Koren, G.

    2001-01-01

    QUESTION: A few women have asked me whether finasteride, taken by their partners for male pattern baldness, will affect their pregnancies. The product monograph is very alarming: it sounds as if even handling the medication could cause harm, especially to a male fetus. Should a man stop taking finasteride if his partner is planning pregnancy or is pregnant? What is the risk to the fetus if its mother accidentally handles crushed or broken tablets? ANSWER: To date, there are no reports of adverse pregnancy outcomes among women exposed to finasteride. Taking 1 mg of finasteride daily did not have any clinically significant effect on men's semen. Absorption through the skin while handling tablets is extremely unlikely to cause fetal exposure or harm. There is no reason to discontinue the drug. Motherisk is currently following up women who are pregnant or planning pregnancy and whose partners are taking finasteride. PMID:11785276

  14. Club Drugs

    MedlinePlus

    ... Rohypnol, ketamine, as well as MDMA (ecstasy) and methamphetamine ( Drug Facts: Club Drugs , National Institute on Drug ... Club Drugs , National Institute on Drug Abuse, 2010). Methamphetamine is a powerfully addictive stimulant associated with serious ...

  15. Antiviral drug vidarabine possessing cardiac type 5 adenylyl cyclase inhibitory property did not affect cardiohemodynamic or electrophysiological variables in the halothane-anesthetized dogs.

    PubMed

    Wada, Takeshi; Nakamura, Yuji; Cao, Xin; Ohara, Hiroshi; Izumi-Nakaseko, Hiroko; Ando, Kentaro; Nakazato, Yuji; Sugiyama, Atsushi

    2016-02-01

    Vidarabine has been used for the treatment of patients with local and systemic herpes virus infection; moreover, it was recently reported that it inhibits cardiac type 5 adenylyl cyclase. Furthermore, vidarabine has been shown to suppress atrial fibrillation and improve congestive heart failure in experimental models of mice induced by the isoproterenol infusion. Since information that can explain its experimentally demonstrated efficacy against congestive heart failure and atrial fibrillation remains limited, in this study we precisely assessed cardio-electropharmacological effect using the halothane-anesthetized canine model. Vidarabine was intravenously administrated in three escalating doses of 1, 10, 100 mg/kg over 10 min with a pause between the doses (n = 4). Meanwhile, the vehicle dimethyl sulfoxide in volumes of 0.033, 0.033 and 0.33 mL/kg was intravenously administrated in the same manner as was vidarabine (n = 4). No significant difference was detected in any cardiohemodynamic or electrophysiological variables between the vehicle- and vidarabine-treated groups, which indicates that effective doses of vidarabine adequately inhibiting type 5 adenylyl cyclase did not affect the cardiovascular variables in vivo at all, showing its cardiac safety profile under physiological condition. Thus, the clinical utility of vidarabine might be limited to the pathological situation including congestive heart failure with increased adrenergic tone and/or sympathetic nerve-dependent atrial fibrillation. PMID:26763398

  16. Drug-drug interactions between moxifloxacin and rifampicin based on pharmacokinetics in vivo in rats.

    PubMed

    Huang, Lifei; Liu, Jiajun; Yu, Xin; Shi, Lei; Liu, Jian; Xiao, Heping; Huang, Yi

    2016-10-01

    , the Caco-2 cell transwell experiment showed that moxifloxacin could not affect the absorption rate of rifampicin. These changes could enhance the drug efficacy, but they could also cause drug accumulation, which might induce adverse effect, so it was suggested that the drug dosage should be adjusted and the drug concentration in plasma should be monitored if moxifloxacin and rifampicin are co-administered. Copyright © 2016 John Wiley & Sons, Ltd.

  17. In Vivo Formation of Cubic Phase in Situ after Oral Administration of Cubic Phase Precursor Formulation Provides Long Duration Gastric Retention and Absorption for Poorly Water-Soluble Drugs.

    PubMed

    Pham, Anna C; Hong, Linda; Montagnat, Oliver; Nowell, Cameron J; Nguyen, Tri-Hung; Boyd, Ben J

    2016-01-01

    Lipid-based liquid crystalline systems based on the combination of digestible and nondigestible lipids have been proposed as potential sustained release delivery systems for oral delivery of poorly water-soluble drugs. The potential for cubic phase liquid crystal formation to induce dramatically extended gastric retention in vivo has been shown previously to strongly influence the resulting pharmacokinetics of incorporated drug. In vitro studies showing the in situ formation of cubic phase from a disordered precursor comprising a mixture of digestible and nondigestible lipids under enzymatic digestion have also recently been reported. Combining both concepts, here we show the potential for such systems to form in vivo, increasing gastric retention, and providing a sustained release effect for a model poorly water-soluble drug cinnarizine. A mixture of phytantriol and tributyrin at an 85:15 mass ratio, shown previously to form cubic phase under the influence of digestion, induced a similar pharmacokinetic profile to that in the absence of tributyrin, but completely different from tributyrin alone. The gastric retention of the formulation, assessed using micro-X-ray CT imaging, was also consistent with the pharmacokinetic behavior, where phytantriol alone and with 15% tributyrin was greater than that of tributyrin in the absence of phytantriol. Thus, the concept of precursor lipid systems that form cubic phase in situ during digestion in vivo has been demonstrated and opens new opportunities for sustained release of poorly water-soluble drugs.

  18. Evidence for a common biological basis of the Absorption trait, hallucinogen effects, and positive symptoms: epistasis between 5-HT2a and COMT polymorphisms.

    PubMed

    Ott, Ulrich; Reuter, Martin; Hennig, Juergen; Vaitl, Dieter

    2005-08-01

    Absorption represents a disposition to experience altered states of consciousness characterized by intensively focused attention. It is correlated with hypnotic susceptibility and includes phenomena ranging from vivid perceptions and imaginations to mystical experiences. Based on the assumption that drug-induced and naturally occurring mystical experiences share common neural mechanisms, we hypothesized that Absorption is influenced by the T102C polymorphism affecting the 5-HT2a receptor, which is known to be an important target site of hallucinogens like LSD. Based on the pivotal role ascribed to the prefrontal executive control network for absorbed attention and positive symptoms in schizophrenia, it was further hypothesized that Absorption is associated with the VAL158MET polymorphism of the catechol-O-methyltransferase (COMT) gene affecting the dopaminergic neurotransmitter system. The Tellegen Absorption Scale was administered to 336 subjects (95 male, 241 female). Statistical analysis revealed that the group with the T/T genotype of the T102C polymorphism, implying a stronger binding potential of the 5-HT2a receptor, indeed had significantly higher Absorption scores (F = 10.00, P = 0.002), while no main effect was found for the COMT polymorphism. However, the interaction between T102C and COMT genotypes yielded significance (F = 3.89; P = 0.049), underlining the known functional interaction between the 5-HT and the dopaminergic system. These findings point to biological foundations of the personality trait of Absorption.

  19. Drug delivery to the nail following topical application.

    PubMed

    Murdan, Sudaxshina

    2002-04-01

    The absorption of drugs into the nail unit, following topical application to the nail plate, is highly desirable to treat nail disorders, such as onychomycosis (fungal infections of the nail). Nail permeability is however quite low and limits topical therapy to early/mild disease states. In this paper, the recent research into ungual drug delivery is reviewed. The nail unit and the two most common diseases affecting the nail--onychomycosis and nail psoriasis--are briefly described to set the scene and to give an overview of the nature and scope of the problem. The factors, which affect drug uptake and permeation through the nail plate such as solute molecular size, hydrophilicity/hydrophobicity, charge, and the nature of the vehicle, are then discussed, followed by ways of enhancing drug transport into and through the nail plate. Finally, drug-containing nail lacquers which, like cosmetic varnish, are brushed onto the nail plates to form a film, and from which drug is released and penetrates into the nail, are reviewed.

  20. Absorption heat pump system

    DOEpatents

    Grossman, G.

    1982-06-16

    The efficiency of an absorption heat pump system is improved by conducting liquid from a second stage evaporator thereof to an auxiliary heat exchanger positioned downstream of a primary heat exchanger in the desorber of the system.

  1. Absorption heat pump system

    DOEpatents

    Grossman, Gershon

    1984-01-01

    The efficiency of an absorption heat pump system is improved by conducting liquid from a second stage evaporator thereof to an auxiliary heat exchanger positioned downstream of a primary heat exchanger in the desorber of the system.

  2. Caveolin-1 affects tumor drug resistance in esophageal squamous cell carcinoma by regulating expressions of P-gp and MRP1.

    PubMed

    Zhang, Song; Cao, Wenbo; Yue, Mingjin; Zheng, Naigang; Hu, Tao; Yang, Shengli; Dong, Ziming; Lu, Shixin; Mo, Saijun

    2016-07-01

    Esophageal squamous cell carcinoma (ESCC) is the most common cancer in China, and multidrug resistance (MDR) remains one of the biggest problems in ESCC chemotherapy. In this study, we aimed to investigate the mechanism of Caveolin-1, an integral membrane protein, on regulating ESCC MDR. First, immunohistochemistry was used to check the protein expression of Caveolin-1, MDR-related protein of P-glycoprotein (P-gp), and multidrug resistance protein 1 (MRP1) in 84 pathologically characterized ESCC tissues, matched adjacent tumor, and adjacent normal-looking tissues. The results showed that Caveolin-1 expression level was elevated in ESCC tissues than that of matched adjacent tumor and adjacent normal-looking tissues (P < 0.05), and the expression of Caveolin-1 has close correlation with P-gp and MRP1 during tumor genesis of ESCC (P = 0.034, P = 0.009, respectively). Then, Caveolin-1 overexpression and knockdown were used to investigate its effect on expressions of P-gp and MRP1 in ESCC cell line Ec9706. The messenger RNA (mRNA) and protein expression levels of P-gp and MRP1 were checked by real-time quantitative reverse transcription-PCR (qRT-PCR) and Western blot (WB). The results showed that Caveolin-1 overexpression significantly promotes the mRNA and protein expression of MRP1 (P < 0.05), while almost has no effect on the mRNA and protein expression of P-gp (P > 0.05); Cavoelin-1 knockdown inhibits the mRNA and protein expressions of both P-gp and MRP1 (P < 0.05). The similar result was found in another ESCC cell line Eca109. So, it is concluded that Caveolin-1 affects ESCC MDR by regulating the expressions of P-gp and MRP1; therefore, it can be taken as a significant marker and target in tumor therapy.

  3. Solar selective absorption coatings

    DOEpatents

    Mahoney, Alan R.; Reed, Scott T.; Ashley, Carol S.; Martinez, F. Edward

    2004-08-31

    A new class of solar selective absorption coatings are disclosed. These coatings comprise a structured metallic overlayer such that the overlayer has a sub-micron structure designed to efficiently absorb solar radiation, while retaining low thermal emissivity for infrared thermal radiation. A sol-gel layer protects the structured metallic overlayer from mechanical, thermal, and environmental degradation. Processes for producing such solar selective absorption coatings are also disclosed.

  4. Solar selective absorption coatings

    DOEpatents

    Mahoney, Alan R.; Reed, Scott T.; Ashley, Carol S.; Martinez, F. Edward

    2003-10-14

    A new class of solar selective absorption coatings are disclosed. These coatings comprise a structured metallic overlayer such that the overlayer has a sub-micron structure designed to efficiently absorb solar radiation, while retaining low thermal emissivity for infrared thermal radiation. A sol-gel layer protects the structured metallic overlayer from mechanical, thermal, and environmental degradation. Processes for producing such solar selective absorption coatings are also disclosed.

  5. Optical absorption measurement system

    DOEpatents

    Draggoo, Vaughn G.; Morton, Richard G.; Sawicki, Richard H.; Bissinger, Horst D.

    1989-01-01

    The system of the present invention contemplates a non-intrusive method for measuring the temperature rise of optical elements under high laser power optical loading to determine the absorption coefficient. The method comprises irradiating the optical element with a high average power laser beam, viewing the optical element with an infrared camera to determine the temperature across the optical element and calculating the absorption of the optical element from the temperature.

  6. 21 CFR 862.2850 - Atomic absorption spectrophotometer for clinical use.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Atomic absorption spectrophotometer for clinical... Laboratory Instruments § 862.2850 Atomic absorption spectrophotometer for clinical use. (a) Identification. An atomic absorption spectrophotometer for clinical use is a device intended to identify and...

  7. 21 CFR 862.2850 - Atomic absorption spectrophotometer for clinical use.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Atomic absorption spectrophotometer for clinical... Laboratory Instruments § 862.2850 Atomic absorption spectrophotometer for clinical use. (a) Identification. An atomic absorption spectrophotometer for clinical use is a device intended to identify and...

  8. 21 CFR 862.2850 - Atomic absorption spectrophotometer for clinical use.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Atomic absorption spectrophotometer for clinical... Laboratory Instruments § 862.2850 Atomic absorption spectrophotometer for clinical use. (a) Identification. An atomic absorption spectrophotometer for clinical use is a device intended to identify and...

  9. Introduction to computational oral absorption simulation.

    PubMed

    Sugano, Kiyohiko

    2009-03-01

    Computational oral absorption simulation (COAS) is anticipated to be a powerful tool in improving the productivity of drug discovery and development. This article reviews the theories of pharmaceutical sciences that consist of COAS. Although most of these theories are classical, they are revisited from the context of modern drug discovery and development. The theories of solubility, diffusion, dissolution, precipitation, intestinal membrane permeation and gastrointestinal transit are comprehensively described. Prediction strategy is then discussed based on the biopharmaceutical classification system. In the final part, good simulation practice is proposed and many frequently asked questions answered.

  10. ORAL ADVERSE DRUG REACTIONS TO CARDIOVASCULAR DRUGS.

    PubMed

    Torpet, Lis Andersen; Kragelund, Camilla; Reibel, Jesper; Nauntofte, Birgitte

    2004-01-01

    A great many cardiovascular drugs (CVDs) have the potential to induce adverse reactions in the mouth. The prevalence of such reactions is not known, however, since many are asymptomatic and therefore are believed to go unreported. As more drugs are marketed and the population includes an increasing number of elderly, the number of drug prescriptions is also expected to increase. Accordingly, it can be predicted that the occurrence of adverse drug reactions (ADRs), including the oral ones (ODRs), will continue to increase. ODRs affect the oral mucous membrane, saliva production, and taste. The pathogenesis of these reactions, especially the mucosal ones, is largely unknown and appears to involve complex interactions among the drug in question, other medications, the patient's underlying disease, genetics, and life-style factors. Along this line, there is a growing interest in the association between pharmacogenetic polymorphism and ADRs. Research focusing on polymorphism of the cytochrome P450 system (CYPs) has become increasingly important and has highlighted the intra- and inter-individual responses to drug exposure. This system has recently been suggested to be an underlying candidate regarding the pathogenesis of ADRs in the oral mucous membrane. This review focuses on those CVDs reported to induce ODRs. In addition, it will provide data on specific drugs or drug classes, and outline and discuss recent research on possible mechanisms linking ADRs to drug metabolism patterns. Abbreviations used will be as follows: ACEI, ACE inhibitor; ADR, adverse drug reaction; ANA, antinuclear antigen; ARB, angiotensin II receptor blocker; BAB, beta-adrenergic blocker; CCB, calcium-channel blocker; CDR, cutaneous drug reaction; CVD, cardiovascular drug; CYP, cytochrome P450 enzyme; EM, erythema multiforme; FDE, fixed drug eruption; I, inhibitor of CYP isoform activity; HMG-CoA, hydroxymethyl-glutaryl coenzyme A; NAT, N-acetyltransferase; ODR, oral drug reaction; RDM, reactive

  11. Food-Drug Interactions

    PubMed Central

    Bushra, Rabia; Aslam, Nousheen; Khan, Arshad Yar

    2011-01-01

    The effect of drug on a person may be different than expected because that drug interacts with another drug the person is taking (drug-drug interaction), food, beverages, dietary supplements the person is consuming (drug-nutrient/food interaction) or another disease the person has (drug-disease interaction). A drug interaction is a situation in which a substance affects the activity of a drug, i.e. the effects are increased or decreased, or they produce a new effect that neither produces on its own. These interactions may occur out of accidental misuse or due to lack of knowledge about the active ingredients involved in the relevant substances. Regarding food-drug interactions physicians and pharmacists recognize that some foods and drugs, when taken simultaneously, can alter the body's ability to utilize a particular food or drug, or cause serious side effects. Clinically significant drug interactions, which pose potential harm to the patient, may result from changes in pharmaceutical, pharmacokinetic, or pharmacodynamic properties. Some may be taken advantage of, to the benefit of patients, but more commonly drug interactions result in adverse drug events. Therefore it is advisable for patients to follow the physician and doctors instructions to obtain maximum benefits with least food-drug interactions. The literature survey was conducted by extracting data from different review and original articles on general or specific drug interactions with food. This review gives information about various interactions between different foods and drugs and will help physicians and pharmacists prescribe drugs cautiously with only suitable food supplement to get maximum benefit for the patient. PMID:22043389

  12. Nasal Absorption of Macromolecules from Powder Formulations and Effects of Sodium Carboxymethyl Cellulose on Their Absorption.

    PubMed

    Tanaka, Akiko; Furubayashi, Tomoyuki; Matsushita, Akifumi; Inoue, Daisuke; Kimura, Shunsuke; Katsumi, Hidemasa; Sakane, Toshiyasu; Yamamoto, Akira

    2016-01-01

    The nasal absorption of macromolecules from powder formulations and the effect of sodium carboxymethyl cellulose (CMC-Na) as a pharmaceutical excipient on their absorption were studied. Model macromolecules were fluorescein isothiocyanate-labeled dextran (average molecular weight of 4.4kDa, FD4) and insulin. The plasma concentration of FD4 after application of the powder containing 50% starch (control) was higher than that after application of the solution, and the absorption from 50% starch powder was enhanced by the substitution of starch with CMC-Na. The fractional absorption of FD4 after administration of the CMC-Na powder formulation was 30% and 40% higher than that after administration from the solution and the starch powder, respectively. The nasal absorption of insulin from the powder and the effect of CMC-Na were similar with those of FD4. The effective absorption of FD4 and insulin after application of powder with CMC-Na could be due to the increase in the nasal residence of FD4 and insulin. No damage in the nasal mucosa or dysfunction of the mucociliary clearance was observed after application of the drug powder and CMC-Na. The present findings indicate that nasal delivery of powder formulations with the addition of CMC-Na as an excipient is a promising approach for improving the nasal absorption of macromolecules. PMID:27598527

  13. Nasal Absorption of Macromolecules from Powder Formulations and Effects of Sodium Carboxymethyl Cellulose on Their Absorption.

    PubMed

    Tanaka, Akiko; Furubayashi, Tomoyuki; Matsushita, Akifumi; Inoue, Daisuke; Kimura, Shunsuke; Katsumi, Hidemasa; Sakane, Toshiyasu; Yamamoto, Akira

    2016-01-01

    The nasal absorption of macromolecules from powder formulations and the effect of sodium carboxymethyl cellulose (CMC-Na) as a pharmaceutical excipient on their absorption were studied. Model macromolecules were fluorescein isothiocyanate-labeled dextran (average molecular weight of 4.4kDa, FD4) and insulin. The plasma concentration of FD4 after application of the powder containing 50% starch (control) was higher than that after application of the solution, and the absorption from 50% starch powder was enhanced by the substitution of starch with CMC-Na. The fractional absorption of FD4 after administration of the CMC-Na powder formulation was 30% and 40% higher than that after administration from the solution and the starch powder, respectively. The nasal absorption of insulin from the powder and the effect of CMC-Na were similar with those of FD4. The effective absorption of FD4 and insulin after application of powder with CMC-Na could be due to the increase in the nasal residence of FD4 and insulin. No damage in the nasal mucosa or dysfunction of the mucociliary clearance was observed after application of the drug powder and CMC-Na. The present findings indicate that nasal delivery of powder formulations with the addition of CMC-Na as an excipient is a promising approach for improving the nasal absorption of macromolecules.

  14. Nasal Absorption of Macromolecules from Powder Formulations and Effects of Sodium Carboxymethyl Cellulose on Their Absorption

    PubMed Central

    Tanaka, Akiko; Furubayashi, Tomoyuki; Matsushita, Akifumi; Inoue, Daisuke; Kimura, Shunsuke; Katsumi, Hidemasa; Sakane, Toshiyasu; Yamamoto, Akira

    2016-01-01

    The nasal absorption of macromolecules from powder formulations and the effect of sodium carboxymethyl cellulose (CMC-Na) as a pharmaceutical excipient on their absorption were studied. Model macromolecules were fluorescein isothiocyanate-labeled dextran (average molecular weight of 4.4kDa, FD4) and insulin. The plasma concentration of FD4 after application of the powder containing 50% starch (control) was higher than that after application of the solution, and the absorption from 50% starch powder was enhanced by the substitution of starch with CMC-Na. The fractional absorption of FD4 after administration of the CMC-Na powder formulation was 30% and 40% higher than that after administration from the solution and the starch powder, respectively. The nasal absorption of insulin from the powder and the effect of CMC-Na were similar with those of FD4. The effective absorption of FD4 and insulin after application of powder with CMC-Na could be due to the increase in the nasal residence of FD4 and insulin. No damage in the nasal mucosa or dysfunction of the mucociliary clearance was observed after application of the drug powder and CMC-Na. The present findings indicate that nasal delivery of powder formulations with the addition of CMC-Na as an excipient is a promising approach for improving the nasal absorption of macromolecules. PMID:27598527

  15. Seven-effect absorption refrigeration

    DOEpatents

    DeVault, R.C.; Biermann, W.J.

    1989-05-09

    A seven-effect absorption refrigeration cycle is disclosed utilizing three absorption circuits. In addition, a heat exchanger is used for heating the generator of the low absorption circuit with heat rejected from the condenser and absorber of the medium absorption circuit. A heat exchanger is also provided for heating the generator of the medium absorption circuit with heat rejected from the condenser and absorber of the high absorption circuit. If desired, another heat exchanger can also be provided for heating the evaporator of the high absorption circuit with rejected heat from either the condenser or absorber of the low absorption circuit. 1 fig.

  16. Seven-effect absorption refrigeration

    DOEpatents

    DeVault, Robert C.; Biermann, Wendell J.

    1989-01-01

    A seven-effect absorption refrigeration cycle is disclosed utilizing three absorption circuits. In addition, a heat exchanger is used for heating the generator of the low absorption circuit with heat rejected from the condenser and absorber of the medium absorption circuit. A heat exchanger is also provided for heating the generator of the medium absorption circuit with heat rejected from the condenser and absorber of the high absorption circuit. If desired, another heat exchanger can also be provided for heating the evaporator of the high absorption circuit with rejected heat from either the condenser or absorber of the low absorption circuit.

  17. Mechanistic understanding of the effect of PPIs and acidic carbonated beverages on the oral absorption of itraconazole based on absorption modeling with appropriate in vitro data.

    PubMed

    Fotaki, Nikoletta; Klein, Sandra

    2013-11-01

    Proton pump inhibitors (PPIs) are potent gastric acid suppressing agents and are among the most widely sold drugs in the world. However, even though these antisecretory agents are regarded as safe, they can alter the pharmacokinetics of coadministered drugs. Due to the suppression of gastric acid secretion, they can significantly alter the intragastric pH conditions and are thus likely to affect the bioavailability of coadministered drugs requiring an acidic gastric environment for dissolution and subsequent absorption. Among these drugs can be found itraconazole, a poorly soluble triazole-type antifungal compound. Based on observations reported in the literature, gastric pH alterations due to the coadministration of PPIs or acidic beverages can significantly decrease (PPI) or increase (e.g., Coca-Cola) the bioavailability of this compound. In the present work we estimated the fraction of itraconazole that can be absorbed (fabs) from Sporanox capsules or an itraconazole-HBenBCD complex formulation after oral administration with and without coadministration of a PPI or an acidic (carbonated) beverage. For this purpose, the sensitivity of the two formulations toward the impact of various gastric variations (pH, volume, and emptying rate) as they can result from such administration conditions was studied using solubility and dissolution experiments and a physiologically based absorption model. Simulating coadministration of the two formulations with a PPI resulted in a significant (∼ 10-fold) decrease in itraconazole fabs, indicating the pH to be essential for in vivo dissolution and subsequent absorption. The fabs of itraconazole after coadministration of an acidic beverage (Coca-Cola) was far lower than the fabs obtained for itraconazole alone and did not support the observations reported in the literature. These results clearly indicate that in contrast to PPIs, which seem to affect itraconazole bioavailability mainly via intragastric pH changes, coadministered

  18. [Intestinal absorption and urinary excretion of triethylenetetramine for Wilson's disease in rat].

    PubMed

    Kobayashi, M; Sugawara, M; Saitoh, H; Iseki, K; Miyazaki, K

    1990-10-01

    Triethylenetetramine.2.HCl (trientine, TE) is an orphan drug for the treatment of Wilson's disease. There has been no reports regarding the absorption, distribution, metabolism, and excretion in the body. In the current study, the absorption and excretion of TE in rats were examined. The observed mean percentage amount of TE absorbed at the jejunum and ileum with the loop method for 1 h was 42.0% and 22.5%, respectively. Tight junction blocking agent inhibited the absorption of TE from the jejunum loop with 27%, but the absorption of TE from the ileum loop was not affected by this blocking agent. Therefore, the main absorption route for TE might be permeation across the plasma membrane of intestinal epithelial cells. TE and amikacin, a polycationic compound like TE, bound to the brush border membrane (BBM) of rat small intestine in the absence of inorganic ions such as Na+, K+, Ca2+, Mg2+ and Cu2+. But the binding of TE to BBM was inhibited markedly under the physiological concentration of these ions. The bioavailability of TE was below 10% and the plasma levels of TE in non-fasted rats were significantly lower than that observed in fasted rats. The urinary excretion of unchanged TE during 24 h was only 3.5% of the orally administered dose. However, the urinary excretion of total TE including metabolites, though they have not been identified, was 35.7%. These results suggest that low bioavailability of TE might be due to the rapid metabolism in the body after absorption from the gastrointestinal tract.

  19. Drug allergies

    MedlinePlus

    Allergic reaction - drug (medication); Drug hypersensitivity; Medication hypersensitivity ... A drug allergy involves an immune response in the body that produces an allergic reaction to a medicine. The ...

  20. Common drugs of abuse--Part II.

    PubMed

    Cuddy, Mary Linda Stotter

    2004-01-01

    Drug abuse affects a significant number of individuals of all ages. Health care practitioners must be knowledgeable about both the physiological effects of such drugs and the impact of drug-seeking behavior on their patients.

  1. The effect of BAY o 2752 on bile acid absorption and cholesterol esterification

    SciTech Connect

    Harnett, K.M.

    1988-01-01

    BAY o 2752 (N,N-(1,11-undecandiyl)bis(2,3-dihydro-2-methyl-1H-indole-1-carboxamide)) has been demonstrated to inhibit intestinal cholesterol absorption in rats. Studies were carried out on male Wistar rats to determine if this drug alters intestinal bile acid absorption or cholesterol esterification by acyl CoA: cholesterol acyltransferase (ACAT) or cholesterol ester hydrolase (CEH). BAY o 2752 did not affect intestinal absorption of taurocholic acid (TC) from ileal segments perfused in vivo with a tragacanth suspension in phosphate buffer containing NaCl, TC, and 24-{sup 14}C-TC as determined by the excretory rate of radioactivity in bile. BAY o 2752 also did not affect the uptake of TC into ileal everted sacs incubated in stirred, gassed Krebs-Ringer bicarbonate buffer with 1 mM TC, 24-{sup 14}C-TC and {sup 3}H-inulin. BAY o 2752 also did not bind TC; TG, in a filtrate of the above solutions remained at 92-98% of control.

  2. Supersaturating drug delivery systems: effect of hydrophilic cyclodextrins and other excipients on the formation and stabilization of supersaturated drug solutions.

    PubMed

    Brewster, M E; Vandecruys, R; Verreck, G; Peeters, J

    2008-03-01

    Supersaturating drug delivery systems (SDDS) utilize two important design elements in their preparation including converting the drug of interest into a high energy state or other rapidly dissolving form to facilitate the formation of supersaturated drug solutions and providing a means for stabilizing the formed supersaturated solution such that significant drug absorption is possible from the gastrointestinal tract. This has been referred to as a "spring" and "parachute" approach. The current effort is designed to assess materials which may affect properties in SDDS. To this end, a series of excipients was tested in a co-solvent/solvent quench method to assess their ability to attain and maintain supersaturation for a group of 14 drug development candidates. The approach focussed on hydrophilic cyclodextrins including hydroxypropyl-beta-cyclodextrin (HPbetaCD) and sulfobutyl-beta-cyclodextrin (SBEbetaCD). Various rheological polymers and surfactants were also included in the study. Consistent with previous investigations, the pharmaceutical polymers, as a class, had minimal effects on the extent of supersaturation but tended to be good stabilizers while the surfactants tended to provide for the greatest degree of supersaturation but the formed systems were poorly stable. This study found that hydrophilic cyclodextrins, especially SBEbetaCD, gave superior results in terms of attaining and maintaining supersaturation. A knowledge of the behavior and performance of excipients in this context can be useful in designing solid oral dosage forms for difficult-to-formulate drugs and drug candidates.

  3. Supersaturating drug delivery systems: effect of hydrophilic cyclodextrins and other excipients on the formation and stabilization of supersaturated drug solutions.

    PubMed

    Brewster, M E; Vandecruys, R; Verreck, G; Peeters, J

    2008-03-01

    Supersaturating drug delivery systems (SDDS) utilize two important design elements in their preparation including converting the drug of interest into a high energy state or other rapidly dissolving form to facilitate the formation of supersaturated drug solutions and providing a means for stabilizing the formed supersaturated solution such that significant drug absorption is possible from the gastrointestinal tract. This has been referred to as a "spring" and "parachute" approach. The current effort is designed to assess materials which may affect properties in SDDS. To this end, a series of excipients was tested in a co-solvent/solvent quench method to assess their ability to attain and maintain supersaturation for a group of 14 drug development candidates. The approach focussed on hydrophilic cyclodextrins including hydroxypropyl-beta-cyclodextrin (HPbetaCD) and sulfobutyl-beta-cyclodextrin (SBEbetaCD). Various rheological polymers and surfactants were also included in the study. Consistent with previous investigations, the pharmaceutical polymers, as a class, had minimal effects on the extent of supersaturation but tended to be good stabilizers while the surfactants tended to provide for the greatest degree of supersaturation but the formed systems were poorly stable. This study found that hydrophilic cyclodextrins, especially SBEbetaCD, gave superior results in terms of attaining and maintaining supersaturation. A knowledge of the behavior and performance of excipients in this context can be useful in designing solid oral dosage forms for difficult-to-formulate drugs and drug candidates. PMID:18444510

  4. The Zone of Inertia: Absorptive Capacity and Organizational Change

    ERIC Educational Resources Information Center

    Godkin, Lynn

    2010-01-01

    Purpose: The purpose of this paper is to describe how interruptions in organizational learning effect institutional absorptive capacity and contribute to organizational inertia. Design/methodology/approach: An exploratory model is presented as a heuristic to describe how interruptions in organizational learning affect absorptive capacity.…

  5. Drug Safety

    MedlinePlus

    ... over-the-counter drug. The FDA evaluates the safety of a drug by looking at Side effects ... clinical trials The FDA also monitors a drug's safety after approval. For you, drug safety means buying ...

  6. Drug effects on spermatogenesis.

    PubMed

    Amory, John K

    2007-10-01

    Many drugs can adversely affect spermatogenesis. These effects can occur either by directly inhibiting sperm or testicular function or indirectly by impairing the hypothalamic pituitary testicular axis. In this paper, we will review the drugs that are known to adversely impact spermatogenesis, and/or sperm function and detail what is known about the mechanisms through which these compounds impair fertility in men.

  7. Potential Drug - Drug Interactions among Medications Prescribed to Hypertensive Patients

    PubMed Central

    Ganguly, Barna

    2014-01-01

    Context: Drug-drug interactions(DDIs) are significant but avoidable causes of iatrogenic morbidity and hospital admission. Aim: To detect potential drug-drug interactions among medications received by hypertensive patients. Materials and Methods: Patients of both sex and all adult age groups, who were attending medicine out -patient department (OPD) of a tertiary care teaching rural hospital since last six months and were being prescribed antihypertensive drug/s for essential hypertension, were selected for the study. Hypertensive patient with co-morbities diabetes mellitus, ischemic heart diseases, congestive heart failure, and chronic renal diseases were also included in the study. Potential drug drug interactions were checked with medscape drug interaction software. Results: With the help of medscape drug interaction software, 71.50% prescriptions were identified having atleast one drug-drug interaction. Total 918 DDIs were found in between 58 drug pairs. 55.23% DDIs were pharmacodynamic, 4.79% pharmacokinetic type of DDIs. 32.24% DDIs were found affecting serum potassium level. 95.42% DDIs were found significant type of DDIs. Drug drug interaction between atenolol & amlodipine was the most common DDI (136) followed by metoprolol and amlodine (88) in this study. Atenolol and amlodipine ( 25.92%) was the most common drugs to cause DDIs in our study. Conclusion: We detected a significant number of drug drug interaction in hypertensive patients. These interactions were between antihypertensive agents or between hypertensive and drug for co-morbid condition. PMID:25584241

  8. Absorption heat pump system

    DOEpatents

    Grossman, Gershon; Perez-Blanco, Horacio

    1984-01-01

    An improvement in an absorption heat pump cycle is obtained by adding adiabatic absorption and desorption steps to the absorber and desorber of the system. The adiabatic processes make it possible to obtain the highest temperature in the absorber before any heat is removed from it and the lowest temperature in the desorber before heat is added to it, allowing for efficient utilization of the thermodynamic availability of the heat supply stream. The improved system can operate with a larger difference between high and low working fluid concentrations, less circulation losses, and more efficient heat exchange than a conventional system.

  9. Oral anticancer drugs: mechanisms of low bioavailability and strategies for improvement.

    PubMed

    Stuurman, Frederik E; Nuijen, Bastiaan; Beijnen, Jos H; Schellens, Jan H M

    2013-06-01

    The use of oral anticancer drugs has increased during the last decade, because of patient preference, lower costs, proven efficacy, lack of infusion-related inconveniences, and the opportunity to develop chronic treatment regimens. Oral administration of anticancer drugs is, however, often hampered by limited bioavailability of the drug, which is associated with a wide variability. Since most anticancer drugs have a narrow therapeutic window and are dosed at or close to the maximum tolerated dose, a wide variability in the bioavailability can have a negative impact on treatment outcome. This review discusses mechanisms of low bioavailability of oral anticancer drugs and strategies for improvement. The extent of oral bioavailability depends on many factors, including release of the drug from the pharmaceutical dosage form, a drug's stability in the gastrointestinal tract, factors affecting dissolution, the rate of passage through the gut wall, and the pre-systemic metabolism in the gut wall and liver. These factors are divided into pharmaceutical limitations, physiological endogenous limitations, and patient-specific limitations. There are several strategies to reduce or overcome these limitations. First, pharmaceutical adjustment of the formulation or the physicochemical characteristics of the drug can improve the dissolution rate and absorption. Second, pharmacological interventions by combining the drug with inhibitors of transporter proteins and/or pre-systemic metabolizing enzymes can overcome the physiological endogenous limitations. Third, chemical modification of a drug by synthesis of a derivative, salt form, or prodrug could enhance the bioavailability by improving the absorption and bypassing physiological endogenous limitations. Although the bioavailability can be enhanced by various strategies, the development of novel oral products with low solubility or cell membrane permeability remains cumbersome and is often unsuccessful. The main reasons are

  10. Oral anticancer drugs: mechanisms of low bioavailability and strategies for improvement.

    PubMed

    Stuurman, Frederik E; Nuijen, Bastiaan; Beijnen, Jos H; Schellens, Jan H M

    2013-06-01

    The use of oral anticancer drugs has increased during the last decade, because of patient preference, lower costs, proven efficacy, lack of infusion-related inconveniences, and the opportunity to develop chronic treatment regimens. Oral administration of anticancer drugs is, however, often hampered by limited bioavailability of the drug, which is associated with a wide variability. Since most anticancer drugs have a narrow therapeutic window and are dosed at or close to the maximum tolerated dose, a wide variability in the bioavailability can have a negative impact on treatment outcome. This review discusses mechanisms of low bioavailability of oral anticancer drugs and strategies for improvement. The extent of oral bioavailability depends on many factors, including release of the drug from the pharmaceutical dosage form, a drug's stability in the gastrointestinal tract, factors affecting dissolution, the rate of passage through the gut wall, and the pre-systemic metabolism in the gut wall and liver. These factors are divided into pharmaceutical limitations, physiological endogenous limitations, and patient-specific limitations. There are several strategies to reduce or overcome these limitations. First, pharmaceutical adjustment of the formulation or the physicochemical characteristics of the drug can improve the dissolution rate and absorption. Second, pharmacological interventions by combining the drug with inhibitors of transporter proteins and/or pre-systemic metabolizing enzymes can overcome the physiological endogenous limitations. Third, chemical modification of a drug by synthesis of a derivative, salt form, or prodrug could enhance the bioavailability by improving the absorption and bypassing physiological endogenous limitations. Although the bioavailability can be enhanced by various strategies, the development of novel oral products with low solubility or cell membrane permeability remains cumbersome and is often unsuccessful. The main reasons are

  11. Lipids: Absorption and transport

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Due to the hydrophobic nature of lipids, dietary fat is handled differently than protein or carbohydrate with respect with digestion and absorption. Dietary fats are broken down throughout the gastrointestinal system. A unique group of enzymes and cofactors allows this process to proceed in an eff...

  12. Absorption driven focus shift

    NASA Astrophysics Data System (ADS)

    Harrop, N.; Wolf, S.; Maerten, O.; Dudek, K.; Ballach, S.; Kramer, R.

    2016-03-01

    Modern high brilliance near infrared lasers have seen a tremendous growth in applications throughout the world. Increased productivity has been achieved by higher laser power and increased brilliance of lasers. Positive impacts on the performance and costs of parts are opposed to threats on process stability and quality, namely shift of focus position over time. A high initial process quality will be reduced by contamination of optics, eventually leading to a focus shift or even destruction of the optics. Focus analysis at full power of multi-kilowatt high brilliance lasers is a very demanding task because of high power densities in the spot and the high power load on optical elements. With the newly developed high power projection optics, the High-Power Micro-Spot Monitor High Brilliance (HP-MSM-HB) is able to measure focus diameter as low as 20 μm at power levels up to 10 kW at very low internal focus shift. A main driving factor behind thermally induced focus shift is the absorption level of the optical element. A newly developed measuring system is designed to determine the relative absorption level in reference to a gold standard. Test results presented show a direct correlation between absorption levels and focus shift. The ability to determine the absorption level of optical elements as well as their performance at full processing power before they are put to use, enables a high level of quality assurance for optics manufacturers and processing head manufacturers alike.

  13. Two-Phonon Absorption

    ERIC Educational Resources Information Center

    Hamilton, M. W.

    2007-01-01

    A nonlinear aspect of the acousto-optic interaction that is analogous to multi-photon absorption is discussed. An experiment is described in which the second-order acousto-optically scattered intensity is measured and found to scale with the square of the acoustic intensity. This experiment using a commercially available acousto-optic modulator is…

  14. [Customizing dosage drugs what contribution in therapeutic drug monitoring?].

    PubMed

    Abdessadek, Mohammed; Magoul, Rabia; Amarti, Afaf; El Ouezzani, Seloua; Khabbal, Youssef

    2014-01-01

    Drug response is often variable from an individual to another: the same dose of drug administered to different patients could cause variable pharmacological effects in nature and intensity. Those effects are often the result of variability in drugs pharmacokinetics (absorption, distribution, metabolism and elimination) which alter their bioavailability. In fact, two factors should be taken into account: the disease(s) from which the patient suffers, and the associated drugs, because many drug interactions may alter their pharmacokinetics causing consequently quite enough of different therapeutic effects. The choice of the assay of the drug subject in monitoring is crucial, it allows quantifying the in vivo dose of the drug and the quality of compliance thereof, the pharmacokinetic characteristics allows the clinician to adjust the dosage by different approaches so that plasma concentrations are included in the therapeutic range. Therapeutic monitoring aims to increase clinical efficacy and to minimize toxicity.

  15. Perspectives on Preventing Student Drug Abuse.

    ERIC Educational Resources Information Center

    Pedone, Ronald, Ed.; Gwaltney, Margaret K., Ed.

    This set of papers is one part of the United States Department of Education's effort to establish a research agenda for drug use. It consists of a foreword and 10 papers that examine issues of drug abuse, students, and schools. It presents different views on the drug abuse problem in order to affect research on schools, drugs, and drug education.…

  16. [Intestinal absorption kinetics of Polygonum capitatum extract in rats].

    PubMed

    Yang, Wu; Hou, Jia; Lu, Yuan; Chen, Peng-cheng; Liao, Shang-gao; Huang, Yong

    2015-11-01

    A UPLC-ESI-MS/MS method was used to determinate the main active fractions gallic acid, protocatechuic acid, myricetrin, hyperoside and quercitrin in Polygonum capitatum extracts by in situ intestinal perfusion models; the absorption rate constants and cumulative penetration rate of absorption were calculated. The effect of different drug concentrations, different intestine segments, bile and P-gp inhibitors on the absorption mechanism of Gallic acid and other compositions in P. capitatum extracts. The experimental results showed that gallic acid, protocatechuic acid, myricetrin and quercitrin were observed saturated at high concentration (P < 0.05). Bile had significant inhibition effect on protocatechuic acid absorption and had promotion effect on myricetrin and hyperoside absorption (P < 0.05). P-gp inhibitor verapamil could significantly enhance the absorption of Protocatechuic acid (P < 0.05). The overall trend for absorption of various compositions was that small intestine > colon. This indicated that the absorption mechanism of P. capitatum extracts in rat intestine was in line with fist-order kinetics characteristics. The composition could be absorbed in all of the different intestinal segments, and the absorption was mainly concentrated in small intestine. The protocatechuic acid may be the substrate of P-gp.

  17. [Intestinal absorption kinetics of Polygonum capitatum extract in rats].

    PubMed

    Yang, Wu; Hou, Jia; Lu, Yuan; Chen, Peng-cheng; Liao, Shang-gao; Huang, Yong

    2015-11-01

    A UPLC-ESI-MS/MS method was used to determinate the main active fractions gallic acid, protocatechuic acid, myricetrin, hyperoside and quercitrin in Polygonum capitatum extracts by in situ intestinal perfusion models; the absorption rate constants and cumulative penetration rate of absorption were calculated. The effect of different drug concentrations, different intestine segments, bile and P-gp inhibitors on the absorption mechanism of Gallic acid and other compositions in P. capitatum extracts. The experimental results showed that gallic acid, protocatechuic acid, myricetrin and quercitrin were observed saturated at high concentration (P < 0.05). Bile had significant inhibition effect on protocatechuic acid absorption and had promotion effect on myricetrin and hyperoside absorption (P < 0.05). P-gp inhibitor verapamil could significantly enhance the absorption of Protocatechuic acid (P < 0.05). The overall trend for absorption of various compositions was that small intestine > colon. This indicated that the absorption mechanism of P. capitatum extracts in rat intestine was in line with fist-order kinetics characteristics. The composition could be absorbed in all of the different intestinal segments, and the absorption was mainly concentrated in small intestine. The protocatechuic acid may be the substrate of P-gp. PMID:27071271

  18. THE ABSORPTION SPECTRUM OF VISUAL PURPLE

    PubMed Central

    Chase, Aurin M.; Haig, Charles

    1938-01-01

    The absorption spectra of visual purple solutions extracted by various means were measured with a sensitive photoelectric spectrophotometer and compared with the classical visual purple absorption spectrum. Hardening the retinas in alum before extraction yielded visual purple solutions of much higher light transmission in the blue and violet, probably because of the removal of light-dispersing substances. Re-extraction indicated that visual purple is more soluble in the extractive than are the other colored retinal components. However, the concentration of the extractive did not affect the color purity of the extraction but did influence the keeping power. This suggests a chemical combination between the extractive and visual purple. The pH of the extractive affected the color purity of the resulting solution. Over the pH range from 5.5 to 10.0, the visual purple color purity was greatest at the low pH. Temperature during extraction was also effective, the color purity being greater the higher the temperature, up to 40°C. Drying and subsequent re-dissolving of visual purple solutions extracted with digitalin freed the solution of some protein impurities and increased its keeping power. Dialysis against distilled water seemed to precipitate visual purple from solution irreversibly. None of the treatments described improved the symmetry of the unbleached visual purple absorption spectrum sufficiently for it to resemble the classical absorption spectrum. Therefore it is very likely that the classical absorption spectrum is that of the light-sensitive group only and that the absorption spectra of our purest unbleached visual purple solutions represent the molecule as a whole. PMID:19873058

  19. 69. INTERIOR VIEW OF THE ABSORPTION TOWER BUILDING, ABSORPTION TOWER ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    69. INTERIOR VIEW OF THE ABSORPTION TOWER BUILDING, ABSORPTION TOWER UNDER CONSTRUCTION. (DATE UNKNOWN). - United States Nitrate Plant No. 2, Reservation Road, Muscle Shoals, Muscle Shoals, Colbert County, AL

  20. Vaginal Absorption of Penicillin.

    PubMed

    Rock, J; Barker, R H; Bacon, W B

    1947-01-01

    Except during the last two months of pregnancy, penicillin is easily absorbed from cocoa butter suppositories in the vagina, ordinarily to give therapeutic blood levels for from 4 to 6 hours. Penicillin in the dosage used seems to have a good effect on vaginal infections. In nonpregnant women, during the ovulation phase, considered as including days 14 +/- 2 in the ordinary menstrual cycle of about 28 days, absorption seemed to be somewhat diminished. Higher levels were found in patients who were near the end of their menstrual cycles and in two patients who were menopausal. Patients who were very near term absorbed little or no penicillin, whereas patients 10 days post partum showed excellent absorption.

  1. Photothermal absorption correlation spectroscopy.

    PubMed

    Octeau, Vivien; Cognet, Laurent; Duchesne, Laurence; Lasne, David; Schaeffer, Nicolas; Fernig, David G; Lounis, Brahim

    2009-02-24

    Fluorescence correlation spectroscopy (FCS) is a popular technique, complementary to cell imaging for the investigation of dynamic processes in living cells. Based on fluorescence, this single molecule method suffers from artifacts originating from the poor fluorophore photophysics: photobleaching, blinking, and saturation. To circumvent these limitations we present here a new correlation method called photothermal absorption correlation spectroscopy (PhACS) which relies on the absorption properties of tiny nano-objects. PhACS is based on the photothermal heterodyne detection technique and measures akin FCS, the time correlation function of the detected signals. Application of this technique to the precise determination of the hydrodynamic sizes of different functionalized gold nanoparticles are presented, highlighting the potential of this method. PMID:19236070

  2. Adverse ocular reactions to drugs.

    PubMed Central

    Spiteri, M. A.; James, D. G.

    1983-01-01

    Drugs acting on various parts of the body may also affect the eye insidiously. Increased awareness of such drug toxicity by the prescribing doctor should encourage him to consider effects on the cornea, lens, retina, optic nerve and elsewhere when checking the patient's progress. The following review concerns adverse ocular effects of systemic drug administration. PMID:6356101

  3. Relic Neutrino Absorption Spectroscopy

    SciTech Connect

    Eberle, b

    2004-01-28

    Resonant annihilation of extremely high-energy cosmic neutrinos on big-bang relic anti-neutrinos (and vice versa) into Z-bosons leads to sizable absorption dips in the neutrino flux to be observed at Earth. The high-energy edges of these dips are fixed, via the resonance energies, by the neutrino masses alone. Their depths are determined by the cosmic neutrino background density, by the cosmological parameters determining the expansion rate of the universe, and by the large redshift history of the cosmic neutrino sources. We investigate the possibility of determining the existence of the cosmic neutrino background within the next decade from a measurement of these absorption dips in the neutrino flux. As a by-product, we study the prospects to infer the absolute neutrino mass scale. We find that, with the presently planned neutrino detectors (ANITA, Auger, EUSO, OWL, RICE, and SalSA) operating in the relevant energy regime above 10{sup 21} eV, relic neutrino absorption spectroscopy becomes a realistic possibility. It requires, however, the existence of extremely powerful neutrino sources, which should be opaque to nucleons and high-energy photons to evade present constraints. Furthermore, the neutrino mass spectrum must be quasi-degenerate to optimize the dip, which implies m{sub {nu}} 0.1 eV for the lightest neutrino. With a second generation of neutrino detectors, these demanding requirements can be relaxed considerably.

  4. Drug-Induced Hematologic Syndromes

    PubMed Central

    Mintzer, David M.; Billet, Shira N.; Chmielewski, Lauren

    2009-01-01

    Objective. Drugs can induce almost the entire spectrum of hematologic disorders, affecting white cells, red cells, platelets, and the coagulation system. This paper aims to emphasize the broad range of drug-induced hematological syndromes and to highlight some of the newer drugs and syndromes. Methods. Medline literature on drug-induced hematologic syndromes was reviewed. Most reports and reviews focus on individual drugs or cytopenias. Results. Drug-induced syndromes include hemolytic anemias, methemoglobinemia, red cell aplasia, sideroblastic anemia, megaloblastic anemia, polycythemia, aplastic anemia, leukocytosis, neutropenia, eosinophilia, immune thrombocytopenia, microangiopathic syndromes, hypercoagulability, hypoprothrombinemia, circulating anticoagulants, myelodysplasia, and acute leukemia. Some of the classic drugs known to cause hematologic abnormalities have been replaced by newer drugs, including biologics, accompanied by their own syndromes and unintended side effects. Conclusions. Drugs can induce toxicities spanning many hematologic syndromes, mediated by a variety of mechanisms. Physicians need to be alert to the potential for iatrogenic drug-induced hematologic complications. PMID:19960059

  5. Drug Resistance

    MedlinePlus

    HIV Treatment Drug Resistance (Last updated 3/1/2016; last reviewed 3/1/2016) Key Points As HIV multiplies in the ... the risk of drug resistance. What is HIV drug resistance? Once a person becomes infected with HIV, ...

  6. [Carbohydrate absorption and malabsorption (author's transl)].

    PubMed

    Caspary, W F

    1977-06-01

    Starch is digested intraluminally by alpha-amylase to maltose, maltotriose, and alpha-limit dextrins. These products, as well as the disaccharides sucrose and lactose, undergo enzymatic hydrolysis to monosaccharides at the brush border surface. The monosaccharides enter the absorbing cell by specific transport mechanisms ("carriers"). Primary carbohydrate (CH) intolerance is characterized by the congenital or acquired absence of individual brush border enzymes or of monosaccharide "carriers" without morphologic abnormalities of the intestinal villus: lactose, sucrose and trehalose intolerance and glucose-galactose malabsorption (brush border diseases). Secondary CH intolerance arises when surface digestion and absorption are reduced due to structural changes of the intestinal mucosa: e.g., decrease or absence of villi with sprue and reduction of the absorbing surface with intestinal resection. Watery diarrhea is the lead symptom. Many drugs delay or interfere with CH absorption. This action may be viewed either as an unwanted side effect or as a welcome therapeutic principle.

  7. Corrosion Problems in Absorption Chillers

    ERIC Educational Resources Information Center

    Stetson, Bruce

    1978-01-01

    Absorption chillers use a lithium bromide solution as the medium of absorption and water as the refrigerant. Discussed are corrosion and related problems, tests and remedies, and cleaning procedures. (Author/MLF)

  8. Acoustic Absorption Characteristics of People.

    ERIC Educational Resources Information Center

    Kingsbury, H. F.; Wallace, W. J.

    1968-01-01

    The acoustic absorption characteristics of informally dressed college students in typical classroom seating are shown to differ substantially from data for formally dressed audiences in upholstered seating. Absorption data, expressed as sabins per person or absorption coefficient per square foot, shows that there is considerable variation between…

  9. Circadian regulators of intestinal lipid absorption.

    PubMed

    Hussain, M Mahmood; Pan, Xiaoyue

    2015-04-01

    Among all the metabolites present in the plasma, lipids, mainly triacylglycerol and diacylglycerol, show extensive circadian rhythms. These lipids are transported in the plasma as part of lipoproteins. Lipoproteins are synthesized primarily in the liver and intestine and their production exhibits circadian rhythmicity. Studies have shown that various proteins involved in lipid absorption and lipoprotein biosynthesis show circadian expression. Further, intestinal epithelial cells express circadian clock genes and these genes might control circadian expression of different proteins involved in intestinal lipid absorption. Intestinal circadian clock genes are synchronized by signals emanating from the suprachiasmatic nuclei that constitute a master clock and from signals coming from other environmental factors, such as food availability. Disruptions in central clock, as happens due to disruptions in the sleep/wake cycle, affect intestinal function. Similarly, irregularities in temporal food intake affect intestinal function. These changes predispose individuals to various metabolic disorders, such as metabolic syndrome, obesity, diabetes, and atherosclerosis. Here, we summarize how circadian rhythms regulate microsomal triglyceride transfer protein, apoAIV, and nocturnin to affect diurnal regulation of lipid absorption.

  10. Absorption Reconstruction Improves Biodistribution Assessment of Fluorescent Nanoprobes Using Hybrid Fluorescence-mediated Tomography

    PubMed Central

    Gremse, Felix; Theek, Benjamin; Kunjachan, Sijumon; Lederle, Wiltrud; Pardo, Alessa; Barth, Stefan; Lammers, Twan; Naumann, Uwe; Kiessling, Fabian

    2014-01-01

    Aim: Fluorescence-mediated tomography (FMT) holds potential for accelerating diagnostic and theranostic drug development. However, for proper quantitative fluorescence reconstruction, knowledge on optical scattering and absorption, which are highly heterogeneous in different (mouse) tissues, is required. We here describe methods to assess these parameters using co-registered micro Computed Tomography (µCT) data and nonlinear whole-animal absorption reconstruction, and evaluate their importance for assessment of the biodistribution and target site accumulation of fluorophore-labeled drug delivery systems. Methods: Besides phantoms with varying degrees of absorption, mice bearing A431 tumors were imaged 15 min and 48 h after i.v. injection of a fluorophore-labeled polymeric drug carrier (pHPMA-Dy750) using µCT-FMT. The outer shape of mice and a scattering map were derived using automated segmentation of the µCT data. Furthermore, a 3D absorption map was reconstructed from the trans-illumination data. We determined the absorption of five interactively segmented regions (heart, liver, kidney, muscle, tumor). Since blood is the main near-infrared absorber in vivo, the absorption was also estimated from the relative blood volume (rBV), determined by contrast-enhanced µCT. We compared the reconstructed absorption with the rBV-based values and analyzed the effect of using the absorption map on the fluorescence reconstruction. Results: Phantom experiments demonstrated that absorption reconstruction is possible and necessary for quantitative fluorescence reconstruction. In vivo, the reconstructed absorption showed high values in strongly blood-perfused organs such as the heart, liver and kidney. The absorption values correlated strongly with the rBV-based absorption values, confirming the accuracy of the absorption reconstruction. Usage of homogenous absorption instead of the reconstructed absorption map resulted in reduced values in the heart, liver and kidney, by

  11. Drug abuse and reproduction.

    PubMed

    Smith, C G; Asch, R H

    1987-09-01

    It is clear that a number of CNS agents, including drugs of abuse, can inhibit reproductive function. Figure 1 shows the chemical diversity of some of the drug groups that affect reproductive hormones. Their structural dissimilarity to the steroid hormones is also readily apparent in the figure. These chemically diverse drugs share an important pharmacologic property: they are highly potent neuroactive drugs, and they can disrupt hypothalamic-pituitary function. Although it is frequently difficult to distinguish between direct drug actions on the hypothalamic-pituitary axis and subsequent effects on gonadal hormones and sex accessory gland function, the distinction is an important one. Most neuroactive drugs produce only transient effects on the central nervous pathways necessary for normal gonadotropin secretion. The disruptive effects of these drugs are likely to be transient and completely reversible, and tolerance to the inhibitory drug effects may occur even with continued drug use. Under these circumstances, normal adults may experience only subtle changes in sexual function. However, individuals with compromised reproductive function may exhibit major problems. It is also likely that adolescents may be at substantial risk for reproductive damage from these neuroactive drugs since the endocrine events associated with puberty are dependent on the normal development of the hypothalamic-pituitary axis.

  12. Factors affecting the morphology of benzoyl peroxide microsponges.

    PubMed

    Nokhodchi, Ali; Jelvehgari, Mitra; Siahi, M Reza; Mozafari, M Reza

    2007-01-01

    Benzoyl peroxide (BPO) is primarily used in the treatment of mild to moderate acne. However, its application is associated with skin irritation. It has been shown that encapsulation and controlled release of BPO could reduce the side effect while also reducing percutaneous absorption when administered to the skin. The aim of the present investigation was to design and formulate an appropriate encapsulated form of BPO, using microsponge technology, and explore the parameters affecting the morphology and other characteristics of the resultant products employing scanning electron microscopy (SEM). Benzoyl peroxide particles were prepared using an emulsion solvent diffusion method by adding an organic internal phase containing benzoyl peroxide, ethyl cellulose and dichloromethane into a stirred aqueous phase containing polyvinyl alcohol (PVA). Different concentrations of BPO microsponges were incorporated in lotion formulations and the drug release from these formulations were studied. The SEM micrographs of the BPO microsponges enabled measurement of their size and showed that they were spherical and porous. Results showed that the morphology and particle size of microsponges were affected by drug:polymer ratio, stirring rate and the amount of emulsifier used. The results obtained also showed that an increase in the ratio of drug:polymer resulted in a reduction in the release rate of BPO from the microsponges. The release data showed that the highest and the lowest release rates were obtained from lotions containing plain BPO particles and BPO microsponges with the drug:polymer ratio of 13:1, respectively. The kinetics of release study showed that the release data followed Peppas model and the main mechanism of drug release from BPO microsponges was diffusion.

  13. Nonlinear intestinal absorption kinetics of cefuroxime axetil in rats.

    PubMed Central

    Ruiz-Balaguer, N; Nacher, A; Casabo, V G; Merino, M

    1997-01-01

    Cefuroxime is commercially available for parenteral administration as a sodium salt and for oral administration as cefuroxime axetil, the 1-(acetoxy)ethyl ester of the drug. Cefuroxime axetil is a prodrug of cefuroxime and has little, if any, antibacterial activity until hydrolyzed in vivo to cefuroxime. In this study, the absorption of cefuroxime axetil in the small intestines of anesthetized rats was investigated in situ, by perfusion at four concentrations (11.8, 5, 118 and 200 microM). Oral absorption of cefuroxime axetil can apparently be described as a specialized transport mechanism which obeys Michaelis-Menten kinetics. Parameters characterizing absorption of prodrug in free solution were obtained: maximum rate of absorption (Vmax) = 289.08 +/- 46.26 microM h-1, and Km = 162.77 +/- 31.17 microM. Cefuroxime axetil transport was significantly reduced in the presence of the enzymatic inhibitor sodium azide. On the other hand, the prodrug was metabolized in the gut wall through contact with membrane-bound enzymes in the brush border membrane before absorption occurred. This process reduces the prodrug fraction directly available for absorption. From a bioavailability point of view, therefore, the effects mentioned above can explain the variable and poor bioavailability following oral administration of cefuroxime axetil. Thus, future strategies in oral cefuroxime axetil absorption should focus on increasing the stability of the prodrug in the intestine by modifying the prodrug structure and/or targeting the compound to the absorption site. PMID:9021205

  14. [Transient UV absorption spectra of artemisinin reacting with sodium hydroxide].

    PubMed

    Gao, Yan-Jun; Ping, Li; Yang, Li-Jun; Wang, Qi-Ming; Xue, Jun-Peng; Wu, Da-Cheng; Li, Rui-Xia

    2009-03-01

    UV absorption spectrum of artemisinin and transient absorption spectra of various concentrations of artemisinin reacting with sodium hydroxide were measured by using an intensified spectroscopic detector ICCD. The exposure time of each spectrum was 0.1 ms. Results indicate that artemisinin has an obvious UV absorption band centered at 212.52 nm and can react with sodium hydroxide easily. All absorption spectra of different concentrations of artemisinin reacting with sodium hydroxide have the similar changes, but the moment at which the changes happened is different. After adding sodium hydroxide into artemisinin in ethanol solution, there was a new absorption band centered at 288 nm appearing firstly. As reaction went on, the intensity of another absorption band centered at 260 nm increased gradually. At the end of the reaction, a continuous absorption band from 200 to 350 nm with the peak at 245 nm formed finally. No other transient absorption spectral data are available on the reaction of artemisinin with sodium hydroxide currently. The new spectral information obtained in this experiment provides very important experimental basis for understanding the properties of artemisinin reacting with alkaline medium and is useful for correctly using of artemisinin as a potential anticancer drug.

  15. Predicting drug disposition via application of a Biopharmaceutics Drug Disposition Classification System.

    PubMed

    Benet, Leslie Z

    2010-03-01

    A Biopharmaceutics Drug Disposition Classification System (BDDCS) was proposed to serve as a basis for predicting the importance of transporters in determining drug bioavailability and disposition. BDDCS may be useful in predicting: routes of drug elimination; efflux and absorptive transporters effects on oral absorption; when transporter-enzyme interplay will yield clinically significant effects (e.g. low drug bioavailability and drug-drug interactions); and transporter effects on post-absorptive systemic drug levels following oral and i.v. dosing. For highly soluble, highly permeable Class 1 compounds, metabolism is the major route of elimination and transporter effects on drug bioavailability and hepatic disposition are negligible. In contrast for the poorly permeable Class 3 and 4 compounds, metabolism only plays a minor role in drug elimination. Uptake transporters are major determinants of drug bioavailability for these poorly permeable drugs and both uptake and efflux transporters could be important for drug elimination. Highly permeable, poorly soluble, extensively metabolized Class 2 compounds present the most complicated relationship in defining the impact of transporters due to a marked transporter-enzyme interplay. Uptake transporters are unimportant for Class 2 drug bioavailability, (ensure space after,) but can play a major role in hepatic and renal elimination. Efflux transporters have major effects on drug bioavailability, absorption, metabolism and elimination of Class 2 drugs. It is difficult to accurately characterize drugs in terms of the high permeability criteria, i.e. > or =90% absorbed. We suggest that extensive metabolism may substitute for the high permeability characteristic, and that BDDCS using elimination criteria may provide predictability in characterizing drug disposition profiles for all classes of compounds.

  16. Absorption heat pumps

    NASA Astrophysics Data System (ADS)

    Huhtinen, M.; Heikkilae, M.; Andersson, R.

    1987-03-01

    The aim of the study was to analyze the technical and economic feasibility of absorption heat pumps in Finland. The work was done as a case study: the technical and economic analyses have been carried out for six different cases, where in each the suitable size and type of the heat pump plant and the auxiliary components and connections were specified. The study also detailed the costs concerning the procurement, installation and test runs of the machinery, as well as the savings in energy costs incurred by the introduction of the plant. Conclusions were drawn of the economic viability of the applications studied. The following cases were analyzed: heat recovery from flue gases and productin of district heat in plants using peat, natural gas, and municipal wastes as a fuel. Heat recovery in the pulp and paper industry for the upgrading of pressure of secondary steam and for the heating of white liquor and combustion and drying the air. Heat recovery in a peat-fulled heat and power plant from flue gases that have been used for the drying of peat. According to the study, the absorption heat pump suits best to the production of district heat, when the heat source is the primary energy is steam produced by the boiler. Included in the flue as condensing is the purification of flue gases. Accordingly, benefit is gained on two levels in thick applications. In heat and power plants the use of absorption heat pumps is less economical, due to the fact that the steam used by the pump reduces the production of electricity, which is rated clearly higher than heat.

  17. Ultraviolet absorption hygrometer

    DOEpatents

    Gersh, Michael E.; Bien, Fritz; Bernstein, Lawrence S.

    1986-01-01

    An ultraviolet absorption hygrometer is provided including a source of pulsed ultraviolet radiation for providing radiation in a first wavelength region where water absorbs significantly and in a second proximate wavelength region where water absorbs weakly. Ultraviolet radiation in the first and second regions which has been transmitted through a sample path of atmosphere is detected. The intensity of the radiation transmitted in each of the first and second regions is compared and from this comparison the amount of water in the sample path is determined.

  18. Ultraviolet absorption hygrometer

    DOEpatents

    Gersh, M.E.; Bien, F.; Bernstein, L.S.

    1986-12-09

    An ultraviolet absorption hygrometer is provided including a source of pulsed ultraviolet radiation for providing radiation in a first wavelength region where water absorbs significantly and in a second proximate wavelength region where water absorbs weakly. Ultraviolet radiation in the first and second regions which has been transmitted through a sample path of atmosphere is detected. The intensity of the radiation transmitted in each of the first and second regions is compared and from this comparison the amount of water in the sample path is determined. 5 figs.

  19. Modular total absorption spectrometer

    NASA Astrophysics Data System (ADS)

    Karny, M.; Rykaczewski, K. P.; Fijałkowska, A.; Rasco, B. C.; Wolińska-Cichocka, M.; Grzywacz, R. K.; Goetz, K. C.; Miller, D.; Zganjar, E. F.

    2016-11-01

    The design and performance of the Modular Total Absorption Spectrometer built and commissioned at the Oak Ridge National Laboratory is presented. The active volume of the detector is approximately one ton of NaI(Tl), which results in very high full γ energy peak efficiency of 71% at 6 MeV and nearly flat efficiency of around 81.5% for low energy γ-rays between 300 keV and 1 MeV. In addition to the high peak efficiency, the modular construction of the detector permits the use of a γ-coincidence technique in data analysis as well as β-delayed neutron observation.

  20. Membrane transporters in drug development

    PubMed Central

    2011-01-01

    Membrane transporters can be major determinants of the pharmacokinetic, safety and efficacy profiles of drugs. This presents several key questions for drug development, including which transporters are clinically important in drug absorption and disposition, and which in vitro methods are suitable for studying drug interactions with these transporters. In addition, what criteria should trigger follow-up clinical studies, and which clinical studies should be conducted if needed. In this article, we provide the recommendations of the International Transporter Consortium on these issues, and present decision trees that are intended to help guide clinical studies on the currently recognized most important drug transporter interactions. The recommendations are generally intended to support clinical development and filing of a new drug application. Overall, it is advised that the timing of transporter investigations should be driven by efficacy, safety and clinical trial enrolment questions (for example, exclusion and inclusion criteria), as well as a need for further understanding of the absorption, distribution, metabolism and excretion properties of the drug molecule, and information required for drug labeling. PMID:20190787

  1. Driving forces for drug loading in drug carriers.

    PubMed

    Li, Yang; Yang, Li

    2015-01-01

    The loading capacity of a drug carrier is determined essentially by intermolecular interactions between drugs and carrier materials. In this review, the process of drug loading is described in detail based on the differences in the driving force for drug incorporation, including hydrophobic interaction, electrostatic interaction, hydrogen bonding, Pi-Pi stacking and van der Waals force. Modifying drug-loading sites of carrier materials with interacting groups aiming at tailoring drug-carrier interactions is reviewed by highlighting its importance for improving in vitro properties such as the loading capacity, release behaviour and stability. Other factors affecting drug loading, methods employed to predict the encapsulation capacity and the techniques to verify intermolecular interactions are also discussed to inform the readers of all-sided information on drug-loading processes and theories. The drug carriers can be designed more reasonably with the better understanding of the nature and interacting mechanism of intermolecular interactions.

  2. Physiologically Based Absorption Modeling for Amorphous Solid Dispersion Formulations.

    PubMed

    Mitra, Amitava; Zhu, Wei; Kesisoglou, Filippos

    2016-09-01

    Amorphous solid dispersion (ASD) formulations are routinely used to enable the delivery of poorly soluble compounds. This type of formulations can enhance bioavailability due to higher kinetic solubility of the drug substance and increased dissolution rate of the formulation, by the virtue of the fact that the drug molecule exists in the formulation in a high energy amorphous state. In this article we report the application of physiologically based absorption models to mechanistically understand the clinical pharmacokinetics of solid dispersion formulations. Three case studies are shown here to cover a wide range of ASD bioperformance in human and modeling to retrospectively understand their in vivo behavior. Case study 1 is an example of fairly linear PK observed with dose escalation and the use of amorphous solubility to predict bioperformance. Case study 2 demonstrates the development of a model that was able to accurately predict the decrease in fraction absorbed (%Fa) with dose escalation thus demonstrating that such model can be used to predict the clinical bioperformance in the scenario where saturation of absorption is observed. Finally, case study 3 shows the development of an absorption model with the intent to describe the observed incomplete and low absorption in clinic with dose escalation. These case studies highlight the utility of physiologically based absorption modeling in gaining a thorough understanding of ASD performance and the critical factors impacting performance to drive design of a robust drug product that would deliver the optimal benefit to the patients. PMID:27442959

  3. Drug Abuse

    MedlinePlus

    ... as drugged driving, violence, stress, and child abuse. Drug abuse can lead to homelessness, crime, and missed work or problems with keeping a job. It harms unborn babies and destroys families. There are different types of treatment for drug abuse. But the best is to prevent drug ...

  4. Controlled drugs.

    PubMed

    2016-05-18

    Essential facts Controlled drugs are defined and governed by the Misuse of Drugs Act 1971 and associated regulations. Examples of controlled drugs include morphine, pethidine and methadone. Since 2012, appropriately qualified nurses and midwives can prescribe controlled drugs for medical conditions within their competence. There are some exceptions when treating addiction. PMID:27191427

  5. Light absorption properties and absorption budget of Southeast Pacific waters

    NASA Astrophysics Data System (ADS)

    Bricaud, Annick; Babin, Marcel; Claustre, Hervé; Ras, JoséPhine; TièChe, Fanny

    2010-08-01

    Absorption coefficients of phytoplankton, nonalgal particles (NAPs), and colored dissolved organic matter (CDOM), and their relative contributions to total light absorption, are essential variables for bio-optical and biogeochemical models. However, their actual variations in the open ocean remain poorly documented, particularly for clear waters because of the difficulty in measuring very low absorption coefficients. The Biogeochemistry and Optics South Pacific Experiment (BIOSOPE) cruise investigated a large range of oceanic regimes, from mesotrophic waters around the Marquesas Islands to hyperoligotrophic waters in the subtropical gyre and eutrophic waters in the upwelling area off Chile. The spectral absorption coefficients of phytoplankton and NAPs were determined using the filter technique, while the CDOM absorption coefficients were measured using a 2 m capillary waveguide. Over the whole transect, the absorption coefficients of both dissolved and particulate components covered approximately two orders of magnitude; in the gyre, they were among the lowest ever reported for open ocean waters. In the oligotrophic and mesotrophic waters, absorption coefficients of phytoplankton and NAPs were notably lower than those measured in other oceanic areas with similar chlorophyll contents, indicating some deviation from the standard chlorophyll-absorption relationships. The contribution of absorption by NAPs to total particulate absorption showed large vertical and horizontal variations. CDOM absorption coefficients covaried with algal biomass, albeit with a high scatter. The spectral slopes of both NAP and CDOM absorption revealed structured spatial variability in relation with the trophic conditions. The relative contributions of each component to total nonwater absorption were (at a given wavelength) weakly variable over the transect, at least within the euphotic layer.

  6. The HI absorption "Zoo"

    NASA Astrophysics Data System (ADS)

    Geréb, K.; Maccagni, F. M.; Morganti, R.; Oosterloo, T. A.

    2015-03-01

    We present an analysis of the H I 21 cm absorption in a sample of 101 flux-selected radio AGN (S1.4 GHz> 50 mJy) observed with the Westerbork Synthesis Radio Telescope (WSRT). We detect H I absorption in 32 objects (30% of the sample). In a previous paper, we performed a spectral stacking analysis on the radio sources, while here we characterize the absorption spectra of the individual detections using the recently presented busy function. The H I absorption spectra show a broad variety of widths, shapes, and kinematical properties. The full width half maximum (FWHM) of the busy function fits of the detected H I lines lies in the range 32 km s-1absorption (FW20) lies in the range 63 km s-1 200 km s-1). We study the kinematical and radio source properties of each group, with the goal of identifying different morphological structures of H I. Narrow lines mostly lie at the systemic velocity and are likely produced by regularly rotating H I disks or gas clouds. More H I disks can be present among galaxies with lines of intermediate widths; however, the H I in these sources is more unsettled. We study the asymmetry parameter and blueshift/redshift distribution of the lines as a function of their width. We find a trend for which narrow profiles are also symmetric, while broad lines are the most asymmetric. Among the broadest lines, more lines appear blueshifted than redshifted, similarly to what was found by previous studies. Interestingly, symmetric broad lines are absent from the sample. We argue that if a profile is broad, it is also asymmetric and shifted relative to the systemic velocity because it is tracing unsettled H I gas. In particular, besides three of the broadest (up to FW20 = 825 km s-1

  7. Supramolecular approaches for drug development.

    PubMed

    Kawakami, K; Ebara, M; Izawa, H; Sanchez-Ballester, N M; Hill, J P; Ariga, K

    2012-01-01

    Various supramolecular systems can be used as drug carriers to alter physicochemical and pharmacokinetic characteristics of drugs. Representative supramolecular systems that can be used for this purpose include surfactant/polymer micelles, (micro)emulsions, liposomes, layer-by-layer assemblies, and various molecular conjugates. Notably, liposomes are established supramolecular drug carriers, which have already been marketed in formulations including AmBisome(®) (for treatment of fungal infection), Doxil(®) (for Kaposi's sarcoma), and Visudyne(®) (for age-related macular degeneration and choroidal neovascularization). Microemulsions have been used oral drug delivery of poorly soluble drugs due to improvements in bioavailability and predictable of absorption behavior. Neoral(®), an immunosuppressant used after transplant operations, is one of the most famous microemulsion-based drugs. Polymer micelles are being increasingly investigated as novel drug carriers and some formulations have already been tested in clinical trials. Supramolecular systems can be functionalized by designing the constituent molecules to achieve efficient delivery of drugs to desired sites in the body. In this review, representative supramolecular drug delivery systems, that may improve usability of candidate drugs or add value to existing drugs, are introduced. PMID:22455591

  8. Fed-state gastric media and drug analysis techniques: Current status and points to consider.

    PubMed

    Baxevanis, Fotios; Kuiper, Jesse; Fotaki, Nikoletta

    2016-10-01

    Gastric fed state conditions can have a significant effect on drug dissolution and absorption. In vitro dissolution tests with simple aqueous media cannot usually predict drugs' in vivo response, as several factors such as the meal content, the gastric emptying and possible interactions between food and drug formulations can affect drug's pharmacokinetics. Good understanding of the effect of the in vivo fed gastric conditions on the drug is essential for the development of biorelevant dissolution media simulating the gastric environment after the administration of the standard high fat meal proposed by the FDA and the EMA in bioavailability/bioequivalence (BA/BE) studies. The analysis of drugs in fed state media can be quite challenging as most analytical protocols currently employed are time consuming and labour intensive. In this review, an overview of the in vivo gastric conditions and the biorelevant media used for their in vitro simulation are described. Furthermore an analysis of the physicochemical properties of the drugs and the formulations related to food effect is given. In terms of drug analysis, the protocols currently used for the fed state media sample treatment and analysis and the analytical challenges and needs emerging for more efficient and time saving techniques for a broad spectrum of compounds are being discussed. PMID:27422208

  9. Fed-state gastric media and drug analysis techniques: Current status and points to consider.

    PubMed

    Baxevanis, Fotios; Kuiper, Jesse; Fotaki, Nikoletta

    2016-10-01

    Gastric fed state conditions can have a significant effect on drug dissolution and absorption. In vitro dissolution tests with simple aqueous media cannot usually predict drugs' in vivo response, as several factors such as the meal content, the gastric emptying and possible interactions between food and drug formulations can affect drug's pharmacokinetics. Good understanding of the effect of the in vivo fed gastric conditions on the drug is essential for the development of biorelevant dissolution media simulating the gastric environment after the administration of the standard high fat meal proposed by the FDA and the EMA in bioavailability/bioequivalence (BA/BE) studies. The analysis of drugs in fed state media can be quite challenging as most analytical protocols currently employed are time consuming and labour intensive. In this review, an overview of the in vivo gastric conditions and the biorelevant media used for their in vitro simulation are described. Furthermore an analysis of the physicochemical properties of the drugs and the formulations related to food effect is given. In terms of drug analysis, the protocols currently used for the fed state media sample treatment and analysis and the analytical challenges and needs emerging for more efficient and time saving techniques for a broad spectrum of compounds are being discussed.

  10. Normal and abnormal intestinal absorption by humans

    PubMed Central

    Heizer, William D.

    1979-01-01

    Adults eating a Western diet digest and absorb ingested food containing approximately 100 g fat, 350 g carbohydrate, and 75 g protein daily. Normal fat absorption requires adequate gastric, pancreatic, liver-biliary, mucosal, and lymphatic function. Carbohydrate and protein absorption is much less dependent on liver-biliary and lymphatic function. The intestine has a large reserve capacity for digestion and absorption of nutrients which is due to both excess function and to adaptive changes which increase function in one segment of the digestive-absorptive system when it is decreased or lost in another segment. The large reserve capacity explains why most of the prevalent intestinal diseases seldom cause clinically detectable changes in absorption. However, there are more than 30 less-common human diseases which cause malabsorption of one or more nutrients. Those that cause the malabsorption syndrome, i.e., steatorrhea and weight loss, can be conveniently categorized according to the major deficiency leading to the absorptive defect as follows: insufficient pancreatic enzyme activity, insufficient bile acid, disease of the small intestinal wall, multiple defects, mechanism unknown, and drug-induced malabsorption. A few diseases, most of which are congenital, cause malabsorption of only one or a few related nutrients such as lactose malabsorption in lactase deficiency. Most of the tests currently in use for detecting and diagnosing the cause of malabsorption are relatively insensitive and nonspecific. Chemical analysis of the fat in a three-day stool collection remains the single best test for diagnosing the malabsorption syndrome. However, a breath test using Triolein labeled with either the radioactive or stable isotope of carbon may be an important recent advance. Other breath tests are also currently being investigated for quantitating absorption or malabsorption of various substances including bile acids and various sugars. Studies of the function of the

  11. Acetaminophen (paracetamol) oral absorption and clinical influences.

    PubMed

    Raffa, Robert B; Pergolizzi, Joseph V; Taylor, Robert; Decker, John F; Patrick, Jeffrey T

    2014-09-01

    Acetaminophen (paracetamol) is a widely used nonopioid, non-NSAID analgesic that is effective against a variety of pain types, but the consequences of overdose can be severe. Because acetaminophen is so widely available as a single agent and is increasingly being formulated in fixed-ratio combination analgesic products for the potential additive or synergistic analgesic effect and/or reduced adverse effects, accidental cumulative overdose is an emergent concern. This has rekindled interest in the sites, processes, and pharmacokinetics of acetaminophen oral absorption and the clinical factors that can influence these. The absorption of oral acetaminophen occurs primarily along the small intestine by passive diffusion. Therefore, the rate-limiting step is the rate of gastric emptying into the intestines. Several clinical factors can affect absorption per se or the rate of gastric emptying, such as diet, concomitant medication, surgery, pregnancy, and others. Although acetaminophen does not have the abuse potential of opioids or the gastrointestinal bleeding or organ adverse effects of NSAIDs, excess amounts can produce serious hepatic injury. Thus, an understanding of the sites and features of acetaminophen absorption--and how they might be influenced by factors encountered in clinical practice--is important for pain management using this agent. It can also provide insight for design of formulations that would be less susceptible to clinical variables.

  12. Acetaminophen (paracetamol) oral absorption and clinical influences.

    PubMed

    Raffa, Robert B; Pergolizzi, Joseph V; Taylor, Robert; Decker, John F; Patrick, Jeffrey T

    2014-09-01

    Acetaminophen (paracetamol) is a widely used nonopioid, non-NSAID analgesic that is effective against a variety of pain types, but the consequences of overdose can be severe. Because acetaminophen is so widely available as a single agent and is increasingly being formulated in fixed-ratio combination analgesic products for the potential additive or synergistic analgesic effect and/or reduced adverse effects, accidental cumulative overdose is an emergent concern. This has rekindled interest in the sites, processes, and pharmacokinetics of acetaminophen oral absorption and the clinical factors that can influence these. The absorption of oral acetaminophen occurs primarily along the small intestine by passive diffusion. Therefore, the rate-limiting step is the rate of gastric emptying into the intestines. Several clinical factors can affect absorption per se or the rate of gastric emptying, such as diet, concomitant medication, surgery, pregnancy, and others. Although acetaminophen does not have the abuse potential of opioids or the gastrointestinal bleeding or organ adverse effects of NSAIDs, excess amounts can produce serious hepatic injury. Thus, an understanding of the sites and features of acetaminophen absorption--and how they might be influenced by factors encountered in clinical practice--is important for pain management using this agent. It can also provide insight for design of formulations that would be less susceptible to clinical variables. PMID:26013309

  13. Lipidomics in drug development.

    PubMed

    Dehairs, Jonas; Derua, Rita; Rueda-Rincon, Natalia; Swinnen, Johannes V

    2015-06-01

    Numerous human pathologies, including common conditions such as obesity, diabetes, cardiovascular disease, cancer, inflammatory disease and neurodegeneration, involve changes in lipid metabolism. Likewise, a growing number of drugs are being developed that directly or indirectly affect lipid metabolic pathways. Instead of classical and cumbrous radiochemical analyses, lipid profiling by mass spectrometry (MS)-based lipidomics holds great potential as companion diagnostic in several steps along the drug development process. In this review we describe some typical lipidomics set-ups and illustrate how these technologies can be implemented in target discovery, compound screening, in vitro and in vivo preclinical testing, toxicity testing of drugs, and prediction and monitoring of response. PMID:26190681

  14. Analyzing Water's Optical Absorption

    NASA Technical Reports Server (NTRS)

    2002-01-01

    A cooperative agreement between World Precision Instruments (WPI), Inc., and Stennis Space Center has led the UltraPath(TM) device, which provides a more efficient method for analyzing the optical absorption of water samples at sea. UltraPath is a unique, high-performance absorbance spectrophotometer with user-selectable light path lengths. It is an ideal tool for any study requiring precise and highly sensitive spectroscopic determination of analytes, either in the laboratory or the field. As a low-cost, rugged, and portable system capable of high- sensitivity measurements in widely divergent waters, UltraPath will help scientists examine the role that coastal ocean environments play in the global carbon cycle. UltraPath(TM) is a trademark of World Precision Instruments, Inc. LWCC(TM) is a trademark of World Precision Instruments, Inc.

  15. Grapefruit and drug interactions.

    PubMed

    2012-12-01

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

  16. Grapefruit and drug interactions.

    PubMed

    2012-12-01

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

  17. Monte Carlo simulation of retinal light absorption by infants.

    PubM