[Synthesis of 1-substituted nitroimidazoles and its evaluation as radiosensitizing agents].

PubMed

Adams, D R; Martul, R; Alvarez, M V; López Zumel, M C; Espada, M

1991-01-01

The synthesis of various substituted nitroimidazoles with lipophilic and hydrophilic side chains as potential radiosensitizing agents is described. The starting material employed was 4(5)-nitroimidazole, which was alkylated via the sodium salt with various chloro-methylated, substituted alcohols and esters, in order to obtain analogues of misonidazole, metronidazole and desmethylmisonidazole of known radiosensitizing and bactericidal activity. Some final products were assayed for their radiosensitizing properties giving negative results under the testing conditions used.

Chloronitroimidazoles as radiosensitizers of hypoxic cells in vitro.

PubMed

Wideł, M; Watras, J; Suwiński, J; Salwińska, E

1987-01-01

Some results of the first more complex studies in vitro on radio-sensitizing efficiency, cytotoxicity and reactivity with blood-thiols of a series of 4- or 5-nitroimidazoles substituted in the 5, 4 or 2 position with chlorine are presented. The derivatives of 4-nitroimidazole substituted in 5 position ("ortho" position) with Cl show higher radiosensitizing efficiency than one may expect from their reduction potential, E1/2. At the same time they are extremely toxic, especially for aerobic cells. It is considered that high biological activity of ortho-substituted 4-nitroimidazoles is connected with their considerable chemical reactivity towards thiols and suppression of those natural protective compounds in the cells. The corresponding 5-nitro isomers are about tenfold weaker sensitizers, and simultaneously much less cytotoxic, either in aerobic or in hypoxic conditions. The chloro-4(5)-nitroimidazoles nonsubstituted at N-1 and ionizable in aqueous solution are relatively weaker at the same time less toxic radiosensitizers. It is evaluated that potential application in radiotherapy may have those chloronitroimidazoles which show low aerobic cytotoxicity, moderate radiosensitizing ability and no reactivity towards thiols. On the basis of the study in vitro, we have selected such a compound: 1-methyl-2-chloro-4-nitroimidazole (P13) for screening in vivo.

Validation of a liquid chromatography-tandem mass spectrometry method for the identification and quantification of 5-nitroimidazole drugs and their corresponding hydroxy metabolites in lyophilised pork meat.

PubMed

Zeleny, Reinhard; Harbeck, Stefan; Schimmel, Heinz

2009-01-09

A liquid chromatography-electrospray ionisation tandem mass spectrometry method for the simultaneous detection and quantitation of 5-nitroimidazole veterinary drugs in lyophilised pork meat, the chosen format of a candidate certified reference material, has been developed and validated. Six analytes have been included in the scope of validation, i.e. dimetridazole (DMZ), metronidazole (MNZ), ronidazole (RNZ), hydroxymetronidazole (MNZOH), hydroxyipronidazole (IPZOH), and 2-hydroxymethyl-1-methyl-5-nitroimidazole (HMMNI). The analytes were extracted from the sample with ethyl acetate, chromatographically separated on a C(18) column, and finally identified and quantified by tandem mass spectrometry in the multiple reaction monitoring mode (MRM) using matrix-matched calibration and (2)H(3)-labelled analogues of the analytes (except for MNZOH, where [(2)H(3)]MNZ was used). The method was validated in accordance with Commission Decision 2002/657/EC, by determining selectivity, linearity, matrix effect, apparent recovery, repeatability and intermediate precision, decision limits and detection capabilities, robustness of sample preparation method, and stability of extracts. Recovery at 1 microg/kg level was at 100% (estimates in the range of 101-107%) for all analytes, repeatabilities and intermediate precisions at this level were in the range of 4-12% and 2-9%, respectively. Linearity of calibration curves in the working range 0.5-10 microg/kg was confirmed, with r values typically >0.99. Decision limits (CCalpha) and detection capabilities (CCbeta) according to ISO 11843-2 (calibration curve approach) were 0.29-0.44 and 0.36-0.54 microg/kg, respectively. The method reliably identifies and quantifies the selected nitroimidazoles in the reconstituted pork meat in the low and sub-microg/kg range and will be applied in an interlaboratory comparison for determining the mass fraction of the selected nitroimidazoles in the candidate reference material currently developed at IRMM.

Genotoxicity profile of fexinidazole--a drug candidate in clinical development for human African trypanomiasis (sleeping sickness).

PubMed

Tweats, David; Bourdin Trunz, Bernadette; Torreele, Els

2012-09-01

The parasitic disease human African trypanomiasis (HAT), also known as sleeping sickness, is a highly neglected fatal condition endemic in sub-Saharan Africa, which is poorly treated with medicines that are toxic, no longer effective or very difficult to administer. New, safe, effective and easy-to-use treatments are urgently needed. Many nitroimidazoles possess antibacterial and antiprotozoal activity and examples such as tinidazole are used to treat trichomoniasis and guardiasis, but concerns about toxicity including genotoxicity limit their usefulness. Fexinidazole, a 2-substituted 5-nitroimidazole rediscovered by the Drugs for Neglected Diseases initiative (DNDi) after extensive compound mining of public and pharmaceutical company databases, has the potential to become a short-course, safe and effective oral treatment, curing both acute and chronic HAT. This paper describes the genotoxicity profile of fexinidazole and its two active metabolites, the sulfoxide and sulfone derivatives. All the three compounds are mutagenic in the Salmonella/Ames test; however, mutagenicity is either attenuated or lost in Ames Salmonella strains that lack one or more nitroreductase(s). It is known that these enzymes can nitroreduce compounds with low redox potentials, whereas their mammalian cell counterparts cannot, under normal conditions. Fexinidazole and its metabolites have low redox potentials and all mammalian cell assays to detect genetic toxicity, conducted for this study either in vitro (micronucleus test in human lymphocytes) or in vivo (ex vivo unscheduled DNA synthesis in rats; bone marrow micronucleus test in mice), were negative. Thus, fexinidazole does not pose a genotoxic hazard to patients and represents a promising drug candidate for HAT. Fexinidazole is expected to enter Phase II clinical trials in 2012.

Screening and confirmation of steroids and nitroimidazoles in urine, blood, and food matrices: Sample preparation methods and liquid chromatography tandem mass spectrometric separations.

PubMed

Tölgyesi, Ádám; Barta, Enikő; Simon, Andrea; McDonald, Thomas J; Sharma, Virender K

2017-10-25

Veterinary drugs containing synthetic anabolic steroid and nitroimidazole active agents are not allowed for their applications in livestock of the European Union (EU). This paper presents analyses of twelve selected steroids and six nitroimidazole antibiotics at low levels (1.56μg/L-4.95μg/L and 0.17μg/kg-2.14μg/kg, respectively) in body fluids and egg incurred samples. Analyses involved clean-up procedures, high performance liquid chromatography (HPLC) separation, and tandem mass spectrometric screening and confirmatory methods. Target steroids and nitroimidazoles in samples were cleaned by two independent supported liquid extraction and solid phase extraction procedures. Separation of the selected compounds was conducted on Kinetex XB C-18 HPLC column using gradient elution. The screening methods utilised supported liquid extraction that enabled fast and cost effective clean-up. The confirmatory methods were improved by extending the number of matrices and compounds, and by introducing an isotope dilution mass spectrometry for nitroimidazoles. The new methods were validated according to the recommendation of the European Union Reference Laboratories and the performance characteristics evaluated met fully the criteria. The methods were applied to incurred samples in the proficiency tests. The obtained results of Z-scores demonstrated the applicability of developed protocols of the methods to real samples. The confirmatory methods were applied to the national monitoring program and natural contamination of prednisolone could be detected in urine at low concentration in few samples. Copyright © 2017 Elsevier B.V. All rights reserved.

Development and Evaluation of Taste Masked Granular Formulation of Satranidazole by Melt Granulation Technique

PubMed Central

Pawar, Harshal Ashok; Joshi, Pooja Rasiklal

2014-01-01

Drugs from nitroimidazole category are generally bitter in taste. Oral formulation with bitter taste is not palatable. Geriatrics and pediatrics patients usually suffer from swallowing difficulties. Many other patients in some disease conditions avoid swallowing tablets. Satranidazole is a new nitro-imidazole derivative with bitter taste and is available in market as film coated tablet. The purpose of this research was to mask the bitter taste of Satranidazole by coating complexation with low melting point wax and Eudragit EPO. Different types of wax (glyceryl monostearate, stearic acid and cetyl alcohol) were tried for taste masking. The drug to stearic acid ratio 1 : 2 was found to be optimum on the basis of taste evaluation and in vitro release. The formulated granules were found to possess good flow property. FTIR studies confirmed that there was no interaction between drug and excipients. Scanning Electron Microscopy of drug and the optimized batch of granules was performed. The in vitro release of drug from granules was compared with marketed tablet formulation. The taste masked granules of optimized batch showed 87.65% release of drug in 1 hr which is comparable to that of marketed tablet formulation. PMID:26556200

Trichomonas vaginalis antimicrobial drug resistance in 6 US cities, STD Surveillance Network, 2009-2010.

PubMed

Kirkcaldy, Robert D; Augostini, Peter; Asbel, Lenore E; Bernstein, Kyle T; Kerani, Roxanne P; Mettenbrink, Christie J; Pathela, Preeti; Schwebke, Jane R; Secor, W Evan; Workowski, Kimberly A; Davis, Darlene; Braxton, Jim; Weinstock, Hillard S

2012-06-01

Nitroimidazoles (metronidazole and tinidazole) are the only recommended drugs for treating Trichomonas vaginalis infection, and previous samples that assessed resistance of such isolates have been limited in geographic scope. We assessed the prevalence of in vitro aerobic metronidazole and tinidazole resistance among T. vaginalis isolates from multiple geographic sites in the United States. Swab specimens were obtained from women who underwent routine pelvic examinations at sexually transmitted disease clinics in 6 US cities. Cultured T. vaginalis isolates were tested for nitroimidazole resistance (aerobic minimum lethal concentration [MLC] >50 µg/mL). Of 538 T. vaginalis isolates, 23 (4.3%) exhibited low-level in vitro metronidazole resistance (minimum lethal concentrations 50-100 µg/mL). No isolates exhibited moderate- to high-level metronidazole resistance or tinidazole resistance. Results highlight the possibility that reliance on a single class of antimicrobial drugs for treating T. vaginalis infections may heighten vulnerability to emergence of resistance. Thus, novel treatment options are needed.

Management of trichomonas vaginalis in women with suspected metronidazole hypersensitivity.

PubMed

Helms, Donna J; Mosure, Debra J; Secor, W Evan; Workowski, Kimberly A

2008-04-01

Standard treatment for Trichomonas vaginalis is metronidazole or tinidazole. Hypersensitivity to these drugs has been documented but is poorly understood. Desensitization is an option described in limited reports of women with hypersensitivity to nitroimidazoles. The purpose of this analysis is to improve documentation of management for trichomonas infections among women with metronidazole hypersensitivity. Clinicians who consulted Centers for Disease Control and Prevention concerning patients with suspected hypersensitivity to metronidazole were provided with treatment options and asked to report outcomes. From September 2003-September 2006, complete information was obtained for 59 women. The most common reactions were urticaria (47%) and facial edema (11%). Fifteen of these women (25.4%) were treated with metronidazole desensitization and all had eradication of their infection. Seventeen women (28.8%) were treated with alternative intravaginal drugs, which were less successful; 5 of 17 infections (29.4%) were eradicated. Metronidazole desensitization was effective in the management of women with nitroimidazole hypersensitivity.

Simultaneous determination of nitroimidazoles, benzimidazoles, and chloramphenicol components in bovine milk by ultra-high performance liquid chromatography-tandem mass spectrometry.

PubMed

Wang, Yuanyuan; Li, Xiaowei; Zhang, Zhiwen; Ding, Shuangyang; Jiang, Haiyang; Li, Jiancheng; Shen, Jianzhong; Xia, Xi

2016-02-01

A sensitive, confirmatory ultra-high performance liquid chromatography-tandem mass spectrometric method was developed and validated to detect 23 veterinary drugs and metabolites (nitroimidazoles, benzimidazoles, and chloramphenicol components) in bovine milk. Compounds of interest were sequentially extracted from milk with acetonitrile and basified acetonitrile using sodium chloride to induce liquid-liquid partition. The extract was purified on a mixed mode solid-phase extraction cartridge. Using rapid polarity switching in electrospray ionization, a single injection was capable of detecting both positively and negatively charged analytes in a 9 min chromatography run time. Recoveries based on matrix-matched calibrations and isotope labeled internal standards for milk ranged from 51.7% to 101.8%. The detection limits and quantitation limits of the analytical method were found to be within the range of 2-20 ng/kg and 5-50 ng/kg, respectively. The recommended method is simple, specific, and reliable for the routine monitoring of nitroimidazoles, benzimidazoles, and chloramphenicol components in bovine milk samples. Copyright © 2015 Elsevier Ltd. All rights reserved.

Trypanocidal nitroimidazole derivatives: relationships among chemical structure and genotoxic activity.

PubMed

Buschini, Annamaria; Giordani, Federica; de Albuquerque, Cristina Northfleet; Pellacani, Claudia; Pelosi, Giorgio; Rossi, Carlo; Zucchi, Tânia Maria Araújo Domingues; Poli, Paola

2007-05-15

Human American trypanosomiasis is resurgent in Latin Americans, and new drugs are urgently required as current medications suffer from a number of drawbacks. Some nitroheterocycles have been demonstrated to exert a potent activity against trypanosomes. However, host toxicity issues halted their development as trypanocides. As part of the efforts to develop new compounds in order to treat parasitic infections, it is important to define their structure-activity relationship. In this study, 5-nitromegazol and two of its analogues, 4-nitromegazol, and 1-methyl-5-nitro-2-imidazolecarboxaldehyde 5-nitroimidazole-thiosemicarbazone, were tested and compared for in vitro induction of DNA damage in human leukocytes by the comet assay, performed at different pHs to better identify the types of damage. Specific oxidatively generated damage to DNA was also measured by using the comet assay with endonucleases. DNA damage was found in 5-nitromegazol-treated cells: oxidative stress appeared as the main source of DNA damage. 4-Nitromegazol did not produce any significant effect, thus confirming that 4-nitroimidazoles isomers have no important biological activity. The 5-nitroimidazole-thiosemicarbazone induced DNA damage with a higher efficiency than 5-nitromegazol. The central role in the reduction process played by the acidic hydrazine proton present in the thiosemicarbazone group but not in the cyclic (thiadiazole) form can contribute to rationalise our results. Given its versatility, thiosemicarbazone moiety could be involved in different reactions with nitrogenous bases (nucleophilic and/or electrophilic attacks).

Immunosuppression by hypoxic cell radiosensitizers: a phenomenon of potential clinical importance

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rockwell, S.; Kapp, D.S.

1982-06-01

The nitroimidazoles metronidazole, misonidazol, and desmethyl misonidazole are currently undergoing clinical trials as possible adjuncts to radiotherapy. Ongoing clinical trials are evaluating the effectiveness of these agents and also documenting the pharmacokinetics and toxicities of radiosensitizing doses of these drugs in man. A variety of toxic effects have been noted in man, including anorexia, nausea and vomiting, peripheral neuropathy, central nervous system symptoms, ototoxicity, allergy, and fear. Laboratory studies have also suggested that these agents have potential to be mutagenic, carcinogenic, and teratogenic. In the editorial presented, the author attempts to draw attention to an additional toxic effect of nitroimidazolesmore » - the inhibition of cell-mediated immune responses. (JMT)« less

Gas-phase acidities of nitrated azoles as determined by the extended kinetic method and computations.

PubMed

Nichols, Charles M; Old, William M; Lineberger, W Carl; Bierbaum, Veronica M

2015-01-15

Making use of the extended kinetic method and the alternative method for data analysis, we have experimentally determined ΔH°acid (kcal/mol) for six mononitrated azole species (2-nitropyrrole = 337.0, 3-nitropyrrole = 335.8, 3-nitropyrazole = 330.5, 4-nitropyrazole = 329.5, 2-nitroimidazole = 327.4, and 4-nitroimidazole = 325.0). We report an absolute uncertainty of ±2.2 kcal/mol that arises from the uncertainties of the reference acids; the relative values are known within 0.4 kcal/mol. Combining these experimental ΔH°acid values with ΔS°acid values calculated at the B3LYP/aug-cc-pVTZ level of theory, we report ΔG°acid (kcal/mol) for the nitroazoles (2-nitropyrrole = 329.4, 3-nitropyrrole = 328.4, 3-nitropyrazole = 323.1, 4-nitropyrazole = 322.0, 2-nitroimidazole = 319.7, and 4-nitroimidazole = 317.6); the absolute uncertainties are ±2.4 kcal/mol. In addition to the experimental studies, we have computationally investigated the gas-phase acidities and electron affinities of the azoles in this work, as well as higher-order aza- and dinitro-substituted azoles. We discuss trends in the stabilities of the deprotonated azoles based on aza substitution and nitro group placement. 4-Nitroimidazole has already found use as the anionic component in ionic liquids, and we propose that the additional nitrated azolate ions are potential candidates for the anionic component of ionic liquids.

New synthesis and antiparasitic activity of model 5-aryl-1-methyl-4-nitroimidazoles.

PubMed

Saadeh, Haythem A; Mosleh, Ibrahim M; El-Abadelah, Mustafa M

2009-07-27

A number of 5-aryl-1-methyl-4-nitroimidazoles 5a-f have been synthesized in good yields by the Suzuki coupling reaction between 5-chloro-1-methyl-4-nitroimidazole (3) and arylboronic acids 4a-f, aided by dichlorobis-(triphenylphosphine)palladium(II), K(2)CO(3, )and tetrabutylammonium bromide in water at 70-80 degrees C. Compounds 5a-f were characterized by elemental analysis, NMR and MS spectral data. On the basis of in vitro screening data, 5-(3-chlorophenyl)-1-methyl-4-nitro-1H-imidazole (5f) exhibited potent lethal activity against Entamoeba histolytica and Giardia intestinalis with IC(50) = 1.47 microM/mL, a value lower by a factor of two than that of the standard drug, metronidazole. The boosted activity of 5f was not accompanied by any increased cytotoxicity.The rest of the series also exhibited potent antiparasitic activity with IC(50 ) values in the 1.72-4.43 microM/mL range. The cytotoxicity of the derivatives 5c and 5e was increased compared to the precursor compound, metronidazole, although they remain non-cytotoxic at concentrations much higher than the antiparasitic concentration of the two derivatives.

Topology and dynamics of the interaction between 5-nitroimidazole radiosensitizers and duplex DNA studied by a combination of docking, molecular dynamic simulations and NMR spectroscopy

NASA Astrophysics Data System (ADS)

Ramalho, Teodorico C.; França, Tanos C. C.; Cortopassi, Wilian A.; Gonçalves, Arlan S.; da Silva, Alan W. S.; da Cunha, Elaine F. F.

2011-04-01

In spite of recent progress, cancer is still one of the most serious health problems of mankind. Recently, it has been discovered that tumor hypoxia can be exploited for selective anticancer treatment using radiosensitizers that are activated only under hypoxic conditions. The most commonly used radiosensitizers are the 5-nitroimidazole derivatives. The toxicity of bioreductive anticancer drugs, such as radiosensitizers is associated to their interaction with DNA. In this work, we have investigated the interaction between the model radiosensitizers metronizole, nimorazole and secnidazole with salmon DNA in order to get insights on the drug-macromolecule interactions. To this end, we have employed NMR techniques (PFG NMR spectra and spin-lattice relaxation rates) in combination with theoretical tools, such as docking calculations and MD simulations. Initially, results show that the δ values are not the most appropriated NMR parameters to map the interaction topology of drug-macromolecule complexes. Furthermore our data indicate that radiosensitizers, in the inactive form, interact considerably with DNA, significantly increasing its toxicity. In fact, we obtained a good agreement between that technique and docking and MD simulations. This suggests that improvements in the structures of these molecules in order to achieve new and more selective bioreductive anticancer drugs are still necessary.

Persistent and recurrent Trichomonas vaginalis infections: epidemiology, treatment and management considerations.

PubMed

Seña, Arlene C; Bachmann, Laura H; Hobbs, Marcia M

2014-06-01

Trichomonas vaginalis (TV) is a common sexually transmitted infection that can cause vaginitis, cervicitis and urethritis. Persistent and recurrent TV infections are frequent in women, potentially due to the lack of routine screening recommendations for this pathogen, the chronic nature of some infections, and drug resistance. Metronidazole and tinidazole are two oral drugs that are effective against trichomoniasis. There are few alternative treatment options for persons with a metronidazole allergy or treatment failure. Most TV isolates from women with treatment failures that have been analyzed for susceptibility testing in the United States have exhibited low-level metronidazole resistance, supporting the initial use of tinidazole for patients who fail metronidazole therapy. Several non-nitroimidazole drugs and other agents have demonstrated acceptable in vitro activity or cure rates in case reports for metronidazole-resistant trichomoniasis; however, clinical trials are imperative to evaluate their efficacy as alternative therapeutic regimens for this highly prevalent infection.

Alternative Pathway of Metronidazole Activation in Trichomonas vaginalis Hydrogenosomes

PubMed Central

Hrdý, Ivan; Cammack, Richard; Stopka, Pavel; Kulda, Jaroslav; Tachezy, Jan

2005-01-01

Metronidazole and related 5-nitroimidazoles are the only available drugs in the treatment of human urogenital trichomoniasis caused by the protozoan parasite Trichomonas vaginalis. The drugs are activated to cytotoxic anion radicals by their reduction within the hydrogenosomes. It has been established that electrons required for metronidazole activation are released from pyruvate by the activity of pyruvate:ferredoxin oxidoreductase and transferred to the drug by a low-redox-potential carrier, ferredoxin. Here we describe a novel pathway involved in the drug activation within the hydrogenosome. The source of electrons is malate, another major hydrogenosomal substrate, which is oxidatively decarboxylated to pyruvate and CO2 by NAD-dependent malic enzyme. The electrons released during this reaction are transferred from NADH to ferredoxin by NADH dehydrogenase homologous to the catalytic module of mitochondrial complex I, which uses ferredoxin as electron acceptor. Trichomonads acquire high-level metronidazole resistance only after both pyruvate- and malate-dependent pathways of metronidazole activation are eliminated from the hydrogenosomes. PMID:16304169

Validation of a method for simultaneous determination of nitroimidazoles, benzimidazoles and chloramphenicols in swine tissues by ultra-high performance liquid chromatography-tandem mass spectrometry.

PubMed

Xia, Xi; Wang, Yuanyuan; Wang, Xia; Li, Yun; Zhong, Feng; Li, Xiaowei; Huang, Yaoling; Ding, Shuangyang; Shen, Jianzhong

2013-05-31

This paper presents a sensitive and confirmatory multi-residue method for the analysis of 23 veterinary drugs and metabolites belonging to three classes (nitroimidazoles, benzimidazoles, and chloramphenicols) in porcine muscle, liver, and kidney. After extracted with ethyl acetate and basic ethyl acetate sequentially, the crude extracts were defatted with hexane and further purified using Oasis MCX solid-phase extraction cartridges. Rapid determination was carried out by ultra-high performance liquid chromatography-electrospray ionization tandem mass spectrometry. Data acquisition was performed under positive and negative mode simultaneously. Recoveries based on matrix-matched calibrations for meat, liver, and kidney ranged from 50.6 to 108.1%. The method quantification limits were in the range of 3-100ng/kg. Copyright © 2012 Elsevier B.V. All rights reserved.

PA-824 Kills Nonreplicating Mycobacterium tuberculosis by Intracellular NO Release

PubMed Central

Singh, Ramandeep; Manjunatha, Ujjini; Boshoff, Helena I. M.; Ha, Young Hwan; Niyomrattanakit, Pornwaratt; Ledwidge, Richard; Dowd, Cynthia S.; Lee, Ill Young; Kim, Pilho; Zhang, Liang; Kang, Sunhee; Keller, Thomas H.; Jiricek, Jan; Barry, Clifton E.

2009-01-01

Bicyclic nitroimidazoles, including PA-824, are exciting candidates for the treatment of tuberculosis. These prodrugs require intracellular activation for their biological function. We found that Rv3547 is a deazaflavin-dependent nitroreductase (Ddn) that converts PA-824 into three primary metabolites; the major one is the corresponding des-nitroimidazole (des-nitro). When derivatives of PA-824 were used, the amount of des-nitro metabolite formed was highly correlated with anaerobic killing of Mycobacterium tuberculosis (Mtb). Des-nitro metabolite formation generated reactive nitrogen species, including nitric oxide (NO), which are the major effectors of the anaerobic activity of these compounds. Furthermore, NO scavengers protected the bacilli from the lethal effects of the drug. Thus, these compounds may act as intracellular NO donors and could augment a killing mechanism intrinsic to the innate immune system. PMID:19039139

The Expanding Diversity of Mycobacterium tuberculosis Drug Targets.

PubMed

Wellington, Samantha; Hung, Deborah T

2018-05-11

After decades of relative inactivity, a large increase in efforts to discover antitubercular therapeutics has brought insights into the biology of Mycobacterium tuberculosis (Mtb) and promising new drugs such as bedaquiline, which inhibits ATP synthase, and the nitroimidazoles delamanid and pretomanid, which inhibit both mycolic acid synthesis and energy production. Despite these advances, the drug discovery pipeline remains underpopulated. The field desperately needs compounds with novel mechanisms of action capable of inhibiting multi- and extensively drug -resistant Mtb (M/XDR-TB) and, potentially, nonreplicating Mtb with the hope of shortening the duration of required therapy. New knowledge about Mtb, along with new methods and technologies, has driven exploration into novel target areas, such as energy production and central metabolism, that diverge from the classical targets in macromolecular synthesis. Here, we review new small molecule drug candidates that act on these novel targets to highlight the methods and perspectives advancing the field. These new targets bring with them the aspiration of shortening treatment duration as well as a pipeline of effective regimens against XDR-TB, positioning Mtb drug discovery to become a model for anti-infective discovery.

Drug Targets and Mechanisms of Resistance in the Anaerobic Protozoa

PubMed Central

Upcroft, Peter; Upcroft, Jacqueline A.

2001-01-01

The anaerobic protozoa Giardia duodenalis, Trichomonas vaginalis, and Entamoeba histolytica infect up to a billion people each year. G. duodenalis and E. histolytica are primarily pathogens of the intestinal tract, although E. histolytica can form abscesses and invade other organs, where it can be fatal if left untreated. T. vaginalis infection is a sexually transmitted infection causing vaginitis and acute inflammatory disease of the genital mucosa. T. vaginalis has also been reported in the urinary tract, fallopian tubes, and pelvis and can cause pneumonia, bronchitis, and oral lesions. Respiratory infections can be acquired perinatally. T. vaginalis infections have been associated with preterm delivery, low birth weight, and increased mortality as well as predisposing to human immunodeficiency virus infection, AIDS, and cervical cancer. All three organisms lack mitochondria and are susceptible to the nitroimidazole metronidazole because of similar low-redox-potential anaerobic metabolic pathways. Resistance to metronidazole and other drugs has been observed clinically and in the laboratory. Laboratory studies have identified the enzyme that activates metronidazole, pyruvate:ferredoxin oxidoreductase, to its nitroso form and distinct mechanisms of decreasing drug susceptibility that are induced in each organism. Although the nitroimidazoles have been the drug family of choice for treating the anaerobic protozoa, G. duodenalis is less susceptible to other antiparasitic drugs, such as furazolidone, albendazole, and quinacrine. Resistance has been demonstrated for each agent, and the mechanism of resistance has been investigated. Metronidazole resistance in T. vaginalis is well documented, and the principal mechanisms have been defined. Bypass metabolism, such as alternative oxidoreductases, have been discovered in both organisms. Aerobic versus anaerobic resistance in T. vaginalis is discussed. Mechanisms of metronidazole resistance in E. histolytica have recently been investigated using laboratory-induced resistant isolates. Instead of downregulation of the pyruvate:ferredoxin oxidoreductase and ferredoxin pathway as seen in G. duodenalis and T. vaginalis, E. histolytica induces oxidative stress mechanisms, including superoxide dismutase and peroxiredoxin. The review examines the value of investigating both clinical and laboratory-induced syngeneic drug-resistant isolates and dissection of the complementary data obtained. Comparison of resistance mechanisms in anaerobic bacteria and the parasitic protozoa is discussed as well as the value of studies of the epidemiology of resistance. PMID:11148007

Reactions in Nitroimidazole and Methylnitroimidazole Triggered by Low-Energy (0-8 eV) Electrons.

PubMed

Tanzer, Katrin; Feketeová, Linda; Puschnigg, Benjamin; Scheier, Paul; Illenberger, Eugen; Denifl, Stephan

2015-06-25

Low-energy electrons (0-8 eV) effectively decompose 4-nitroimidazole (4NI) and the two methylated isomers 1-methyl-5-nitroimidazole and 1-methyl-4-nitroimidazole via dissociative electron attachment (DEA). The involved unimolecular decompositions range from simple bond cleavages (loss of H(•), formation of NO2(-)) to complex reactions possibly leading to a complete degradation of the target molecule (formation of CN(-), etc.). At energies below 2 eV, the entire rich chemistry induced by DEA is completely quenched by methylation, as demonstrated in a previous communication (Tanzer, K.; Feketeová, L.; Puschnigg, B.; Scheier, P.; Illenberger. E.; Denifl, S. Angew. Chem., Int. Ed. 2014, 53, 12240). The observation that in 4NI neutral radicals and radical anions are formed via DEA at high efficiency already at threshold (0 eV) may have significant implications for the development of nitroimidazole-based radiosensitizers in tumor radiation therapy.

Communication: "Position" does matter: The photofragmentation of the nitroimidazole isomers

NASA Astrophysics Data System (ADS)

Bolognesi, P.; Casavola, A. R.; Cartoni, A.; Richter, R.; Markus, P.; Borocci, S.; Chiarinelli, J.; Tošić, S.; Sa'adeh, H.; Masič, M.; Marinković, B. P.; Prince, K. C.; Avaldi, L.

2016-11-01

A combined experimental and theoretical approach has been used to disentangle the fundamental mechanisms of the fragmentation of the three isomers of nitroimidazole induced by vacuum ultra-violet (VUV) radiation, namely, 4-, 5-, and 2-nitroimidazole. The results of mass spectrometry as well as photoelectron-photoion coincidence spectroscopy display striking differences in the radiation-induced decomposition of the different nitroimidazole radical cations. Based on density functional theory (DFT) calculations, a model is proposed which fully explains such differences, and reveals the subtle fragmentation mechanisms leading to the release of neutral species like NO, CO, and HCN. Such species have a profound impact in biological media and may play a fundamental role in radiosensitising mechanisms during radiotherapy.

DNA-Targeted 2-Nitroimidazoles: Studies of the Influence of the Phenanthridine-Linked Nitroimidazoles, 2-NLP-3 and 2-NLP-4, on DNA Damage Induced by Ionizing Radiation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Buchko, Garry W.; Weinfeld, Michael

The nitroimidazole-linked phenanthridines 2-NLP-3 (5-[3-(2-nitro-1-imidazoyl)-propyl]-phenanthridinium bromide) and 2-NLP-4 (5-[3-(2-nitro-1-imidazoyl)-butyl1]-phenanthridinium bromide) are composed of the radiosensitizer, 2-nitroimidazole, attached to the DNA intercalator phenanthridine via a 3- and 4-carbon linker, respectively. Previous in vitro assays show both compounds to be 10 - 100 times more efficient as hypoxic cell radiosensitizer, misonidazole[Cowan et al., Radiat. Res. 127, 81-89, 1991]. Here we have used a 32P postlabeling assay and 5'-end labeled oligonucleotide assay to compare the radiogenic DNA damage generated in the presence of 2-NLP-3, 2-NLP-4 compared to irradiation in the presence of misonidazole. This may account, at least in part, for the greatermore » cellular radiosensitization shown by the nitroimidazole-linked phenanthridines over misonidazole.« less

Validated method for determination of eight banned nitroimidazole residues in natural casings by LC/MS/MS with solid-phase extraction.

PubMed

Sun, Hanwen; Wang, Fengchi; Ai, Lianfeng; Guo, Chunhai; Chen, Ruichun

2009-01-01

A sensitive method based on solid-phase extraction-liquid chromatography-tandem mass spectrometry interfaced with electrospray ionization (SPE-LC-MS/MS-ESI) was developed for the simultaneous determination of 8 banned nitroimidazole (NOZ) drugs including metronidazole (MNZ), ronidazole (RNZ), dimetridazole (DMZ), tinidazole, ornidazole, secnidazole, metronidazole-OH (MNZOH, the metabolite of MNZ), and 2-hydroxymethyl-1-methyl-5-nitroimidazole (HMMNI, the metabolite of RNZ and DMZ) in natural casings. After extraction with ethyl acetate and evaporation, the NOZs were reconstituted in ethyl acetate and purified on a strong cation-exchange SPE column, and then LC/MS/MS analysis was performed by positive ESI applying multiple reaction monitoring of 2 transition reactions for each compound. The method was validated according to the European Union requirements (Commission Decision 2002/657/EC). Specificity, linearity, decision limit (CCalpha), detection capability (CCbeta), accuracy, and precision were determined. Average recoveries of the 8 NOZs from natural animal casing fortified at 3 levels (0.1, 0.5, and 1 microg/kg) ranged from 87.3 to 116.5%. The calculated CCalpha for NOZs ranged from 0.029 to 0.049 microg/kg, and CCbeta ranged from 0.049 to 0.083 microg/kg. Repeatability was in the range of 3.35-10.1%, and within-laboratory reproducibility was <10.3%.

Validation of a new screening, determinative, and confirmatory multi-residue method for nitroimidazoles and their hydroxy metabolites in turkey muscle tissue by liquid chromatography-tandem mass spectrometry.

PubMed

Boison, Joe O; Asea, Philip A; Matus, Johanna L

2012-08-01

A new and sensitive multi-residue method (MRM) with detection by LC-MS/MS was developed and validated for the screening, determination, and confirmation of residues of 7 nitroimidazoles and 3 of their metabolites in turkey muscle tissues at concentrations ≥ 0.05 ng/g. The compounds were extracted into a solvent with an alkali salt. Sample clean-up and concentration was then done by solid-phase extraction (SPE) and the compounds were quantified by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The characteristic parameters including repeatability, selectivity, ruggedness, stability, level of quantification, and level of confirmation for the new method were determined. Method validation was achieved by independent verification of the parameters measured during method characterization. The seven nitroimidazoles included are metronidazole (MTZ), ronidazole (RNZ), dimetridazole (DMZ), tinidazole (TNZ), ornidazole (ONZ), ipronidazole (IPR), and carnidazole (CNZ). It was discovered during the single laboratory validation of the method that five of the seven nitroimidazoles (i.e. metronidazole, dimetridazole, tinidazole, ornidazole and ipronidazole) and the 3 metabolites (1-(2-hydroxyethyl)-2-hydroxymethyl-5-nitroimidazole (MTZ-OH), 2-hydroxymethyl-1-methyl-5-nitroimidazole (HMMNI, the common metabolite of ronidazole and dimetridazole), and 1-methyl-2-(2'-hydroxyisopropyl)-5-nitroimidazole (IPR-OH) included in this study could be detected, confirmed, and quantified accurately whereas RNZ and CNZ could only be detected and confirmed but not accurately quantified. © Her Majesty the Queen in Right of Canada as Represented by the Minister of Agriculture and Agri-food Canada 2012.

Treatment of Giardiasis

PubMed Central

Gardner, Timothy B.; Hill, David R.

2001-01-01

Giardia lamblia is both the most common intestinal parasite in the United States and a frequent cause of diarrheal illness throughout the world. In spite of its recognition as an important human pathogen, there have been relatively few agents used in therapy. This paper discusses each class of drugs used in treatment, along with their mechanism of action, in vitro and clinical efficacy, and side effects and contraindications. Recommendations are made for the preferred treatment in different clinical situations. The greatest clinical experience is with the nitroimidazole drugs, i.e., metronidazole, tinidazole, and ornidazole, which are highly effective. A 5- to 7-day course of metronidazole can be expected to cure over 90% of individuals, and a single dose of tinidazole or ornidazole will cure a similar number. Quinacrine, which is no longer produced in the United States, has excellent efficacy but may be poorly tolerated, especially in children. Furazolidone is an effective alternative but must be administered four times a day for 7 to 10 days. Paromomycin may be used during early pregnancy, because it is not systematically absorbed, but it is not always effective. Patients who have resistant infection can usually be cured by a prolonged course of treatment with a combination of a nitroimidazole with quinacrine. PMID:11148005

Utility of antimicrobial susceptibility testing in Trichomonas vaginalis-infected women with clinical treatment failure.

PubMed

Bosserman, Elizabeth A; Helms, Donna J; Mosure, Debra J; Secor, W Evan; Workowski, Kimberly A

2011-10-01

Antimicrobial resistance is one of the causes of treatment failure in women after standard nitroimidazole therapy for Trichomonas vaginalis infections. The Centers for Disease Control and Prevention provides drug susceptibility testing and guidance for treatment failures but the efficacy of the alternate recommendations has not been assessed. T. vaginalis isolates from women who had failed at least 2 courses of standard therapy for trichomoniasis were submitted to the Centers for Disease Control and Prevention for susceptibility testing. Alternative treatment recommendations were provided based on in vitro drug susceptibility results and clinical outcomes were collected. Drug susceptibility results were available for 175 women tested between January 2002 and January 2008. In vitro, 115 of the 175 isolates demonstrated metronidazole resistance. For all isolates resistant to metronidazole, in vitro resistance to tinidazole was similar or lower. Clinical treatment outcomes were available for 72 women. Of the women receiving an alternative recommended nitroimidazole regimen, 30 (83%) of 36 were cured compared with 8 (57%) of 14 women who received a lower dose than recommended. Clinical and microbiologic success was attained in 59 (82%) of 72 women whose follow-up information was available, with some women requiring multiple treatment courses. Clinical and microbiologic cure rates were higher for women who were treated in accordance with the recommendation provided after in vitro testing compared with those who received a lower dose or a different drug. Susceptibility testing leading to tailored treatment may have a beneficial role for management of women with persistent trichomoniasis.

A new-generation 5-nitroimidazole can induce highly metronidazole-resistant Giardia lamblia in vitro

PubMed Central

Dunn, Linda A.; Burgess, Anita G.; Krauer, Kenia G.; Eckmann, Lars; Vanelle, Patrice; Crozet, Maxime D.; Gillin, Frances D.; Upcroft, Peter; Upcroft, Jacqueline A.

2010-01-01

The 5-nitroimidazole (NI) compound C17, with a side chain carrying a remote phenyl group in the 2-position of the imidazole ring, is at least 14-fold more active against the gut protozoan parasite Giardia lamblia than the 5-NI drug metronidazole (MTR), with a side chain in the 1-position of the imidazole ring, which is the primary drug for the treatment of giardiasis. Over 10 months, lines resistant to C17 were induced in vitro and were at least 12-fold more resistant to C17 than the parent strains. However, these lines had ID90 values (concentration of drug at which 10% of control parasite ATP levels are detected) for MTR of >200 μM, whilst lines induced to be highly resistant to MTR in vitro have maximum ID90 values around 100 μM (MTR-susceptible isolates typically have an ID90 of 5–12.8 μM). The mechanism of MTR activation in Giardia apparently involves reduction to toxic radicals by the activity of pyruvate:ferredoxin oxidoreductase (PFOR) and the electron acceptor ferredoxin. MTR-resistant Giardia have decreased PFOR activity, which is consistent with decreased activation of MTR in these lines, but C17-resistant lines have normal levels of PFOR. Therefore, an alternative mechanism of resistance in Giardia must account for these super-MTR-resistant cells. PMID:20456926

Evaluation of antitumor activity and development of solid lipid nanoparticles of metronidazole analogue.

PubMed

Lages, Eduardo Burgarelli; de Freitas, Maria Betânia; Gonçalves, Isadora Marques Brum; Alves, Ricardo José; Vianna-Soares, Cristina Duarte; Ferreira, Lucas Antônio Miranda; de Oliveira, Mônica Cristina; de Oliveira, Renata Barbosa

2013-11-01

Nitroheterocyclic compounds have received considerable interest as hypoxia-selective cytotoxins (HSC) for cancer treatment. In the present study, we investigated antitumor activity of an iodide analogue of metronidazole, 1-(2-iodoethyl)-2-methyl-5-nitroimidazole (MTZ-I), using Swiss mice bearing solid Ehrlich tumor. MTZ-I showed potent anti-cancer activity at a dose of 40 mg/kg. MTZ-I loaded solid lipid nanoparticles (SLN) were developed as an alternative colloidal carrier system to enhance tumor drug uptake. SLN were characterized for particle size, polydispersity index, zeta potential and entrapment efficiency. In addition, the influence of presence of the cationic lipid stearylamine (STE) on stability of formulation was assessed. The results of DSC study showed that MTZ-I exhibited interaction with STE.

A rare adverse effect of metronidazole: nervous system symptoms.

PubMed

Kafadar, Ihsan; Moustafa, Fatma; Yalçın, Koray; Klç, Betül Aydn

2013-06-01

Metronidazole, as a 5-nitroimidazole compound, is effective on anaerobic bacteria and protozoon diseases. Mostly, metronidazole is a tolerable drug but rarely presents serious adverse effects on the nervous system. In case of these adverse effects, treatment must be stopped.In this report, a 3-year-old child hospitalized because of diarrhea is presented. During the metronidazole treatment, loss of sight, vertigo, ataxia, and headache occurred as the adverse effects. By this report, we want to express the rare adverse effects of drugs in the differential diagnoses of nervous system diseases.

5-Nitroimidazole-derived Schiff bases and their copper(II) complexes exhibit potent antimicrobial activity against pathogenic anaerobic bacteria.

PubMed

Oliveira, Alexandre A; Oliveira, Ana P A; Franco, Lucas L; Ferencs, Micael O; Ferreira, João F G; Bachi, Sofia M P S; Speziali, Nivaldo L; Farias, Luiz M; Magalhães, Paula P; Beraldo, Heloisa

2018-05-07

In the present work a family of novel secnidazole-derived Schiff base compounds and their copper(II) complexes were synthesized. The antimicrobial activities of the compounds were evaluated against clinically important anaerobic bacterial strains. The compounds exhibited in vitro antibacterial activity against Bacteroides fragilis, Bacteroides thetaiotaomicron, Bacteroides vulgatus, Bacteroides ovatus, Parabacteroides distasonis and Fusubacterium nucleatum pathogenic anaerobic bacteria. Upon coordination to copper(II) the antibacterial activity significantly increased in several cases. Some derivatives were even more active than the antimicrobial drugs secnidazole and metronidazole. Therefore, the compounds under study are suitable for in vivo evaluation and the microorganisms should be classified as susceptible to them. Electrochemical studies on the reduction of the nitro group revealed that the compounds show comparable reduction potentials, which are in the same range of the bio-reducible drugs secnidazole and benznidazole. The nitro group reduction potential is more favorable for the copper(II) complexes than for the starting ligands. Hence, the antimicrobial activities of the compounds under study might in part be related to intracellular bio-reduction activation. Considering the increasing resistance rates of anaerobic bacteria against a wide range of antimicrobial drugs, the present work constitutes an important contribution to the development of new antibacterial drug candidates.

Design and synthesis of 2-nitroimidazoles with variable alkylating and acylating functionality.

PubMed

Winters, Thomas; Sercel, Anthony; Suto, Carla; Elliott, William; Leopold, Wilbur; Leopold, Judith; Showalter, Hollis

2014-01-01

The synthesis of a small series of 2-nitroimidazoles in which the β-amino alcohol side chain was amidated with a range of alkylating/acylating functionality is described. Synthetic methodologies were developed that generally provided for selective N-acyl versus N,O-bisacyl products. In vitro, target analogs showed minimal radiosensitization activity, with only a few exhibiting a sensitizer enhancement ratio (SER) >2.0 and C(1.6) values comparable to reference agents RB-6145 and RSU-1069. In an assay to determine potential to alkylate biomolecules, representative analogs showed <1% of the alkylating activity of RSU-1069. In vivo, one analog showed an enhancement ratio of 1.6 relative to vehicle control when tested in B6C3F1 mice with an implanted KHT sarcoma. The data reinforce prior findings that there is a correlation between alkylation potential and in vivo activity.

Removal of nitroimidazole antibiotics from aqueous solution by adsorption/bioadsorption on activated carbon.

PubMed

Rivera-Utrilla, J; Prados-Joya, G; Sánchez-Polo, M; Ferro-García, M A; Bautista-Toledo, I

2009-10-15

The objective of the present study was to analyse the behaviour of activated carbon with different chemical and textural properties in nitroimidazole adsorption, also assessing the combined use of microorganisms and activated carbon in the removal of these compounds from waters and the influence of the chemical nature of the solution (pH and ionic strength) on the adsorption process. Results indicate that the adsorption of nitroimidazoles is largely determined by activated carbon chemical properties. Application of the Langmuir equation to the adsorption isotherms showed an elevated adsorption capacity (X(m)=1.04-2.04 mmol/g) for all contaminants studied. Solution pH and electrolyte concentration did not have a major effect on the adsorption of these compounds on activated carbon, confirming that the principal interactions involved in the adsorption of these compounds are non-electrostatic. Nitroimidazoles are not degraded by microorganisms used in the biological stage of a wastewater treatment plant. However, the presence of microorganisms during nitroimidazole adsorption increased their adsorption on the activated carbon, although it weakened interactions between the adsorbate and carbon surface. In dynamic regime, the adsorptive capacity of activated carbon was markedly higher in surface water and groundwater than in urban wastewaters.

Journal of Special Operations Medicine. Volume 7, Edition 1, Winter 2007. Training Supplement: USSOCOM Medic Certification Program

DTIC Science & Technology

2007-01-01

Complicated intra-abdominal infections Complicated skin infections Pneumonia Complicated UTI , including pyelonephritis Acute pelvic infections Drug of...nitroimidazole derivatives. Pregnancy (first trimester in patients with Trichomoniasis). Administer with caution to patients with CNS diseases. Use with caution...under 12 years Dehydration Use with caution in pregnancy . Dosage: Patient in shock, bleeding not controlled: hold fluid and control bleeding. Patient

Transfer of nitroimidazoles from contaminated beeswax to honey.

PubMed

Mitrowska, Kamila; Antczak, Maja

2017-04-01

Nitroimidazoles are not authorised for the treatment of honey bees in the European Union. However, they can be found in honey largely because they are illegally used in apiculture for the treatment of Nosema. The aim of the study was to examine the possible transfer of nitroimidazoles (metronidazole, ronidazole, dimetridazole and ipronidazole) from contaminated beeswax to honey. The wax foundations fortified with a mixture of four nitroimidazoles at three concentration levels (1000, 10,000 and 100,000 μg kg - 1 ) were placed in beehives to let the honeybees (Apis mellifera L.) draw out the contaminated wax foundations to honeycombs. At 1 month from the start, the frames filled with capped honey were removed from the hives for a first sampling of honey. Next, the honeycombs were further incubated for 5 months in the laboratory at 35°C and sampled monthly. In the sampled honey, the concentrations of nitroimidazoles and their main metabolites (hydroxymetronidazole, 2-hydroxymethyl-1-methyl-5-nitroimidazole, hydroxyipronidazole) were determined by LC-MS/MS and compared with those determined in the nitroimidazole-containing wax foundations. Each of the tested nitroimidazoles could migrate from beeswax to honey kept in the contaminated combs at each tested concentration level. Higher maximum concentrations of residues in honey sampled from contaminated combs at 1000, 10,000 and 100,000 μg kg - 1 were observed for metronidazole (28.9, 368.5 and 2589.4 μg kg - 1 respectively) and ronidazole (27.4, 232.9 and 2351.2 μg kg - 1 respectively), while lower maximum concentrations were measured for dimetridazole (0.98, 8.4 and 67.7 μg kg - 1 ) and ipronidazole (0.9, 7.9 and 35.7 μg kg - 1 respectively). When we took into account that a frame completely filled with honey on both sides of the comb contained 110 g of beeswax and 2488 g of honey, and that this ratio was constant, then maximum amounts of initial metronidazole, ronidazole, dimetridazole and ipronidazole that migrated from contaminated wax foundations to honey could be calculated: 65-89%, 55-63%, 1.7-2.7% and 1.4-2.3%, respectively.

Anti-Trichomonas vaginalis activity of saponins from Quillaja, Passiflora, and Ilex species.

PubMed

Rocha, Tábitha Dahmer; de Brum Vieira, Patrícia; Gnoatto, Simone Cristina Baggio; Tasca, Tiana; Gosmann, Grace

2012-06-01

Trichomonas vaginalis is a flagellated protozoan that causes trichomonosis, the most prevalent non-viral STD worldwide. The pathogen has been associated with serious health consequences including predisposition to cervical cancer and adverse pregnancy outcomes and infertility. It also acts as a co-factor in HIV transmission and acquisition. The 5-nitroimidazole drugs are used in the treatment, however, treatment noncompliance is observed, and a growing number of T. vaginalis isolates resistant to the drugs have been related. Saponins are natural products possessing many biological activities such as antiprotozoan activity. The aim of this study was to evaluate the anti-T. vaginalis activity of saponins from Quillaja, Passiflora, and Ilex species. Saponins from Passiflora alata and Quillaja saponaria presented the best anti-T. vaginalis activity (MIC = 0.025%). In addition, all samples induced erythrocyte lysis and LDH release. As far as we know, this is the first report demonstrating the potential anti-T. vaginalis activity of these saponins.

A new look into the quantum chemical and spectroscopic investigations of 5-chloro-1-methyl-4-nitroimidazole.

PubMed

Arjunan, V; Raj, Arushma; Anitha, R; Mohan, S

2014-05-05

Optimised geometrical structural parameters, harmonic vibrational frequencies, natural bonding orbital analysis and frontier molecular orbitals are determined by B3LYP and B3PW91 methods. The exact geometry of 5-chloro-1-methyl-4-nitroimidazole is determined through conformational analysis. The experimentally observed infrared and Raman bands have been assigned and analysed. The (13)C and (1)H NMR chemical shifts of the compound are investigated. The total electron density and molecular electrostatic potentials are determined. The electrostatic potential (electron+nuclei) distribution, molecular shape, size and dipole moments of the molecule have been displayed. The energies of the frontier molecular orbitals and LUMO-HOMO energy gap are measured. The possible electronic transitions of the molecule are studied by TD-DFT method along with the UV-Visible spectrum. The structure-activity relationship of the compound is also investigated by conceptual DFT methods. Copyright © 2014 Elsevier B.V. All rights reserved.

Metronidazole as a protector of cells from electromagnetic radiation of extremely high frequencies

NASA Astrophysics Data System (ADS)

Kuznetsov, Pavel E.; Malinina, Ulia A.; Popyhova, Era B.; Rogacheva, Svetlana M.; Somov, Alexander U.

2006-08-01

It is well known that weak electromagnetic fields of extremely high frequencies cause significant modification of the functional status of biological objects of different levels of organization. The aim of the work was to study the combinatory effect of metronidazole - the drug form of 1-(2'hydroxiethil)-2-methil-5-nitroimidazole - and electromagnetic radiation of extremely high frequencies (52...75 GHz) on the hemolytic stability of erythrocytes and hemotaxis activity of Infusoria Paramecium caudatum.

Nitrotriazole- and imidazole-based amides and sulfonamides as antitubercular agents.

PubMed

Papadopoulou, Maria V; Bloomer, William D; Rosenzweig, Howard S; Arena, Alexander; Arrieta, Francisco; Rebolledo, Joseph C J; Smith, Diane K

2014-11-01

Twenty-three 3-nitrotriazole-based and 2-nitroimidazole-based amides and sulfonamides were screened for antitubercular (anti-TB) activity in aerobic Mycobacterium tuberculosis H37Rv by using the BacTiter-Glo (BTG) microbial cell viability assay. In general, 3-nitrotriazole-based sulfonamides demonstrated anti-TB activity, whereas 3-nitrotriazole-based amides and 2-nitroimidazole-based amides and sulfonamides were inactive. Three 3-nitrotriazole-based sulfonamides (compounds 4, 2, and 7) demonstrated 50% inhibitory concentration (IC50), IC90, and MIC values of 0.38, 0.43, and 1.56 μM (compound 4), 0.57, 0.98, and 3.13 μM (compound 2), and 0.79, 0.87, and 3.13 μM (compound 7), respectively. For 3-nitrotriazole-based sulfonamides, anti-TB activity increased with lipophilicity, whereas the one-electron reduction potential (E1/2) did not play a role. 2-Nitroimidazole-based analogs, which were inactive in the BTG assay, were significantly more active in the low-oxygen assay and more active than the 3-nitrotriazoles. All active nitrotriazoles in the BTG assay were similarly active or more potent (lower MIC values) against resistant strains, with the exception of compounds 2, 3, 4, and 8, which demonstrated greater MIC values against isoniazid-resistant strains. Five 3-nitrotriazole-based sulfonamides demonstrated activity in infected murine J774 macrophages, causing log reductions similar to those seen with rifampin. However, some compounds caused toxicity in uninfected macrophages. In conclusion, the classes of 3-nitrotriazole-based amides and sulfonamides merit further investigation as potential antitubercular agents. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

Nitrotriazole- and Imidazole-Based Amides and Sulfonamides as Antitubercular Agents

PubMed Central

Bloomer, William D.; Rosenzweig, Howard S.; Arena, Alexander; Arrieta, Francisco; Rebolledo, Joseph C. J.; Smith, Diane K.

2014-01-01

Twenty-three 3-nitrotriazole-based and 2-nitroimidazole-based amides and sulfonamides were screened for antitubercular (anti-TB) activity in aerobic Mycobacterium tuberculosis H37Rv by using the BacTiter-Glo (BTG) microbial cell viability assay. In general, 3-nitrotriazole-based sulfonamides demonstrated anti-TB activity, whereas 3-nitrotriazole-based amides and 2-nitroimidazole-based amides and sulfonamides were inactive. Three 3-nitrotriazole-based sulfonamides (compounds 4, 2, and 7) demonstrated 50% inhibitory concentration (IC50), IC90, and MIC values of 0.38, 0.43, and 1.56 μM (compound 4), 0.57, 0.98, and 3.13 μM (compound 2), and 0.79, 0.87, and 3.13 μM (compound 7), respectively. For 3-nitrotriazole-based sulfonamides, anti-TB activity increased with lipophilicity, whereas the one-electron reduction potential (E1/2) did not play a role. 2-Nitroimidazole-based analogs, which were inactive in the BTG assay, were significantly more active in the low-oxygen assay and more active than the 3-nitrotriazoles. All active nitrotriazoles in the BTG assay were similarly active or more potent (lower MIC values) against resistant strains, with the exception of compounds 2, 3, 4, and 8, which demonstrated greater MIC values against isoniazid-resistant strains. Five 3-nitrotriazole-based sulfonamides demonstrated activity in infected murine J774 macrophages, causing log reductions similar to those seen with rifampin. However, some compounds caused toxicity in uninfected macrophages. In conclusion, the classes of 3-nitrotriazole-based amides and sulfonamides merit further investigation as potential antitubercular agents. PMID:25182645

Treatment of Infections Caused by Metronidazole-Resistant Trichomonas vaginalis

PubMed Central

Cudmore, Sarah L.; Delgaty, Kiera L.; Hayward-McClelland, Shannon F.; Petrin, Dino P.; Garber, Gary E.

2004-01-01

Infections with the sexually transmitted protozoan Trichomonas vaginalis are usually treated with metronidazole, a 5-nitroimidazole drug derived from the antibiotic azomycin. Metronidazole treatment is generally efficient in eliminating T. vaginalis infection and has a low risk of serious side effects. However, studies have shown that at least 5% of clinical cases of trichomoniasis are caused by parasites resistant to the drug. The lack of approved alternative therapies for T. vaginalis treatment means that higher and sometimes toxic doses of metronidazole are the only option for patients with resistant disease. Clearly, studies of the treatment and prevention of refractory trichomoniasis are essential. This review describes the mechanisms of metronidazole resistance in T. vaginalis and provides a summary of trichomonicidal and vaccine candidate drugs. PMID:15489348

Structure/activity relationships for the enhancement by electron-affinic drugs of the anti-tumour effect of CCNU.

PubMed Central

Workman, P.; Twentyman, P. R.

1982-01-01

Using a regrowth-delay assay, we investigated structure/activity relationships for the enhancement by electron-affinic agents of the anti-tumour effect of the nitrosourea CCNU against the KHT sarcoma in C3H mice. A series of neutral 2-nitroimidazoles similar in electron affinity but varying in octanol/water partition coefficient (PC) over 4 orders of magnitude (0.016- greater than 200, Misonidazole = 0.43) were examined at a fixed dose of 2.5 mmol/kg. A parabolic (quadratic) dependence of activity on log PC was observed. Analogues more hydrophilic than misonidazole (MISO) were inactive as were those with very high PCs (greater than 20). Those with PC 0.43--20 were usually more active than MISO, some considerably so. The fairly lipophilic 5-nitroimidazoles nimorazole and metronidazole (METRO) had similar activity to MISO, despite their reduced electron affinity. Two basic 2-nitroimidazoles more efficient as radiosensitizers in vitro likewise showed activity comparable to MISO. We also investigated several agents more electron-affinic than MISO, including some non-nitro compounds. Most were inactive at maximum tolerated doses, but nitrofurazone showed reasonable activity. Sensitizer dose-response curves were obtained for MISO, METRO and two of the most effective agents, benznidazole (Ro 07-1051) and Ro 07-1902. The two latter agents were both considerably more active than MISO at low doses (0.1--0.9 mmol/kg). These studies indicate that the structural features of electron-affinic agents responsible for the enhancement of KHT tumour response to CCNU, are quite different from those affecting radiosensitization, lipophilicity being particularly important. The microsomal enzyme-inhibitor SKF 525A increased the anti-tumour effect of CCNU, suggesting inhibition of CCNU metabolism as one possible mechanism contributing to chemosensitization by lipophilic electron-affinic agents in mice. PMID:7150475

A simple reagent-free spectrophotometric assay for monitoring metronidazole therapy in aquarium water.

PubMed

Webb, D Harry; Marrero, Cynthia; Ellis, Helen; Merriwether, Lea; Dove, Alistair D M

2013-09-01

A reagent-free spectrophotometric assay was developed to measure the concentration of metronidazole (a 5-nitroimidazole) in both freshwater and seawater matrices. This assay is simple, repeatable, sensitive, and precise and is ideal for use when a rapid, selective test to determine metronidazole concentration in aqueous matrices is necessary. The assay was practically tested on a South American fishes display during treatment with metronidazole for an outbreak of the flagellated parasite Spironucleus in a mixed cichlid (family Cichlidae) and tetra (family Characidae) community. The assay clearly illustrated the course of treatment for the system during a real clinical application. The assay is not without limitations, as interferences can occur from other drugs in the matrix with similar absorbance spectra. Nonetheless, this type of assay illustrates the potential for use of native absorbance assays in aqueous matrices for this and other therapeutic compounds.

In vivo click reaction between Tc-99m-labeled azadibenzocyclooctyne-MAMA and 2-nitroimidazole-azide for tumor hypoxia targeting.

PubMed

Sun, Wenjing; Chu, Taiwei

2015-10-15

The bioactivity of nitroimidazole in Tc-99m-labeled 2-nitroimidazole, a traditional solid tumor hypoxia-imaging agent for single photon emission computed tomography (SPECT), is reduced by the presence of large ligand and metallic radionuclide, exhibiting lower tumor-to-nontumor ratios. In an effort to solve this general problem, a pretargeting strategy based on click chemistry (strain-promoted cyclooctyne-azide cycloaddition) was applied. The functional click synthons were synthesized as pretargeting components: an azide group linked to 2-nitroimidazole (2NIM-Az) serves for tumor hypoxia-targeting and azadibenzocyclooctyne conjugated with monoamine monoamide dithiol ligand (AM) functions as radiolabeling and binding group to azides in vivo. 2NIM-triazole-MAMA was obtained from in vitro click reaction with a reaction rate constant of 0.98M(-1)s(-1). AM and 2NIM-triazole-MAMA were radiolabeled with Tc-99m. The hypoxia-pretargeting biodistribution was studied in Kunming mice bearing S180 tumor; (99m)Tc-AM and (99m)Tc-triazole-2NIM were used as blank control and conventional control. Compared to the control groups, the pretargeting experiment exhibits the best radio-uptake and retention in tumor, with higher tumor-to-muscle and tumor-to-blood ratios (up to 8.55 and 1.44 at 8h post-(99m)Tc-complex-injection, respectively). To some extent, the pretargeting strategy protects the bioactivity of nitroimidazole and therefore provides an innovative approach for the development of tumor hypoxia-SPECT imaging agents. Copyright © 2015 Elsevier Ltd. All rights reserved.

Delamanid (OPC-67683) for treatment of multi-drug-resistant tuberculosis.

PubMed

Sotgiu, Giovanni; Pontali, Emanuele; Centis, Rosella; D'Ambrosio, Lia; Migliori, Giovanni Battista

2015-03-01

The research and development of delamanid was carried out by Otsuka Pharmaceutical Development and Commercialization (Osaka, Tokyo, Japan). It belongs to the group of nitroimidazoles. It inhibits the synthesis of mycolic acids, crucial component of the cell wall of the Mycobacterium tuberculosis complex. It is insoluble in water and its activity was proven in several in vitro and in vivo studies. Its market approval was obtained in April 2014 in Europe. Its bactericidal activity was demonstrated in individuals with drug-susceptible and drug-resistant tuberculosis (MDR- and XDR-TB). The safety and tolerability profile was good; the notified increased QT interval was not clinically relevant. It was approved for adults but ongoing clinical trials and clinical experiences have been proving its efficacy in the pediatric population.

Targeting hypoxia in tumors using 2-nitroimidazoles with peptidic chelators for technetium-99m: effect of lipophilicity.

PubMed

Zhang, X; Su, Z F; Ballinger, J R; Rauth, A M; Pollak, A; Thornback, J R

2000-01-01

Tumor hypoxia is an important prognostic factor for response to therapy. Radiolabeled 2-nitroimidazoles have been used for imaging hypoxia, and the octanol/water partition coefficient (P) of these compounds appears to play a crucial role in their suitability for imaging. A series of 11 2-nitroimidazoles coupled to peptidic chelators for (99m)Tc with divergent P was developed and evaluated in an in vitro system. Two classes of N(3)S chelators were used: dialkyl-Gly-Ser-Cys-linker-2-nitroimidazole (Class I) and dialkyl-Gly-Lys(2-nitroimidazole)-Cys (Class II). The chelators were prepared by automated solid-phase peptide synthesis. Xanthine oxidase was able to reduce the 2-nitroimidiazole moiety on the ligands, but the rate of reduction varied 5-fold among the different chelators. The chelators were labeled by transchelation from [(99m)Tc]gluconate at temperatures between 22 and 100 degrees C. The reaction mixtures were analyzed by HPLC and their P values determined. The accumulation of each complex in suspension cultures of Chinese hamster ovary cells incubated under aerobic or extremely hypoxic conditions was determined. Radiochemical yields ranged from 5 to 80% for the 11 compounds. HPLC showed that some of the compounds formed two complexes with (99m)Tc, possibly syn and anti conformations with respect to the Tc=O bond. In general, the Class I chelators labeled more readily than the class II chelators. The P values of the (99m)Tc complexes varied from 0.0002 to 5 and were generally in accordance with predictions based on structure. There were also differences in P as a function of pH; the free acids had a lower P at pH 7.4 than at pH 2.0 due to ionization, whereas the amides did not show this effect. Accumulation levels in aerobic cells were related to P but varied over a narrow range. Four of the 11 compounds showed selective accumulation in hypoxic cells. The peptidic class of 2-nitroimidazoles, with flexible design and convenient solid-phase synthesis, deserves further study as agents for imaging hypoxia in tumors.

[Sensitivity of microbial associations of periodontal lesions to antibacterial agents].

PubMed

Makeeva, I M; Daurova, F Yu; Byakova, S F; Ippolitov, E V; Gostev, M S; Polikushina, A O; Shubin, E V

2016-01-01

The aim of the study was the development of approaches to improve the effectiveness of antibiotic therapy in dental practice on the basis of determining the sensitivity of pathogenic microorganisms to antibiotics of different groups. The study included determination of the sensitivity of the microbial complexes from wound exudate of periodontal pocket and apical abscess to macrolides, quinolones, penicillins, lincosamides and 5-nitroimidazole. A survey of dentists and dental clinics patients to identify the cause and frequency of use of antibiotics and to identify possible adverse reactions was also conducted. Dentists prefer macrolide antibiotics, protected penicillins, and fluoroquinolone combined with 5-nitroimidazole. All patients have taken antibiotics themselves at least once a year. Microbial complexes in patients with acute and exacerbated apical periodontitis in 79% of cases are susceptible to amoxicillin/clavulanic acid, to azithromycin - 52%, lincomycin - 36%, 5-nitroimidazole - 68%, ciprofloxacin - 73.7%. In patients with apical abscess high rates of resistance of microbial complexes to all types of antibiotics was revealed (33% for lincomycin 76,1% for ciprofloxacin, 28,6% for 5-nitroimidazole). Patients with moderate to severe periodontitis in 90.5% are sensitive to amoxicillin/clavulanic acid and azithromycin, in 62.4% to lincomycin. Sensitivity to ciprofloxacin was detected in 85.7% of patients, in 14.3% - moderate resistance.

Nitroimidazoles adsorption on activated carbon cloth from aqueous solution.

PubMed

Ocampo-Pérez, R; Orellana-Garcia, F; Sánchez-Polo, M; Rivera-Utrilla, J; Velo-Gala, I; López-Ramón, M V; Alvarez-Merino, M A

2013-07-01

The objective of this study was to analyze the equilibrium and adsorption kinetics of nitroimidazoles on activated carbon cloth (ACC), determining the main interactions responsible for the adsorption process and the diffusion mechanism of these compounds on this material. The influence of the different operational variables, such as ionic strength, pH, temperature, and type of water (ultrapure, surface, and waste), was also studied. The results obtained show that the ACC has a high capacity to adsorb nitroimidazoles in aqueous solution. Electrostatic interactions play an important role at pH<3, which favors the repulsive forces between dimetridazole or metronidazole and the ACC surface. The formation of hydrogen bonds and dispersive interactions play the predominant role at higher pH values. Modifications of the ACC with NH3, K2S2O8, and O3 demonstrated that its surface chemistry plays a predominant role in nitroimidazole adsorption on this material. The adsorption capacity of ACC is considerably high in surface waters and reduced in urban wastewater, due to the levels of alkalinity and dissolved organic matter present in the different types of water. Finally, the results of applying kinetic models revealed that the global adsorption rate of dimetridazole and metronidazole is controlled by intraparticle diffusion. Copyright © 2013 Elsevier Inc. All rights reserved.

W/O/W multiple emulsions containing nitroimidazole derivates for vaginal delivery.

PubMed

Ozer, Ozgen; Ozyazici, Mine; Tedajo, Muriel; Taner, Memduh S; Köseoglu, Kamil

2007-03-01

The aim of our study was to formulate a stable multiple emulsions containing two nitroimidazole derivates, metronidazole (MT) and ornidazole (OR), for vaginal therapy. MT and OR were located internal and external phases of multiple emulsion, respectively, and the in vitro release studies were realized in phosphate (pH 7) and lactate buffer (pH 4.5) solutions to investigate better the effect of pH and location of active substance on the release. The imaging studies were realized in rabbits following labeling MT and OR with Technethium-99m ((99m)Tc) to evaluate the in vivo absorption characteristics. The percentage of MT and OR released from the multiple emulsions in alkaline media were 3.2- and 2.8-fold greater than that observed in acidic media, respectively, when they were introduced in the internal phase of the multiple emulsions. The absorption rate of MT from vaginal epithelium was faster than OR. We observed that especially in alkaline medium a high release was found that was convenient for the vaginal infections seen in the alkaline pH. We concluded that W/O/W multiple emulsions were locally effective in vagina and they could be introduced as a new drug carrier system for vaginal delivery.

Nitrimidazine Compared with Metronidazole in the Treatment of Vaginal Trichomoniasis

PubMed Central

Evans, B. A.; Catterall, R. D.

1971-01-01

A new substituted nitroimidazole, nitrimidazine (Naxogin), is compared with the established drug, metronidazole (Flagyl), for the treatment of vaginal trichomoniasis in a randomized double-blind trial. Nitrimidazine cured 39 (68%) out of 57 patients and showed no undesirable effects other than nausea in one patient. Metronidazole cured 51 (89%) out of 57 patients and also caused nausea in one patient; this cure rate corresponds with that previously reported in other trials. In the recommended dosage nitrimidazine is inferior to metronidazole, but is sufficiently effective to be useful in cases of intolerance to metronidazole. PMID:4939601

Anti-Trichomonas vaginalis activity of ursolic acid derivative: a promising alternative.

PubMed

Bitencourt, Fernanda Gobbi; de Brum Vieira, Patrícia; Meirelles, Lucia Collares; Rigo, Graziela Vargas; da Silva, Elenilson Figueiredo; Gnoatto, Simone Cristina Baggio; Tasca, Tiana

2018-05-01

Trichomonas vaginalis is an extracellular parasite that binds to the epithelium of the human urogenital tract and causes the sexually transmitted infection, trichomoniasis. In view of increased resistance to drugs belonging to the 5-nitroimidazole class, new treatment alternatives are urgently needed. In this study, eight semisynthetized triterpene derivatives were evaluated for in vitro anti-T. vaginalis activity. Ursolic acid and its derivative, 3-oxime-urs-12-en-28-oic-ursolic acid (9), presented the best anti-T. vaginalis activity when compared to other derivatives, with minimum inhibitory concentration (MIC) at 25 μM. Moreover, 9 was active against several T. vaginalis fresh clinical isolates. Hemolysis assay demonstrated that 9 presented a low hemolytic effect. Importantly, 25 μM 9 was not cytotoxic against the Vero cell lineage. Finally, we demonstrated that compound 9 acts synergistically with metronidazole against a T. vaginalis metronidazole-resistant isolate. This report reveals the high potential of the triterpenoid derivative 9 as trichomonicidal agent.

Synthesis and evaluation of an 18 F-labeled trifluoroborate derivative of 2-nitroimidazole for imaging tumor hypoxia with positron emission tomography.

PubMed

Nunes, Paulo Sérgio Gonçalves; Zhang, Zhengxing; Kuo, Hsiou-Ting; Zhang, Chengcheng; Rousseau, Julie; Rousseau, Etienne; Lau, Joseph; Kwon, Daniel; Carvalho, Ivone; Bénard, François; Lin, Kuo-Shyan

2018-04-01

2-Nitroimidazole-based hypoxia imaging tracers such as 18 F-FMISO are normally imaged at late time points (several hours post-injection) due to their slow clearance from background tissues. Here, we investigated if a hydrophilic zwitterion-based ammoniomethyl-trifluoroborate derivative of 2-nitroimidazole, 18 F-AmBF 3 -Bu-2NI, could have the potential to image tumor hypoxia at earlier time points. AmBF 3 -Bu-2NI was prepared in 4 steps. 18 F labeling was conducted via 18 F- 19 F isotope exchange reaction, and 18 F-AmBF 3 -Bu-2NI was obtained in 14.8 ± 0.4% (n = 3) decay-corrected radiochemical yield with 24.5 ± 5.2 GBq/μmol specific activity and >99% radiochemical purity. Imaging and biodistribution studies in HT-29 tumor-bearing mice showed that 18 F-AmBF 3 -Bu-2NI cleared quickly from blood and was excreted via the hepatobiliary and renal pathways. However, the tumor was not visualized in PET images until 3 hours post-injection due to low tumor uptake (0.54 ± 0.13 and 0.19 ± 0.04%ID/g at 1 and 3 hours post-injection, respectively). The low tumor uptake is likely due to the highly hydrophilic motif of ammoniomethyl-trifluoroborate that prevents free diffusion of 18 F-AmBF 3 -Bu-2NI across the cell membrane. Our results suggest that highly hydrophilic 18 F-labeled ammoniomethyl-trifluoroborate derivatives might not be suitable for imaging intracellular targets including nitroreductase, a common tumor hypoxia imaging target. Copyright © 2017 John Wiley & Sons, Ltd.

Investigational Drugs for Visceral Leishmaniasis

PubMed Central

Sundar, Shyam; Chakravarty, Jaya

2014-01-01

Introduction The armamentarium of antileishmanials is small. It is further being threatened by development of resistance and decreasing sensitivity to the available drugs. Development of newer drugs are sorely needed. Areas covered Literature search on investigational drugs for visceral leishmaniasis (VL) was done on PubMed. Those candidates with at least in vitro and in vivo activity against leishmania species causing VL were reviewed. Among the investigational drugs the nitroimidazole compound fexinidazole is the one of the few drugs which has reached phase II trials. Although the (S)-PA-824 is in phase II trials for the treatment of tuberculosis its R enantiomer has shown good antileishmanial activity. Development of sitamaquin, which has completed phase II studies has been stopped for VL due to its low efficacy. Many novel delivery system and oral formulations of Amphotericin B which are cheap and less toxic are in investigational stages, and will go a long way in improving the treatment of VL. Expert opinion Very few new drugs have reached the clinical stage in the treatment of this neglected tropical disease. Thus, there is an urgent need for support from public private partnerships to ensure that drug candidates are promptly taken forward into development. PMID:25409760

Medicinal plants and their isolated compounds showing anti-Trichomonas vaginalis- activity.

PubMed

Mehriardestani, Mozhgan; Aliahmadi, Atousa; Toliat, Tayebeh; Rahimi, Roja

2017-04-01

Trichomonas vaginalis is a major of non-viral sexually-transmitted infection and an important cause of serious obstetrical and gynecological complications. Treatment options for trichomoniasis are limited to nitroimidazole compounds. The increasing resistance and allergic reactions to nitroimidazole and recurrent trichomoniasis make it essential to identify and develop new drugs against trichomoniasis. Medicinal plants are an important source for discovery of new medications. This review discusses the anti-trichomonas effects of medicinal plants and their chemical constituents to find better options against this pathogenic protozoon. Electronic databases were searched to collect all data from the year 2000 through September 2015 for in vitro, in vivo and clinical studies on the effect of medicinal plants on T. vaginalis. A total of 95 in vitro and clinical studies were identified. Only four human studies were found in this review. The Asteracea, Lamiaceae and Myrtaceae families contained the greatest number of plants with anti-trichomonas activity. Persea americana, Ocimum basilicum and Verbascum thapsus were the most efficacious against T. vaginalis. Plant metabolites containing alkaloids, isoflavonoid glucosides, essential oils, lipids, saponins and sesquiterpene lactones were found to possess anti-trichomonas properties. Assessing the structure-activity of highly-potent anti-trichomonas phytochemicals is suggested for finding natural, semisynthetic and synthetic anti-trichomonas compounds. Further clinical studies are necessary for confirmation of natural anti-trichomonas substances and completion of their safety profiles. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Fexinidazole: A Potential New Drug Candidate for Chagas Disease

PubMed Central

Bahia, Maria Terezinha; de Andrade, Isabel Mayer; Martins, Tassiane Assíria Fontes; do Nascimento, Álvaro Fernando da Silva; Diniz, Lívia de Figueiredo; Caldas, Ivo Santana; Talvani, André; Trunz, Bernadette Bourdin; Torreele, Els; Ribeiro, Isabela

2012-01-01

Background New safe and effective treatments for Chagas disease (CD) are urgently needed. Current chemotherapy options for CD have significant limitations, including failure to uniformly achieve parasitological cure or prevent the chronic phase of CD, and safety and tolerability concerns. Fexinidazole, a 2-subsituted 5-nitroimidazole drug candidate rediscovered following extensive compound mining by the Drugs for Neglected Diseases initiative and currently in Phase I clinical study for the treatment of human African trypanosomiasis, was evaluated in experimental models of acute and chronic CD caused by different strains of Trypanosoma cruzi. Methods and Findings We investigated the in vivo activity of fexinidazole against T. cruzi, using mice as hosts. The T. cruzi strains used in the study were previously characterized in murine models as susceptible (CL strain), partially resistant (Y strain), and resistant (Colombian and VL-10 strains) to the drugs currently in clinical use, benznidazole and nifurtimox. Our results demonstrated that fexinidazole was effective in suppressing parasitemia and preventing death in infected animals for all strains tested. In addition, assessment of definitive parasite clearance (cure) through parasitological, PCR, and serological methods showed cure rates of 80.0% against CL and Y strains, 88.9% against VL-10 strain, and 77.8% against Colombian strain among animals treated during acute phase, and 70% (VL-10 strain) in those treated in chronic phase. Benznidazole had a similar effect against susceptible and partially resistant T. cruzi strains. Fexinidazole treatment was also shown to reduce myocarditis in all animals infected with VL-10 or Colombian resistant T. cruzi strains, although parasite eradication was not achieved in all treated animals at the tested doses. Conclusions Fexinidazole is an effective oral treatment of acute and chronic experimental CD caused by benznidazole-susceptible, partially resistant, and resistant T. cruzi. These findings illustrate the potential of fexinidazole as a drug candidate for the treatment of human CD. PMID:23133682

Conjugation of metronidazole with dextran: a potential pharmaceutical strategy to control colonic distribution of the anti-amebic drug susceptible to metabolism by colonic microbes

PubMed Central

Kim, Wooseong; Yang, Yejin; Kim, Dohoon; Jeong, Seongkeun; Yoo, Jin-Wook; Yoon, Jeong-Hyun; Jung, Yunjin

2017-01-01

Metronidazole (MTDZ), the drug of choice for the treatment of protozoal infections such as luminal amebiasis, is highly susceptible to colonic metabolism, which may hinder its conversion from a colon-specific prodrug to an effective anti-amebic agent targeting the entire large intestine. Thus, in an attempt to control the colonic distribution of the drug, a polymeric colon-specific prodrug, MTDZ conjugated to dextran via a succinate linker (Dex-SA-MTDZ), was designed. Upon treatment with dextranase for 8 h, the degree of Dex-SA-MTDZ depolymerization (%) with a degree of substitution (mg of MTDZ bound in 100 mg of Dex-SA-MTDZ) of 7, 17, and 30 was 72, 38, and 8, respectively, while that of dextran was 85. Depolymerization of Dex-SA-MTDZ was found to be necessary for the release of MTDZ, because dextranase pretreatment ensures that de-esterification occurs between MTDZ and the dextran backbone. In parallel, Dex-SA-MTDZ with a degree of substitution of 17 was found not to release MTDZ upon incubation with the contents of the small intestine and stomach of rats, but it released MTDZ when incubated with rat cecal contents (including microbial dextranases). Moreover, Dex-SA-MTDZ exhibited prolonged release of MTDZ, which contrasts with drug release by small molecular colon-specific prodrugs, MTDZ sulfate and N-nicotinoyl-2-{2-(2-methyl-5-nitroimidazol-1-yl)ethyloxy}-d,l-glycine. These prodrugs were eliminated very rapidly, and no MTDZ was detected in the cecal contents. Consistent with these in vitro results, we found that oral gavage of Dex-SA-MTDZ delivered MTDZ (as MTDZ conjugated to [depolymerized] dextran) to the distal colon. However, upon oral gavage of the small molecular prodrugs, no prodrugs were detected in the distal colon. Collectively, these data suggest that dextran conjugation is a potential pharmaceutical strategy to control the colonic distribution of drugs susceptible to colonic microbial metabolism. PMID:28243064

Conjugation of metronidazole with dextran: a potential pharmaceutical strategy to control colonic distribution of the anti-amebic drug susceptible to metabolism by colonic microbes.

PubMed

Kim, Wooseong; Yang, Yejin; Kim, Dohoon; Jeong, Seongkeun; Yoo, Jin-Wook; Yoon, Jeong-Hyun; Jung, Yunjin

2017-01-01

Metronidazole (MTDZ), the drug of choice for the treatment of protozoal infections such as luminal amebiasis, is highly susceptible to colonic metabolism, which may hinder its conversion from a colon-specific prodrug to an effective anti-amebic agent targeting the entire large intestine. Thus, in an attempt to control the colonic distribution of the drug, a polymeric colon-specific prodrug, MTDZ conjugated to dextran via a succinate linker (Dex-SA-MTDZ), was designed. Upon treatment with dextranase for 8 h, the degree of Dex-SA-MTDZ depolymerization (%) with a degree of substitution (mg of MTDZ bound in 100 mg of Dex-SA-MTDZ) of 7, 17, and 30 was 72, 38, and 8, respectively, while that of dextran was 85. Depolymerization of Dex-SA-MTDZ was found to be necessary for the release of MTDZ, because dextranase pretreatment ensures that de-esterification occurs between MTDZ and the dextran backbone. In parallel, Dex-SA-MTDZ with a degree of substitution of 17 was found not to release MTDZ upon incubation with the contents of the small intestine and stomach of rats, but it released MTDZ when incubated with rat cecal contents (including microbial dextranases). Moreover, Dex-SA-MTDZ exhibited prolonged release of MTDZ, which contrasts with drug release by small molecular colon-specific prodrugs, MTDZ sulfate and N -nicotinoyl-2-{2-(2-methyl-5-nitroimidazol-1-yl)ethyloxy}-d,l-glycine. These prodrugs were eliminated very rapidly, and no MTDZ was detected in the cecal contents. Consistent with these in vitro results, we found that oral gavage of Dex-SA-MTDZ delivered MTDZ (as MTDZ conjugated to [depolymerized] dextran) to the distal colon. However, upon oral gavage of the small molecular prodrugs, no prodrugs were detected in the distal colon. Collectively, these data suggest that dextran conjugation is a potential pharmaceutical strategy to control the colonic distribution of drugs susceptible to colonic microbial metabolism.

Synthesis of 68Ga-labeled DOTA-nitroimidazole derivatives and their feasibilities as hypoxia imaging PET tracers.

PubMed

Hoigebazar, Lathika; Jeong, Jae Min; Hong, Mee Kyung; Kim, Young Ju; Lee, Ji Youn; Shetty, Dinesh; Lee, Yun-Sang; Lee, Dong Soo; Chung, June-Key; Lee, Myung Chul

2011-04-01

The imaging of hypoxia is important for therapeutic decision making in various diseases. (68)Ga is an important radionuclide for positron emission tomography (PET), and its usage is increasing, due to the development of the (68)Ge/(68)Ga-generator. In the present study, the authors synthesized two nitroimidazole derivatives by conjugating nitroimidazole and 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) via an amide bond (4) and a thiourea bond (5). Both derivatives were labeled with (68)Ga with high labeling efficiency and were stable after labeling. The low partition coefficients (logP) of (68)Ga-4 (-4.6) and (68)Ga-5 (-4.5) demonstrated the hydrophilic natures of the derivatives, and both showed higher uptake in cancer cell lines cultured under hypoxic condition than under normoxic condition. However, (68)Ga-5 showed higher liver uptake than (68)Ga-4 in a biodistribution study due to higher lipophilicity. In an animal PET study, (68)Ga-4 showed higher standard uptake values (SUV) in tumors than (68)Ga-5 in mice xenografted with CT-26 mouse colon cancer cells. Copyright © 2011 Elsevier Ltd. All rights reserved.

Synthesis and preclinical characterization of 1-(6'-deoxy-6'-[18F]fluoro-β-d-allofuranosyl)-2-nitroimidazole (β-6'-[18F]FAZAL) as a positron emission tomography radiotracer to assess tumor hypoxia.

PubMed

Wanek, Thomas; Kreis, Katharina; Križková, Petra; Schweifer, Anna; Denk, Christoph; Stanek, Johann; Mairinger, Severin; Filip, Thomas; Sauberer, Michael; Edelhofer, Patricia; Traxl, Alexander; Muchitsch, Viktoria E; Mereiter, Kurt; Hammerschmidt, Friedrich; Cass, Carol E; Damaraju, Vijaya L; Langer, Oliver; Kuntner, Claudia

2016-11-01

Positron emission tomography (PET) using fluorine-18 ( 18 F)-labeled 2-nitroimidazole radiotracers has proven useful for assessment of tumor oxygenation. However, the passive diffusion-driven cellular uptake of currently available radiotracers results in slow kinetics and low tumor-to-background ratios. With the aim to develop a compound that is actively transported into cells, 1-(6'-deoxy-6'-[ 18 F]fluoro-β-d-allofuranosyl)-2-nitroimidazole (β-[ 18 F]1), a putative nucleoside transporter substrate, was synthetized by nucleophilic [ 18 F]fluoride substitution of an acetyl protected labeling precursor with a tosylate leaving group (β-6) in a final radiochemical yield of 12±8% (n=10, based on [ 18 F]fluoride starting activity) in a total synthesis time of 60min with a specific activity at end of synthesis of 218±58GBq/μmol (n=10). Both radiolabeling precursor β-6 and unlabeled reference compound β-1 were prepared in multistep syntheses starting from 1,2:5,6-di-O-isopropylidene-α-d-allofuranose. In vitro experiments demonstrated an interaction of β-1 with SLC29A1 and SLC28A1/2/3 nucleoside transporter as well as hypoxia specific retention of β-[ 18 F]1 in tumor cell lines. In biodistribution studies in healthy mice β-[ 18 F]1 showed homogenous tissue distribution and excellent metabolic stability, which was unaffected by tissue oxygenation. PET studies in tumor bearing mice showed tumor-to-muscle ratios of 2.13±0.22 (n=4) at 2h after administration of β-[ 18 F]1. In ex vivo autoradiography experiments β-[ 18 F]1 distribution closely matched staining with the hypoxia marker pimonidazole. In conclusion, β-[ 18 F]1 shows potential as PET hypoxia radiotracer which merits further investigation. Copyright © 2016 Elsevier Ltd. All rights reserved.

High Sensitivity of Giardia duodenalis to Tetrahydrolipstatin (Orlistat) In Vitro

PubMed Central

Hahn, Juliane; Seeber, Frank; Kolodziej, Herbert; Ignatius, Ralf; Laue, Michael; Aebischer, Toni; Klotz, Christian

2013-01-01

Giardiasis, a gastrointestinal disease caused by Giardia duodenalis, is currently treated mainly with nitroimidazoles, primarily metronidazole (MTZ). Treatment failure rates of up to 20 percent reflect the compelling need for alternative treatment options. Here, we investigated whether orlistat, a drug approved to treat obesity, represents a potential therapeutic agent against giardiasis. We compared the growth inhibitory effects of orlistat and MTZ on a long-term in vitro culture adapted G. duodenalis strain, WB-C6, and on a new isolate, 14-03/F7, from a patient refractory to MTZ treatment using a resazurin assay. The giardiacidal concentration of the drugs and their combined in vitro efficacy was determined by median-effect analysis. Morphological changes after treatment were analysed by light and electron microscopy. Orlistat inhibited the in vitro growth of G. duodenalis at low micromolar concentrations, with isolate 14-03/F7 (IC5024h = 2.8 µM) being more sensitive than WB-C6 (IC5024h = 6.2 µM). The effect was significantly more potent compared to MTZ (IC5024h = 4.3 µM and 11.0 µM, respectively) and led to specific undulated morphological alterations on the parasite surface. The giardiacidal concentration of orlistat was >14 µM for 14-03/F7 and >43 µM for WB-C6, respectively. Importantly, the combination of both drugs revealed no interaction on their inhibitory effects. We demonstrate that orlistat is a potent inhibitor of G. duodenalis growth in vitro and kills parasites at concentrations achievable in the gut by approved treatment regimens for obesity. We therefore propose to investigate orlistat in controlled clinical studies as a new drug in giardiasis. PMID:23977083

Fexinidazole--a new oral nitroimidazole drug candidate entering clinical development for the treatment of sleeping sickness.

PubMed

Torreele, Els; Bourdin Trunz, Bernadette; Tweats, David; Kaiser, Marcel; Brun, Reto; Mazué, Guy; Bray, Michael A; Pécoul, Bernard

2010-12-21

Human African trypanosomiasis (HAT), also known as sleeping sickness, is a fatal parasitic disease caused by trypanosomes. Current treatment options for HAT are scarce, toxic, no longer effective, or very difficult to administer, in particular for the advanced, fatal stage of the disease (stage 2, chronic HAT). New safe, effective and easy-to-use treatments are urgently needed. Here it is shown that fexinidazole, a 2-substituted 5-nitroimidazole rediscovered by the Drugs for Neglected Diseases initiative (DNDi) after extensive compound mining efforts of more than 700 new and existing nitroheterocycles, could be a short-course, safe and effective oral treatment curing both acute and chronic HAT and that could be implemented at the primary health care level. To complete the preclinical development and meet the regulatory requirements before initiating human trials, the anti-parasitic properties and the pharmacokinetic, metabolic and toxicological profile of fexinidazole have been assessed. Standard in vitro and in vivo anti-parasitic activity assays were conducted to assess drug efficacy in experimental models for HAT. In parallel, a full range of preclinical pharmacology and safety studies, as required by international regulatory guidelines before initiating human studies, have been conducted. Fexinidazole is moderately active in vitro against African trypanosomes (IC₅₀ against laboratory strains and recent clinical isolates ranged between 0.16 and 0.93 µg/mL) and oral administration of fexinidazole at doses of 100 mg/kg/day for 4 days or 200 mg/kg/day for 5 days cured mice with acute and chronic infection respectively, the latter being a model for the advanced and fatal stage of the disease when parasites have disseminated into the brain. In laboratory animals, fexinidazole is well absorbed after oral administration and readily distributes throughout the body, including the brain. The absolute bioavailability of oral fexinidazole was 41% in mice, 30% in rats, and 10% in dogs. Furthermore, fexinidazole is rapidly metabolised in vivo to at least two biologically active metabolites (a sulfoxide and a sulfone derivative) that likely account for a significant portion of the therapeutic effect. Key pharmacokinetic parameter after oral absorption in mice for fexinidazole and its sulfoxide and sulfone metabolites are a C(max) of 500, 14171 and 13651 ng/mL respectively, and an AUC₀₋₂₄ of 424, 45031 and 96286 h.ng/mL respectively. Essentially similar PK profiles were observed in rats and dogs. Toxicology studies (including safety pharmacology and 4-weeks repeated-dose toxicokinetics in rat and dog) have shown that fexinidazole is well tolerated. The No Observed Adverse Event Levels in the 4-weeks repeated dose toxicity studies in rats and dogs was 200 mg/kg/day in both species, with no issues of concern identified for doses up to 800 mg/kg/day. While fexinidazole, like many nitroheterocycles, is mutagenic in the Ames test due to bacterial specific metabolism, it is not genotoxic to mammalian cells in vitro or in vivo as assessed in an in vitro micronucleus test on human lymphocytes, an in vivo mouse bone marrow micronucleus test, and an ex vivo unscheduled DNA synthesis test in rats. The results of the preclinical pharmacological and safety studies indicate that fexinidazole is a safe and effective oral drug candidate with no untoward effects that would preclude evaluation in man. The drug has entered first-in-human phase I studies in September 2009. Fexinidazole is the first new clinical drug candidate with the potential for treating advanced-stage sleeping sickness in thirty years.

Trichomonicidal and parasite membrane damaging activity of bidesmosic saponins from Manilkara rufula.

PubMed

de Brum Vieira, Patrícia; Silva, Nícolas Luiz Feijó; Menezes, Camila Braz; da Silva, Márcia Vanusa; Silva, Denise Brentan; Lopes, Norberto Peporine; Macedo, Alexandre José; Bastida, Jaume; Tasca, Tiana

2017-01-01

The infection caused by Trichomonas vaginalis is the most common but overlooked non-viral sexually transmitted disease worldwide. Treatment relies on one class of drugs, the 5-nitroimidazoles, but resistance is widespread. New drugs are urgently needed. We reported the effect of crude and purified saponin fractions of Manilkara rufula against Trichomonas vaginalis. The compound responsible for antitrichomonal activity was isolated and identified as an uncommon bidesmosic saponin, Mi-saponin C. This saponin eliminated parasite viability without toxicity against the human vaginal epithelial line (HMVII). In addition, the isolated saponin fraction improved the metronidazole effect against a metronidazole-resistant isolate and dramatically reduced the cytoadherence of T. vaginalis to human cells. Investigation of the mechanism of death showed that the saponin fraction induced the parasite death due to profound membrane damage, inducing a disturbance of intracellular content without nuclear damage. To the best of our knowledge, this is the first report of antitrichomonal activity in the bidesmosic saponins of Manilkara rufula.

Trichomonicidal and parasite membrane damaging activity of bidesmosic saponins from Manilkara rufula

PubMed Central

Silva, Nícolas Luiz Feijó; Menezes, Camila Braz; da Silva, Márcia Vanusa; Silva, Denise Brentan; Lopes, Norberto Peporine; Macedo, Alexandre José; Bastida, Jaume; Tasca, Tiana

2017-01-01

The infection caused by Trichomonas vaginalis is the most common but overlooked non-viral sexually transmitted disease worldwide. Treatment relies on one class of drugs, the 5-nitroimidazoles, but resistance is widespread. New drugs are urgently needed. We reported the effect of crude and purified saponin fractions of Manilkara rufula against Trichomonas vaginalis. The compound responsible for antitrichomonal activity was isolated and identified as an uncommon bidesmosic saponin, Mi-saponin C. This saponin eliminated parasite viability without toxicity against the human vaginal epithelial line (HMVII). In addition, the isolated saponin fraction improved the metronidazole effect against a metronidazole-resistant isolate and dramatically reduced the cytoadherence of T. vaginalis to human cells. Investigation of the mechanism of death showed that the saponin fraction induced the parasite death due to profound membrane damage, inducing a disturbance of intracellular content without nuclear damage. To the best of our knowledge, this is the first report of antitrichomonal activity in the bidesmosic saponins of Manilkara rufula. PMID:29190689

Phase solubility studies and anti-Trichomonas vaginalis activity evaluations of metronidazole and methylated β-cyclodextrin complexes: Comparison of CRYSMEB and RAMEB.

PubMed

Malli, Sophia; Bories, Christian; Ponchel, Gilles; Loiseau, Philippe M; Bouchemal, Kawthar

2018-06-01

Metronidazole (MTZ) is a 5-nitroimidazole drug used for the treatment of Trichomonas vaginalis parasitic infection. Aqueous formulations containing MTZ are restricted because apparent solubility in water of this drug is low. In this context, two methylated-β-cyclodextrins (CRYSMEB and RAMEB) were used as a tool to increase apparent solubility of MTZ in water. CRYSMEB was limited by its own solubility in water (15% w/w, 12.59 mM), while RAMEB at a concentration of 40% w/w (300.44 mM) allowed a maximal increase of apparent solubility of MTZ (3.426% w/w, 200.19 mM). From our knowledge, this corresponds to the highest enhancement of MTZ apparent aqueous solubility ever reported in the literature using methylated cyclodextrins. In vitro evaluations showed that anti-T. vaginalis activity of MTZ formulated with CRYSMEB and RAMEB was preserved. Copyright © 2018 Elsevier Inc. All rights reserved.

Toward hypoxia-selective rhenium and technetium tricarbonyl complexes.

PubMed

North, Andrea J; Hayne, David J; Schieber, Christine; Price, Katherine; White, Anthony R; Crouch, Peter J; Rigopoulos, Angela; O'Keefe, Graeme J; Tochon-Danguy, Henri; Scott, Andrew M; White, Jonathan M; Ackermann, Uwe; Donnelly, Paul S

2015-10-05

With the aim of preparing hypoxia-selective imaging and therapeutic agents, technetium(I) and rhenium(I) tricarbonyl complexes with pyridylhydrazone, dipyridylamine, and pyridylaminocarboxylate ligands containing nitrobenzyl or nitroimidazole functional groups have been prepared. The rhenium tricarbonyl complexes were synthesized with short reaction times using microwave irradiation. Rhenium tricarbonyl complexes with deprotonated p-nitrophenyl pyridylhydrazone ligands are luminescent, and this has been used to track their uptake in HeLa cells using confocal fluorescent microscopy. Selected rhenium tricarbonyl complexes displayed higher uptake in hypoxic cells when compared to normoxic cells. A (99m)Tc tricarbonyl complex with a dipyridylamine ligand bearing a nitroimidazole functional group is stable in human serum and was shown to localize in a human renal cell carcinoma (RCC; SK-RC-52) tumor in a mouse.

Association of Metronidazole with Cancer: A Potential Risk Factor or Inconsistent Deductions?

PubMed

Adil, Muhammad; Iqbal, Waheed; Adnan, Fazal; Wazir, Shabnam; Khan, Imran; Khayam, Mohammad Umar; Kamal, Mohammad Amjad; Ahmad, Shafiq; Ahmad, Jawad; Khan, Ishaq N

2018-03-29

Metronidazole is a synthetic derivative of nitroimidazole that has been widely used for the treatment of several bacterial and protozoal parasitic infections including trichomoniasis, amoebiasis, giardiasis, liver abscess, acute ulcerative gingivitis, syphilis and tropical phagedena. In addition to its toxicity in the gastrointestinal tract and central/peripheral nervous system, metronidazole has been reported to cause mucosal imbalance by affecting the expression of mucin (Muc2 gene), which is responsible to form an insoluble mucous barrier that protects the gut lumen from microbial colonization. Since metronidazole is a nitro-group containing compound and used significantly for therapeutic purposes, scientists evaluated its carcinogenicity in different preclinical in-vitro and in-vivo studies. In addition to the preclinical in-vitro validation of DNA damage, metronidazole has been reported to induce cancer in the variety of animal models including lung cancer, malignant lymphomas, breast cancer, hepatocellular carcinoma, pituitary tumors, testicular neoplasms and uterine cancer. Several retrospective cohort studies have reported metronidazole as a potential risk factor for lung cancer (n = 771), cervical cancer (n = 2500), breast cancer (n = 2), cholangiocarcinoma (n = 1), and neuroblastoma (n = 28). So far, all the reported data have confirmed metronidazole carcinogenicity in animals; however, it is still controversial in humans. Based on previous observations, the oxidative metabolites from metronidazole metabolism are shown to have more carcinogenic effects than the parent drug itself. Since ~40% of drug metabolism is reliant on cytochromes, the inter-patient' differences in metronidazole metabolism potentially indicate the individual susceptibility to developing cancer. Due to these potent carcinogenic behaviors, use of metronidazole for animals treatment and its uses in animal food products are barred in the USA and European countries; however, its clinical use in human population is increasing. For this purpose, updated and improved research studies are required to explicate its mechanism/s involved in carcinogenesis. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Guanylhydrazones in therapy of Pneumocystis carinii pneumonia in immunosuppressed rats.

PubMed Central

Walzer, P D; Foy, J; Runck, J; Steele, P; White, M; Klein, R S; Otter, B A; Sundberg, R J

1994-01-01

Guanylhydrazones are cationic heteroaromatic drugs similar to the diamidines which are effective in the treatment of African trypanosomiasis and pneumocystosis. On the basis of their antitrypanosomal activity, different guanylhydrazones were selected for evaluation in a rat model of Pneumocystis carinii pneumonia. The most active compounds were the 2-(4'-formylphenyl)-1-methylimidazo-[1,2-a] pyridinium guanylhydrazones which, at a dose of 2 mg/kg/day, were about as effective as trimethoprim-sulfamethoxazole at a dose of 50 mg of trimethoprim per kg/day plus 250 mg of sulfamethoxazole per kg/day. The anti-P. carinii activity of these guanylhydrazone derivatives was found with parenteral but not with oral administration. The 1,3-arylene diketone bis(guanylhydrazones) were generally ineffective, although a triacetyl derivative showed some anti-P. carinii activity. Nitroimidazole guanylhydrazone derivatives were also ineffective. Attempts to improve the therapeutic efficacy of the different guanylhydrazones were limited by problems of toxicity. We conclude that some guanylhydrazone derivatives are potent anti-P. carinii drugs and that further studies should be pursued to develop safer compounds and investigate structure-activity relationships. PMID:7872750

Metronidazole Vaginal

MedlinePlus

... is used to treat vaginal infections such as bacterial vaginosis (an infection caused from too much of certain bacteria in the vagina). Metronidazole is in a class of medications called nitroimidazole antimicrobials. It works by stopping the growth of bacteria.

Enhancement of radiosensitizing effect of the nitroimidazole derivative RK28 on the proliferation of MethA tumor cells in combined use with diethyldithiocarbamate

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mashiba, Harukazu; Matsunaga, Keiko; Hata, Kazuo

1991-01-01

The radiosensitizing effect of the nitroimidazole derivative RK28 and diethyldithiocarbamate (DDC), which is an inhibitor of superoxide dismutase activity, was examined in vitro by using Meth A tumor cells. The radiosensitizing effect of 0.5 mM RK28 was observed in both of 10 Gy and 15 Gy irradiated groups. The addition of 5 {times} 10{sup {minus}7} M DDC also enhanced the radiation-induced proliferation inhibition. Marked enhancement of the anti-proliferative effect was observed in combined use of 0.2 mM or 0.5 mM RK28 with 2 {times} 10 M or 5 {times} 10{sup {minus}7} M DDC. These results suggest that enhanced oxygen effectmore » could be expected through combined use of the ionizing irradiation with both of these agents.« less

How does methylation suppress the electron-induced decomposition of 1-methyl-nitroimidazoles?

NASA Astrophysics Data System (ADS)

Kossoski, F.; Varella, M. T. do N.

2017-10-01

The efficient decomposition of nitroimidazoles (NIs) by low energy electrons is believed to underlie their radiosensitizing properties. Recent dissociative electron attachment (DEA) measurements showed that methylation at the N1 site unexpectedly suppresses the electron-induced reactions in 4(5)-NI. We report theoretical results that provide a clear interpretation of that astounding finding. Around 1.5 eV, DEA reactions into several fragments are initiated by a π* resonance, not considered in previous studies. The autoionization lifetime of this anion state, which limits the predissociation dynamics, is considerably shorter in the methylated species, thereby suppressing the DEA signals. On the other hand, the lifetime of the π* resonance located around 3 eV is less affected by methylation, which explains why DEA is still observed at these energies. Our results demonstrate how even a simple methylation can significantly modify the probabilities for DEA reactions, which may be significant for NI-based cancer therapy.

Covalent triazine framework-1 as adsorbent for inline solid phase extraction-high performance liquid chromatographic analysis of trace nitroimidazoles in porcine liver and environmental waters.

PubMed

Zhong, Cheng; Chen, Beibei; He, Man; Hu, Bin

2017-02-03

In this study, covalent triazine framework-1 (CTF-1) was adopted as solid phase extraction (SPE) sorbents, and a method of SPE inline coupled with high performance liquid chromatography-ultraviolet (HPLC-UV) detection was developed for trace analysis of three nitroimidazolaes (including metronidazole, ronidazole and dimetridazole) in porcine liver and environmental water samples. CTF-1 has rich π-electron and N containing triazine, thus can form π-π interaction and intermolecular hydrogen bond with three target polar nitroimidazoles, resulting in high extraction efficiency (87%-98%). Besides, CTF-1 has large specific area, which benefits rapid mass transfer and low column pressure, leading to fast adsorption/desorption dynamics. Several parameters affecting inline SPE including pH, sample flow rate, sample volume, desorption reagents, elution flow rate, elution volume, and ionic strength were investigated. Under the optimal experimental conditions, the limits of detection (S/N=3) were found to be in the range of 0.11-0.13μg/L. The enrichment factors (EFs) ranged from 52 to 59 fold (theoretical EF was 60-fold). The relative standard deviations were in the range of 4.3-9.4% (n=7, c=1μg/L), and the linear range was 0.5-500μg/L for three target analytes. The sample throughput is 7/h. The proposed method was successfully applied to the analysis of nitroimidazoles in porcine liver and environmental water samples with good recoveries for the spiked samples. Copyright © 2016 Elsevier B.V. All rights reserved.

Demonstration of tumor-selective retention of fluorinated nitroimidazole probes by /sup 19/F magnetic resonance spectroscopy in vivo

DOE Office of Scientific and Technical Information (OSTI.GOV)

Maxwell, R.J.; Workman, P.; Griffiths, J.R.

1989-04-01

We have evaluated two fluorinated misonidazole analogues, Ro 07-0741 and CCI-103F, as potential probes for the non-invasive identification of hypoxic tumor cells by /sup 19/F magnetic resonance spectroscopy (MRS) in vivo. The equipment used was a 1.9 T Oxford Research Systems TMR-32 spectrometer, fitted with a 15 mm diameter surface coil. Signal was readily detectable, with similar intensity from EMT6 tumor, liver, and brain at early times (1-2 hr) after i.v. injection in BALB/c mice, indicative of an initial uniform biodistribution of parent probes. At later times (5-10 hr) there was a progressive reduction in signal intensity from brain andmore » liver, but tumor levels remained constant or declined more slowly. This is illustrated by tumor/brain ratios at 6-7 hr of 2.9 (Ro 07-0741) and 4.2 (CCI-103F). In 4/5 mice analyzed at 20-24 hr after Ro 07-0741, and 1/2 following CCI-103F, tumor signal remained detectable. This occurred in the absence of parent probe as measured by HPLC, suggesting the involvement of a product of nitroreductive bioactivation. Studies with KHT and RIF-1 tumors in C3H/He mice showed a similar trend but retention in RIF-1 was less dramatic, and this was consistent with the known hypoxic fractions and comparative in vivo nitroreductase activities. These promising results support the continuing development of /sup 19/F nitroimidazole probes for non-invasive identification of hypoxic cells in vivo.« less

Synthesis, QSAR and calcium channel modulator activity of new hexahydroquinoline derivatives containing nitroimidazole.

PubMed

Miri, Ramin; Javidnia, Katayoun; Mirkhani, Hossein; Hemmateenejad, Bahram; Sepeher, Zahra; Zalpour, Masomeh; Behzad, Taherh; Khoshneviszadeh, Mehdi; Edraki, Najmeh; Mehdipour, Ahmad R

2007-10-01

The discovery that 1,4-dihydropyridine class of calcium channel antagonists inhibit Ca2+ influx represented a major therapeutic advance in the treatment of cardiovascular disease. In contrast to the effects of known calcium channel blockers of the Nifedipine-type, the so-called calcium channel agonists, such as Bay K8644 and CGP 28392, increase calcium influx by binding at the same receptor regions. Our goal was to discover a dual cardioselective Ca2+-channel agonist/vascular selective smooth muscle Ca2+ channel antagonist third-generation 1,4-dihydropyridine drug which would have a suitable therapeutic profile for treating congestive heart failure (CHF) patients. A series of unsymmetrical alkyl, cycloalkyl and aryl ester analogues of 2-methyl-4-(1-methyl)-5-nitro-2-imidazolyl-5-oxo-1,4,5,6,7, 8-hexahydroquinolin-3-arboxylate were synthesized using modified Hantzsch reaction. All compounds show calcium antagonist activity on guinea-pig ileum longitudinal smooth muscle and some of them show agonist effect activity on guinea-pig auricle. Effect of structural parameters on the Ca2+ channel agonist/antagonist was evaluated by quantitative structure-activity relationship analysis. These compounds could be considered as a synthon for developing a suitable drug for treating CHF patients.

Comprehensive screening and quantification of veterinary drugs in milk using UPLC–ToF-MS

PubMed Central

Rutgers, P.; Oosterink, E.; Lasaroms, J. J. P.; Peters, R. J. B.; van Rhijn, J. A.; Nielen, M. W. F.

2008-01-01

Ultra-performance liquid chromatography combined with time-of-flight mass spectrometry (UPLC–ToF-MS) has been used for screening and quantification of more than 100 veterinary drugs in milk. The veterinary drugs represent different classes including benzimidazoles, macrolides, penicillins, quinolones, sulphonamides, pyrimidines, tetracylines, nitroimidazoles, tranquillizers, ionophores, amphenicols and non-steroidal anti-inflammatory agents (NSAIDs). After protein precipitation, centrifugation and solid-phase extraction (SPE), the extracts were analysed by UPLC–ToF-MS. From the acquired full scan data the drug-specific ions were extracted for construction of the chromatograms and evaluation of the results. The analytical method was validated according to the EU guidelines (2002/657/EC) for a quantitative screening method. At the concentration level of interest (MRL level) the results for repeatability (%RSD < 20% for 86% of the compounds), reproducibility (%RSD < 40% for 96% of the compounds) and the accuracy (80–120% for 88% of the compounds) were satisfactory. Evaluation of the CCβ values and the linearity results demonstrates that the developed method shows adequate sensitivity and linearity to provide quantitative results. Furthermore, the method is accurate enough to differentiate between suspected and negative samples or drug concentrations below or above the MRL. A set of 100 samples of raw milk were screened for residues. No suspected (positive) results were obtained except for the included blind reference sample containing sulphamethazine (88 μg/l) that tested positive for this compound. UPLC–ToF-MS combines high resolution for both LC and MS with high mass accuracy which is very powerful for the multi-compound analysis of veterinary drugs. The technique seems to be powerful enough for the analysis of not only veterinary drugs but also organic contaminants like pesticides, mycotoxins and plant toxins in one single method. PMID:18491081

Qualitative screening of veterinary anti-microbial agents in tissues, milk, and eggs of food-producing animals using liquid chromatography coupled with tandem mass spectrometry.

PubMed

Chen, Dongmei; Yu, Jie; Tao, Yanfei; Pan, Yuanhu; Xie, Shuyu; Huang, Lingli; Peng, Dapeng; Wang, Xu; Wang, Yulian; Liu, Zhenli; Yuan, Zonghui

2016-04-01

A method for the analysis of 120 drugs in animal derived food was developed using liquid chromatography-tandem mass spectrometry (LC-MS/MS). These analytes belong to 12 families of veterinary anti-microbial agents (quinolones, macrolides, β-lactams, nitroimidazoles, sulfonamides, lincomycines, chloramphenicols, quinoxalines, tetracyclines, polypeptides, and antibacterial synergists) as well as other compounds not assigned to a particular drug family. The animal derived food samples include muscle and liver of swine, bovine, sheep, and chicken, as well as hen eggs and dairy milk. The sample preparation included ultrasound-assisted extraction (UAE) with acetonitrile-water and a final clean-up with auto solid-phase extraction (SPE) on HLB cartridges. The detection and quantification of 120 anti-microbial agents was performed using LC-MS/MS in positive and negative ion mode. The chromatographic separation was performed on a C18 column using acetonitrile and 0.1% formic acid as the mobile phase. The limit of detection (LOD) and limit of quantification (LOQ) of all drugs in food-producing animals were 0.5-3.0μg/kg and 1.5-10.0μg/kg, respectively. The developed method was successfully utilized to monitor real samples, which demonstrated that it is a simple, fast, and robust method, and could be used as a regulatory to screen for the presence of residues from veterinary anti-microbial drugs in animal-derived foods. Copyright © 2016 Elsevier B.V. All rights reserved.

An effective tumor-targeting strategy utilizing hypoxia-sensitive siRNA delivery system for improved anti-tumor outcome.

PubMed

Kang, Lin; Fan, Bo; Sun, Ping; Huang, Wei; Jin, Mingji; Wang, Qiming; Gao, Zhonggao

2016-10-15

Hypoxia is a feature of most solid tumors, targeting hypoxia is considered as the best validated yet not extensively exploited strategy in cancer therapy. Here, we reported a novel tumor-targeting strategy using a hypoxia-sensitive siRNA delivery system. In the study, 2-nitroimidazole (NI), a hydrophobic component that can be converted to hydrophilic 2-aminoimidazole (AI) through bioreduction under hypoxic conditions, was conjugated to the alkylated polyethyleneimine (bPEI1.8k-C6) to form amphiphilic bPEI1.8k-C6-NI polycations. bPEI1.8k-C6-NI could self-assemble into micelle-like aggregations in aqueous, which contributed to the improved stability of the bPEI1.8k-C6-NI/siRNA polyplexes, resulted in increased cellular uptake. After being transported into the hypoxic tumor cells, the selective nitro-to-amino reduction would cause structural change and elicit a relatively loose structure to facilitate the siRNA dissociation in the cytoplasm, for enhanced gene silencing efficiency ultimately. Therefore, the conflict between the extracellular stability and the intracellular siRNA release ability of the polyplexes was solved by introducing the hypoxia-responsive unit. Consequently, the survivin-targeted siRNA loaded polyplexes shown remarkable anti-tumor effect not only in hypoxic cells, but also in tumor spheroids and tumor-bearing mice, indicating that the hypoxia-sensitive siRNA delivery system had great potential for tumor-targeted therapy. Hypoxia is one of the most remarkable features of most solid tumors, and targeting hypoxia is considered as the best validated strategy in cancer therapy. However, in the past decades, there were few reports about using this strategy in the drug delivery system, especially in siRNA delivery system. Therefore, we constructed a hypoxia-sensitive siRNA delivery system utilizing a hypoxia-responsive unit, 2-nitroimidazole, by which the unavoidable conflict between improved extracellular stability and promoted intracellular siRNA release in the same delivery system could be effectively solved, resulting in enhanced siRNA silencing efficiency in tumor cells. To our knowledge, the described work is the first demonstration of a siRNA delivery system using a hypoxia trigger for regulation of siRNA release, which represents a new strategy for tumor-targeted therapy, and it is expected that this meaningful strategy must be widely applied in the future. Copyright © 2016 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Analytical method for fast screening and confirmation of multi-class veterinary drug residues in fish and shrimp by LC-MS/MS.

PubMed

Kim, Junghyun; Suh, Joon Hyuk; Cho, Hyun-Deok; Kang, Wonjae; Choi, Yong Seok; Han, Sang Beom

2016-01-01

A multi-class, multi-residue analytical method based on LC-MS/MS detection was developed for the screening and confirmation of 28 veterinary drug and metabolite residues in flatfish, shrimp and eel. The chosen veterinary drugs are prohibited or unauthorised compounds in Korea, which were categorised into various chemical classes including nitroimidazoles, benzimidazoles, sulfones, quinolones, macrolides, phenothiazines, pyrethroids and others. To achieve fast and simultaneous extraction of various analytes, a simple and generic liquid extraction procedure using EDTA-ammonium acetate buffer and acetonitrile, without further clean-up steps, was applied to sample preparation. The final extracts were analysed by ultra-high-performance liquid chromatography coupled with tandem mass spectrometry (UHPLC-MS/MS). The method was validated for each compound in each matrix at three different concentrations (5, 10 and 20 ng g(-1)) in accordance with Codex guidelines (CAC/GL 71-2009). For most compounds, the recoveries were in the range of 60-110%, and precision, expressed as the relative standard deviation (RSD), was in the range of 5-15%. The detection capabilities (CCβs) were below or equal to 5 ng g(-1), which indicates that the developed method is sufficient to detect illegal fishery products containing the target compounds above the residue limit (10 ng g(-1)) of the new regulatory system (Positive List System - PLS).

Use of antibiotics in the treatment of Crohn's disease.

PubMed

Scribano, Maria Lia; Prantera, Cosimo

2013-02-07

Many data coming from animal models and clinical observations support an involvement of intestinal microbiota in the pathogenesis of Crohn's disease (CD). It is hypothesized in fact, that the development of chronic intestinal inflammation is caused by an abnormal immune response to normal flora in genetically susceptible hosts. The involvement of bacteria in CD inflammation has provided the rationale for including antibiotics in the therapeutic armamentarium. However, randomized controlled trials have failed to demonstrate an efficacy of these drugs in patients with active uncomplicated CD, even if a subgroup of patients with colonic location seems to get benefit from antibiotics. Nitroimidazole compounds have been shown to be efficacious in decreasing CD recurrence rates in operated patients, and the use of metronidazole and ciprofloxacin is recommended in perianal disease. However, the appearance of systemic side effects limits antibiotic long-term employment necessary for treating a chronic relapsing disease. Rifaximin, characterized by an excellent safety profile, has provided promising results in inducing remission of CD.

Preliminary research on 1-(4-bromo-2-nitroimidazol-1-yl)-3-[(18)F]fluoropropan-2-ol as a novel brain hypoxia PET tracer in a rodent model of stroke.

PubMed

Nieto, Elena; Delgado, Mercedes; Sobrado, Mónica; de Ceballos, María L; Alajarín, Ramón; García-García, Luis; Kelly, James; Lizasoain, Ignacio; Pozo, Miguel A; Álvarez-Builla, Julio

2015-08-28

The synthesis of the new radiotracer precursor 4-Br-NITTP and the radiolabeling of the new tracer 1-(4-bromo-2-nitroimidazol-1-yl)-3-[(18)F]fluoropropan-2-ol (4-Br-[(18)F]FMISO) is reported. The cyclic voltammetry behaviour, neuronal cell toxicity, transport through the brain endothelial cell monolayer, in vivo PET imaging and preliminary calculations of the tracer uptake for a rodent model of stroke were studied for the new compound and the results were compared to those obtained with [(18)F]FMISO, the current gold standard PET hypoxia tracer. The new PET brain hypoxia tracer is more easily reduced, has higher CLogP than [(18)F]FMISO and it diffuses more rapidly through brain endothelial cells. The new compound is non-toxic to neuronal cells and it allows the in vivo mapping of stroke in mice with higher sensitivity. 4-Br-[(18)F]FMISO is a good candidate for further development in ischemic stroke. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Aggregate Formation of Oligonucleotides that Assist Molecular Imaging for Tracking of the Oxygen Status in Tumor Tissue.

PubMed

Yoshihara, Kazuki; Takagi, Kohei; Son, Aoi; Kurihara, Ryohsuke; Tanabe, Kazuhito

2017-08-17

The use of DNA aggregates could be a promising strategy for the molecular imaging of biological functions. Herein, phosphorescent oligodeoxynucleotides were designed with the aim of visualizing oxygen fluctuation in tumor cells. DNA-ruthenium conjugates (DRCs) that consisted of oligodeoxynucleotides, a phosphorescent ruthenium complex, a pyrene unit for high oxygen responsiveness, and a nitroimidazole unit as a tumor-targeting unit were prepared. In general, oligonucleotides have low cell permeability because of their own negative charges; however, the DRC formed aggregates in aqueous solution due to the hydrophobic pyrene and nitroimidazole groups, and smoothly penetrated the cellular membrane to accumulate in tumor cells in a hypoxia-selective manner. The oxygen-dependent phosphorescence of DRC in cells was also observed. In vivo experiments revealed that aggregates of DRC accumulated in hypoxic tumor tissue that was transplanted into the left leg of mice, and showed that oxygen fluctuations in tumor tissue could be monitored by tracking of the phosphorescence emission of DRC. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

The drug ornidazole inhibits photosynthesis in a different mechanism described for protozoa and anaerobic bacteria.

PubMed

Marcus, Yehouda; Tal, Noam; Ronen, Mordechai; Carmieli, Raanan; Gurevitz, Michael

2016-12-01

Ornidazole of the 5-nitroimidazole drug family is used to treat protozoan and anaerobic bacterial infections via a mechanism that involves preactivation by reduction of the nitro group, and production of toxic derivatives and radicals. Metronidazole, another drug family member, has been suggested to affect photosynthesis by draining electrons from the electron carrier ferredoxin, thus inhibiting NADP + reduction and stimulating radical and peroxide production. Here we show, however, that ornidazole inhibits photosynthesis via a different mechanism. While having a minute effect on the photosynthetic electron transport and oxygen photoreduction, ornidazole hinders the activity of two Calvin cycle enzymes, triose-phosphate isomerase (TPI) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Modeling of ornidazole's interaction with ferredoxin of the protozoan Trichomonas suggests efficient electron tunneling from the iron-sulfur cluster to the nitro group of the drug. A similar docking site of ornidazole at the plant-type ferredoxin does not exist, and the best simulated alternative does not support such efficient tunneling. Notably, TPI was inhibited by ornidazole in the dark or when electron transport was blocked by dichloromethyl diphenylurea, indicating that this inhibition was unrelated to the electron transport machinery. Although TPI and GAPDH isoenzymes are involved in glycolysis and gluconeogenesis, ornidazole's effect on respiration of photoautotrophs is moderate, thus raising its value as an efficient inhibitor of photosynthesis. The scarcity of Calvin cycle inhibitors capable of penetrating cell membranes emphasizes on the value of ornidazole for studying the regulation of this cycle. © 2016 The Author(s); published by Portland Press Limited on behalf of the Biochemical Society.

HYPOXIA-ACTIVATED PRO-DRUG TH-302 EXHIBITS POTENT TUMOUR SUPPRESSIVE ACTIVITY AND COOPERATES WITH CHEMOTHERAPY AGAINST OSTEOSARCOMA

PubMed Central

Liapis, Vasilios; Labrinidis, Agatha; Zinonos, Irene; Hay, Shelley; Ponomarev, Vladimir; Panagopoulos, Vasilios; DeNichilo, Mark; Ingman, Wendy; Atkins, Gerald J.; Findlay, David M.; Zannettino, Andrew CW.; Evdokiou, Andreas

2015-01-01

Tumour hypoxia is a major cause of treatment failure for a variety of malignancies. However, tumour hypoxia also offers treatment opportunities, exemplified by the development compounds that target hypoxic regions within tumours. TH-302 is a pro-drug created by the conjugation of 2-nitroimidazole to bromo-isophosphoramide (Br-IPM). When TH-302 is delivered to regions of hypoxia, Br-IPM, the DNA cross linking toxin, is released. In this study we assessed the cytotoxic activity of TH-302 against osteosarcoma cells in vitro and evaluated its anticancer efficacy as a single agent, and in combination with doxorubicin, in an orthotopic mouse model of human osteosarcoma (OS). In vitro, TH-302 was potently cytotoxic to osteosarcoma cells selectively under hypoxic conditions, whereas primary normal human osteoblasts were protected. Animals transplanted with OS cells directly into their tibiae and left untreated developed mixed osteolytic/osteosclerotic bone lesions and subsequently developed lung metastases. TH-302 reduced tumor burden in bone and cooperated with doxorubicin to protect bone from osteosarcoma induced bone destruction, while it also reduced lung metastases. TH-302 may therefore be an attractive therapeutic agent with strong activity as a single agent and in combination with chemotherapy against OS. PMID:25444931

Hypoxia-activated pro-drug TH-302 exhibits potent tumor suppressive activity and cooperates with chemotherapy against osteosarcoma.

PubMed

Liapis, Vasilios; Labrinidis, Agatha; Zinonos, Irene; Hay, Shelley; Ponomarev, Vladimir; Panagopoulos, Vasilios; DeNichilo, Mark; Ingman, Wendy; Atkins, Gerald J; Findlay, David M; Zannettino, Andrew C W; Evdokiou, Andreas

2015-02-01

Tumor hypoxia is a major cause of treatment failure for a variety of malignancies. However, tumor hypoxia also offers treatment opportunities, exemplified by the development compounds that target hypoxic regions within tumors. TH-302 is a pro-drug created by the conjugation of 2-nitroimidazole to bromo-isophosphoramide (Br-IPM). When TH-302 is delivered to regions of hypoxia, Br-IPM, the DNA cross linking toxin, is released. In this study we assessed the cytotoxic activity of TH-302 against osteosarcoma cells in vitro and evaluated its anticancer efficacy as a single agent, and in combination with doxorubicin, in an orthotopic mouse model of human osteosarcoma (OS). In vitro, TH-302 was potently cytotoxic to osteosarcoma cells selectively under hypoxic conditions, whereas primary normal human osteoblasts were protected. Animals transplanted with OS cells directly into their tibiae and left untreated developed mixed osteolytic/osteosclerotic bone lesions and subsequently developed lung metastases. TH-302 reduced tumor burden in bone and cooperated with doxorubicin to protect bone from osteosarcoma induced bone destruction, while it also reduced lung metastases. TH-302 may therefore be an attractive therapeutic agent with strong activity as a single agent and in combination with chemotherapy against OS. Crown Copyright © 2014. Published by Elsevier Ireland Ltd. All rights reserved.

Nitration Enzyme Toolkit for the Biosynthesis of Energetic Materials

DTIC Science & Technology

by - products that degrade performance of the energetic products . To reduce the...bionitration mechanisms used by microorganisms to produce nitro-containing natural products . We investigated biosynthetic pathways for 2-nitroimidazole...producing a diverse set of nitrophenols. This growing bionitration toolkit represents a diverse range of nitration mechanisms and products that can be adapted for the green chemistry production of nitro compounds and

The antimicrobial effect of boric acid on Trichomonas vaginalis.

PubMed

Brittingham, Andrew; Wilson, Wayne A

2014-12-01

The treatment options for trichomoniasis are largely limited to nitroimidazole compounds (metronidazole and tinidazole). Few alternatives exist in cases of recalcitrant infections or in cases of nitroimidazole hypersensitivity. Recently, the intravaginal administration of boric acid has been advocated as an alternative treatment of trichomoniasis. However, no in vitro studies are available that directly assess the sensitivity of Trichomonas vaginalis to boric acid. We examined the sensitivity of common laboratory strains and recent clinical isolates of T. vaginalis to boric acid. The effect of increasing concentrations of boric acid on parasite growth and viability was determined, and a minimal lethal concentration was reported. The effect of pH on boric acid toxicity was assessed and compared with that of lactic and acetic acid. Boric acid is microbicidal to T. vaginalis, and its antitrichomonal activity is independent of environmental acidification. Unlike acetic acid and lactic acid, boric acid exposure results in growth suppression and lethality over a wide range of pH (5-7) and under conditions that are normally permissible for growth in vitro. The microbicidal effect of boric acid on T. vaginalis, coupled with its previous clinical use in treating vaginal candidiasis, supports the continued inclusion of boric acid in the therapeutic arsenal for treating trichomoniasis.

Dual Mechanism of Action of 5-Nitro-1,10-Phenanthroline against Mycobacterium tuberculosis

PubMed Central

Kidwai, Saqib; Park, Chan-Yong; Mawatwal, Shradha; Tiwari, Prabhakar; Jung, Myung Geun; Gosain, Tannu Priya; Kumar, Pradeep; Alland, David; Kumar, Sandeep; Bajaj, Avinash; Hwang, Yun-Kyung; Song, Chang Sik; Dhiman, Rohan

2017-01-01

ABSTRACT New chemotherapeutic agents with novel mechanisms of action are urgently required to combat the challenge imposed by the emergence of drug-resistant mycobacteria. In this study, a phenotypic whole-cell screen identified 5-nitro-1,10-phenanthroline (5NP) as a lead compound. 5NP-resistant isolates harbored mutations that were mapped to fbiB and were also resistant to the bicyclic nitroimidazole PA-824. Mechanistic studies confirmed that 5NP is activated in an F420-dependent manner, resulting in the formation of 1,10-phenanthroline and 1,10-phenanthrolin-5-amine as major metabolites in bacteria. Interestingly, 5NP also killed naturally resistant intracellular bacteria by inducing autophagy in macrophages. Structure-activity relationship studies revealed the essentiality of the nitro group for in vitro activity, and an analog, 3-methyl-6-nitro-1,10-phenanthroline, that had improved in vitro activity and in vivo efficacy in mice compared with that of 5NP was designed. These findings demonstrate that, in addition to a direct mechanism of action against Mycobacterium tuberculosis, 5NP also modulates the host machinery to kill intracellular pathogens. PMID:28893784

Boron doped diamond sensor for sensitive determination of metronidazole: Mechanistic and analytical study by cyclic voltammetry and square wave voltammetry.

PubMed

Ammar, Hafedh Belhadj; Brahim, Mabrouk Ben; Abdelhédi, Ridha; Samet, Youssef

2016-02-01

The performance of boron-doped diamond (BDD) electrode for the detection of metronidazole (MTZ) as the most important drug of the group of 5-nitroimidazole was proven using cyclic voltammetry (CV) and square wave voltammetry (SWV) techniques. A comparison study between BDD, glassy carbon and silver electrodes on the electrochemical response was carried out. The process is pH-dependent. In neutral and alkaline media, one irreversible reduction peak related to the hydroxylamine derivative formation was registered, involving a total of four electrons. In acidic medium, a prepeak appears probably related to the adsorption affinity of hydroxylamine at the electrode surface. The BDD electrode showed higher sensitivity and reproducibility analytical response, compared with the other electrodes. The higher reduction peak current was registered at pH11. Under optimal conditions, a linear analytical curve was obtained for the MTZ concentration in the range of 0.2-4.2μmolL(-1), with a detection limit of 0.065μmolL(-1). Copyright © 2015 Elsevier B.V. All rights reserved.

Cordyceps sinensis promotes immune regulation and enhances bacteriostatic activity of PA-824 via IL-10 in Mycobacterium tuberculosis disease

PubMed Central

Li, D.G.; Ren, Z.X.

2017-01-01

PA-824 is a novel bicyclic nitroimidazole anti-tuberculosis (TB) drug. Cordyceps sinensis (Berk.) Sacc. (CS) was proven to be a good immunomodulatory compound. This research aimed to investigate the effect of CS on PA-824 in Mycobacterium tuberculosis (M.tb) infected mice (female CBA/J mice, 6 to 8 weeks of age and 20±2 g of weight). Mice were randomly assigned to 4 groups: PA-824, CS, PA-824+CS, and control. To verify the effect of PA-824 and CS on M.tb, after drug administration, mice lungs were harvested and bacterial colony formations were measured. Cells were isolated from infected lungs and spleens to analyze the percentage of CD4+ T cells (CD11a positive). Lung cells were cultured to detect the secretion of interferon-γ (IFN-γ) and interleukin-10 (IL-10) by ELISA. IFN-γ and IL-10 double-positive CD4+ cells in peripheral blood were measured by flow cytometry. The expression levels of IL-2 and IL-10 in mice lungs were analyzed by real-time PCR and western blot. Results showed that PA-824 combined with CS led to the lowest lung colony-forming units (CFU) counts among treated groups. Furthermore, this beneficial outcome might be associated with the decreased CD11a on CD4+ cells in mice lungs and spleens. Moreover, the suppressed secretion of IFN-γ and IL-10, and IL-10 expressions, as well as the decreased IFN-γ and IL-10 double-positive CD4+ cells in blood, could also be associated with the positive effect. However, no significant effect on IL-2 production was found. The combination of PA-824 and CS had more effective bacteriostatic and immunomodulatory effects on M.tb infected mice than PA-824 alone. In conclusion, CS has the potential to be an effective adjuvant in TB treatment. PMID:28793052

Cordyceps sinensis promotes immune regulation and enhances bacteriostatic activity of PA-824 via IL-10 in Mycobacterium tuberculosis disease.

PubMed

Li, D G; Ren, Z X

2017-08-07

PA-824 is a novel bicyclic nitroimidazole anti-tuberculosis (TB) drug. Cordyceps sinensis (Berk.) Sacc. (CS) was proven to be a good immunomodulatory compound. This research aimed to investigate the effect of CS on PA-824 in Mycobacterium tuberculosis (M.tb) infected mice (female CBA/J mice, 6 to 8 weeks of age and 20±2 g of weight). Mice were randomly assigned to 4 groups: PA-824, CS, PA-824+CS, and control. To verify the effect of PA-824 and CS on M.tb, after drug administration, mice lungs were harvested and bacterial colony formations were measured. Cells were isolated from infected lungs and spleens to analyze the percentage of CD4+ T cells (CD11a positive). Lung cells were cultured to detect the secretion of interferon-γ (IFN-γ) and interleukin-10 (IL-10) by ELISA. IFN-γ and IL-10 double-positive CD4+ cells in peripheral blood were measured by flow cytometry. The expression levels of IL-2 and IL-10 in mice lungs were analyzed by real-time PCR and western blot. Results showed that PA-824 combined with CS led to the lowest lung colony-forming units (CFU) counts among treated groups. Furthermore, this beneficial outcome might be associated with the decreased CD11a on CD4+ cells in mice lungs and spleens. Moreover, the suppressed secretion of IFN-γ and IL-10, and IL-10 expressions, as well as the decreased IFN-γ and IL-10 double-positive CD4+ cells in blood, could also be associated with the positive effect. However, no significant effect on IL-2 production was found. The combination of PA-824 and CS had more effective bacteriostatic and immunomodulatory effects on M.tb infected mice than PA-824 alone. In conclusion, CS has the potential to be an effective adjuvant in TB treatment.

Effect of misonidazole or metronidazole pretreatment on the response of the RIF-1 mouse sarcoma to melphalan, cyclophosphamide, chlorambucil and CCNU.

PubMed Central

Twentyman, P.; Workman, P.

1982-01-01

The effect has been studied of adding either misonidazole (MISO) or metronidazole (METRO) to cytotoxic drug treatment of C3H mice bearing the RIF-1 sarcoma. The nitroimidazoles were injected 30 min before the cytotoxic drugs at a dose of 2 . 5 mmol/kg. Both clonogenic-cell survival and growth delay were measured as indicators of tumour response and depression in WBC count and acute lethality were used to indicate normal-tissue response. For melphalan, neither pretreatment agent produced any change in tumor response. For cyclophosphamide, no change was produced by METRO but a minimal increase in tumour response occurred with MISO. An enhancement of cell killing by CCNU was seen with MISO pretreatment, but there was no increase in tumour growth delay. METRO, however, did not enhance tumour response by either endpoint. WBC depression by CCNU was not enhanced by MISO pretreatment, and there was no significant reduction in the acute LD50. This indicates a therapeutic advantage from the addition of MISO to CCNU in this model system. For chlorambucil, considerable enhancement of tumour response followed either MISO or METRO pretreatment (dose-modifying factors of 2 . 0 and 1 . 4 respectively). However, the modification by MISO of normal-tissue response to chlorambucil was also enhanced by about a factor of 2, with no therapeutic gain. PMID:7073938

Applicability of the 2-nitroimidazole-sodium borocaptate-10B conjugate, TX-2060, as a 10B-carrier in boron neutron capture therapy.

PubMed

Masunaga, Shin-Ichiro; Nagasawa, Hideko; Hiraoka, Masamitsu; Sakurai, Yoshinori; Uto, Yoshihiro; Hori, Hitoshi; Nagata, Kenji; Suzuki, Minoru; Maruhashi, Akira; Kinashi, Yuko; Ono, Koji

2004-01-01

It is difficult to deliver a therapeutic amount of 10B from conventional 10B-carriers for boron neutron capture therapy (BNCT) throughout the target tumors, especially into the intratumor hypoxic cells which have low uptake capacities. We evaluated the usefulness of 5 new 10B-compounds (TX-2041, TX-2042, TX-2058, TX-2059 and TX-2060) as 10B-carriers in BNCT. They are 2-nitroimidazole-sodium borocaptate-10B (BSH) conjugates, that is, hybrid compounds that have both a hypoxic tumor cell sensitizing unit under gamma-ray irradiation, 2-nitroimidazoles and a thermal neutron-sensitizing unit, BSH. The 5 new compounds were administered to SCC VII tumor-bearing mice intraperitoneally. As a control, BSH was also administered in the same manner. Then, the 10B concentrations in the tumors and normal tissues were measured by gamma-ray spectrometry. Based on the data of the pharmacokinetics analyses, TX-2060 was chosen for a subsequent tumor-irradiation study. SCC VII tumor-bearing mice were continuously given 5-bromo-2'-deoxyuridine (BrdU) to label all proliferating (P) cells in the tumors, then treated with TX-2060 or BSH in the same manner as in the pharmacokinetics analyses. To obtain similar intratumor 10B concentrations during radiation exposure, irradiation with thermal neutrons or gamma-rays was started from 60 min after administration of the 10B-carrier. Right after irradiation, the tumors were excised, minced and trypsinized. The tumor cell suspensions thus obtained were incubated with cytochalasin-B (a cytokinesis blocker), and the micronucleus (MN) frequency in cells without BrdU-labelling (= quiescent (Q) cells) was determined using immunofluorescence staining for BrdU. Meanwhile, the MN frequency in total (P + Q) tumor cells was determined from the tumors that were not pretreated with BrdU. The clonogenic cell survival was also determined in mice given no BrdU. 10B distribution analyses in tumors, muscles, blood and liver indicated that TX-2060 has the most favorable characteristics for concentrating a sufficient amount of 10B in tumors and maintaining a high enough 10B concentration during irradiation. In addition, TX-2060 had a significantly stronger radio-sensitization effect with reactor thermal neutron beams than BSH on both total and Q cells in solid tumors. Further, TX-2060 clearly exhibited a radio-sensitization effect with gamma-rays, not only on total cells but also on Q and hypoxic tumor cells, which was not achieved by BSH. 10B-carrier, with a gamma-ray-sensitizing effect on tumor cells as well as the potential to keep 10B in tumors and sensitize tumor cells more markedly than conventional 10B-carriers, such as TX-2060, is a promising candidate for use in BNCT.

Temporal associations with declining Trichomonas vaginalis diagnosis rates among women in the state of Victoria, Australia, 1947 to 2005.

PubMed

Marrone, John; Fairley, Christopher K; Saville, Marian; Bradshaw, Catriona; Bowden, Francis J; Horvath, Leonie B; Donovan, Basil; Chen, Marcus; Hocking, Jane S

2008-06-01

To investigate the temporal associations between Trichomonas vaginalis (TV) diagnoses in women at a large urban sexual health clinic and a major Papanicolaou (Pap) smear screening laboratory in Victoria, Australia with Pap smear screening rates and the introduction of nitroimidazole treatments. An ecological analysis of TV diagnosis rates at the Melbourne Sexual Health Centre and the Victorian Cytology Service, Pap smear screening rates and nitroimidazole prescription data. Diagnoses of TV at the Melbourne Sexual Health Centre peaked in the 1950s at 20% to 30% and then rapidly declined through the 1960s and 1970s to below 1% in 1990. A similar pattern was observed at the Victorian Cytology Service. Metronidazole prescribing and opportunistic Pap smear screening began in Victoria in the 1960s coinciding with declining TV. The availability of tinidazole in 1976 led to further declines in TV in the late 1970s. A national cervical screening program introduced in 1991 was temporally associated with further declines in TV. Our analyses suggest that the introduction of metronidazole was associated with a large reduction in TV among Victorian women in the 1960s. The subsequent availability of tinidazole and increased Pap smear screening may have contributed to the current low TV prevalence in Victoria.

Trichomonads, hydrogenosomes and drug resistance.

PubMed

Kulda, J

1999-02-01

Trichomonas vaginalis and Tritrichomonas foetus are sexually transmitted pathogens of the genito-urinary tract of humans and cattle, respectively. These organisms are amitochondrial anaerobes possessing hydrogenosomes, double membrane-bound organelles involved in catabolic processes extending glycolysis. The oxidative decarboxylation of pyruvate in hydrogenosomes is coupled to ATP synthesis and linked to ferredoxin-mediated electron transport. This pathway is responsible for metabolic activation of 5-nitroimidazole drugs, such as metronidazole, used in chemotherapy of trichomoniasis. Prolonged cultivation of trichomonads under sublethal pressure of metronidazole results in development of drug resistance. In both pathogenic species the resistance develops in a multistep process involving a sequence of stages that differ in drug susceptibility and metabolic activities. Aerobic resistance, similar to that occurring in clinical isolates of T. vaginalis from treatment-refractory patients, appears as the earliest stage. The terminal stage is characterised by stable anaerobic resistance at which the parasites show very high levels of minimal lethal concentration for metronidazole under anaerobic conditions (approximately 1000 microg ml(-1)). The key event in the development of resistance is progressive decrease and eventual loss of the pyruvate:ferredoxin oxidoreductase so that the drug-activating process is averted. In T. vaginalis at least, the development of resistance is also accompanied by decreased expression of ferredoxin. The pyruvate:ferredoxin oxidoreductase deficiency completely precludes metronidazole activation in T. foetus, while T. vaginalis possesses an additional drug-activating system which must be eliminated before the full resistance is acquired. This alternative pathway involves the hydrogenosomal malic enzyme and NAD:ferredoxin oxidoreductase. Metronidazole-resistant trichomonads compensate for the hydrogenosomal deficiency by an increased rate of glycolysis and by changes in their cytosolic pathways. Trichomonas vaginalis enhances lactate fermentation while T. foetus activates pyruvate conversion to ethanol. Drug-resistant T. foetus also increases activity of the cytosolic NADP-dependent malic enzyme, to enhance the pyruvate producing bypass and provide NADPH required by alcohol dehydrogenase. Production of succinate by this species is abolished. Metabolic changes accompanying in-vitro development of metronidazole resistance demonstrate the versatility of trichomonad metabolism and provide an interesting example of how unicellular eukaryotes can adjust their metabolism in response to the pressure of an unfavorable environment.

Metronidazole and the immune system.

PubMed

Shakir, L; Javeed, A; Ashraf, M; Riaz, A

2011-06-01

Metronidazole (MTZ) is a nitroimidazole antibiotic used mainly for the treatment of infections caused by susceptible organisms, particularly anaerobic bacteria and protozoa. Distinct from its antibiotic, amoebicidal, and antiprotozoal effects, MTZ displays immunopharmacological behaviour. This review outlines multiple effects of MTZ on different aspects of immunity, including innate and acquired immunity, and also highlights the immunopharmacological behaviour of MTZ in terms of its relevance to inflammation, delayed type hypersensitivity (DTH) and graft versus host disease (GVHD).

Comprehensive comparison of liquid chromatography selectivity as provided by two types of liquid chromatography detectors (high resolution mass spectrometry and tandem mass spectrometry): "where is the crossover point?".

PubMed

Kaufmann, A; Butcher, P; Maden, K; Walker, S; Widmer, M

2010-07-12

The selectivity of mass traces obtained by monitoring liquid chromatography coupled to high resolution mass spectrometry (LC-HRMS) and liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) was compared. A number of blank extracts (fish, pork kidney, pork liver and honey) were separated by ultra performance liquid chromatography (UPLC). Detected were some 100 dummy transitions respectively dummy exact masses (traces). These dummy masses were the product of a random generator. The range of the permitted masses corresponded to those which are typical for analytes (e.g. veterinary drugs). The large number of monitored dummy traces ensured that endogenous compounds present in the matrix extract, produced a significant number of detectable chromatographic peaks. All obtained chromatographic peaks were integrated and standardized. Standardisation was done by dividing these absolute peak areas by the average response of a set of 7 different veterinary drugs. This permitted a direct comparison between the LC-HRMS and LC-MS/MS data. The data indicated that the selectivity of LC-HRMS exceeds LC-MS/MS, if high resolution mass spectrometry (HRMS) data is recorded with a resolution of 50,000 full width at half maximum (FWHM) and a corresponding mass window. This conclusion was further supported by experimental data (MS/MS based trace analysis), where a false positive finding was observed. An endogenous matrix compound present in honey matrix behaved like a banned nitroimidazole drug. This included identical retention time and two MRM traces, producing an MRM ratio between them, which perfectly matched the ratio observed in the external standard. HRMS measurement clearly resolved the interfering matrix compound and unmasked the false positive MS/MS finding. Copyright 2010 Elsevier B.V. All rights reserved.

Down-regulation of flavin reductase and alcohol dehydrogenase-1 (ADH1) in metronidazole-resistant isolates of Trichomonas vaginalis

PubMed Central

Leitsch, David; Drinić, Mirjana; Kolarich, Daniel; Duchêne, Michael

2012-01-01

The microaerophilic parasite Trichomonas vaginalis is a causative agent of painful vaginitis or urethritis, termed trichomoniasis, and can also cause preterm delivery or stillbirth. Treatment of trichomoniasis is almost exclusively based on the nitroimidazole drugs metronidazole and tinidazole. Metronidazole resistance in T. vaginalis does occur and is often associated with treatment failure. In most cases, metronidazole-resistant isolates remain susceptible to tinidazole, but cross resistance between the two closely related drugs can be a problem. In this study we measured activities of thioredoxin reductase and flavin reductase in four metronidazole-susceptible and five metronidazole-resistant isolates. These enzyme activities had been previously found to be downregulated in T. vaginalis with high-level metronidazole resistance induced in the laboratory. Further, we aimed at identifying factors causing metronidazole resistance and compared the protein expression profiles of all nine isolates by application of two-dimensional gel electrophoresis (2DE). Thioredoxin reductase activity was nearly equal in all strains assayed but flavin reductase activity was clearly down-regulated, or even absent, in metronidazole-resistant strains. Since flavin reductase has been shown to reduce oxygen to hydrogen peroxide, its down-regulation could significantly contribute to the impairment of oxygen scavenging as reported by others for metronidazole-resistant strains. Analysis by 2DE revealed down-regulation of alcohol dehydrogenase 1 (ADH1) in strains with reduced sensitivity to metronidazole, an enzyme that could be involved in detoxification of intracellular acetaldehyde. PMID:22449940

First report of anti-Trichomonas vaginalis activity of the medicinal plant Polygala decumbens from the Brazilian semi-arid region, Caatinga.

PubMed

Frasson, Amanda Piccoli; dos Santos, Odelta; Duarte, Mariana; da Silva Trentin, Danielle; Giordani, Raquel Brandt; da Silva, Alexandre Gomes; da Silva, Márcia Vanusa; Tasca, Tiana; Macedo, Alexandre José

2012-06-01

Trichomonosis, caused by the flagellate protozoan Trichomonas vaginalis, is the most common non-viral sexually transmitted disease worldwide. Actually, the infection treatment is based on 5-nitroimidazole drugs. However, an emergent number of resistant isolates makes important the search for new therapeutic arsenal. In this sense, the investigation of plants and their metabolites is an interesting approach. In the present study, the anti-T. vaginalis activity of 44 aqueous extracts from 23 Caatinga plants used in folk medicine was evaluated. After screening 44 aqueous extracts from 23 distinct plants against two isolates from ATCC and four fresh clinical isolates, only the Polygala decumbens root extract was effective in reducing significantly the trophozoite viability. The MIC value against all isolates tested, including the metronidazole resistant, was 1.56 mg/mL. The kinetic growth assays showed that the extract was able to completely abolish the parasite density in the first hours of incubation, confirmed by microscopy. In summary, this study describes the first report on the activity of P. decumbens from Caatinga against T. vaginalis, being directly related to the popular knowledge and use.

A Randomised Trial of empiric 14-day Triple, five-day Concomitant, and ten-day Sequential Therapies for Helicobacter pylori in Seven Latin American Sites

PubMed Central

Greenberg, E. Robert; Anderson, Garnet L.; Morgan, Douglas R.; Torres, Javier; Chey, William D.; Bravo, Luis Eduardo; Dominguez, Ricardo L.; Ferreccio, Catterina; Herrero, Rolando; Lazcano-Ponce, Eduardo C.; Meza-Montenegro, Mercedes María; Peña, Rodolfo; Peña, Edgar M.; Salazar-Martínez, Eduardo; Correa, Pelayo; Martínez, María Elena; Valdivieso, Manuel; Goodman, Gary E.; Crowley, John J.; Baker, Laurence H.

2011-01-01

Summary Background Evidence from Europe, Asia, and North America suggests that standard three-drug regimens of a proton pump inhibitor plus amoxicillin and clarithromycin are significantly less effective for eradicating Helicobacter pylori (H. pylori) infection than five-day concomitant and ten-day sequential four-drug regimens that include a nitroimidazole. These four-drug regimens also entail fewer antibiotic doses and thus may be suitable for eradication programs in low-resource settings. Studies are limited from Latin America, however, where the burden of H. pylori-associated diseases is high. Methods We randomised 1463 men and women ages 21–65 selected from general populations in Chile, Colombia, Costa Rica, Honduras, Nicaragua, and Mexico (two sites) who tested positive for H. pylori by a urea breath test (UBT) to: 14 days of lansoprazole, amoxicillin, and clarithromycin (standard therapy); five days of lansoprazole, amoxicillin, clarithromycin, and metronidazole (concomitant therapy); or five days of lansoprazole and amoxicillin followed by five of lansoprazole, clarithromycin, and metronidazole (sequential therapy). Eradication was assessed by UBT six–eight weeks after randomisation. Findings In intention-to-treat analyses, the probability of eradication with standard therapy was 82·2%, which was 8·6% higher (95% adjusted CI: 2·6%, 14·5%) than with concomitant therapy (73·6%) and 5·6% higher (95% adjusted CI: −0·04%, 11·6%) than with sequential therapy (76·5%). In analyses limited to the 1314 participants who adhered to their assigned therapy, the probabilities of eradication were 87·1%, 78·7%, and 81·1% with standard, concomitant, and sequential therapies, respectively. Neither four-drug regimen was significantly better than standard triple therapy in any of the seven sites. Interpretation Standard 14-day triple-drug therapy is preferable to five-day concomitant or ten-day sequential four-drug regimens as empiric therapy for H. pylori among diverse Latin American populations. Funding Bill & Melinda Gates Foundation and US National Institutes of Health. PMID:21777974

Stereospecific deuteration of alpha-furanosyl azomycin nucleosides: a model reaction for tritium radiolabeling.

PubMed

Kumar, Piyush; Emami, Saeed; McEwan, Alexander J B; Wiebe, Leonard I

2008-06-01

Stereospecific synthesis of 1-alpha-d-(2-deuteroribofuranosyl)-2-nitroimidazole (2'-[(2)H]-alpha-AZR) is reported. This, deuteration was independent of the configuration of C-2' -OH group (arabinose or ribose) in sugar moiety of starting molecules. Slightly better yield (>37%) of the deuterated product, 6, from arabinosyl precursor in comparison to corresponding ribose precursor (29%) was obtained which may reflect better stereochemical availability of C-2' -OH in arabinose during oxidation.

The Associate Program on Ethnobiology, Socio-Economic Value Assessment and Community Based Conservation

DTIC Science & Technology

2000-10-01

resistant isolates of Trichomonas vaginalis and a Tritrichomonas foetus isolate. Of these, five had MIC values of < 0.1 mg/ml including an extract...significance was the low IC50 values obtained for the T. foetus extracts (SU-1461, 1464). Further studies will examine secondary extracts of the...nitroimidazole resistance in Tritrichomonas foetus . Anitmicrob. Agents Chemother. 13:1-13. 22 13. Urbina, J.A., Lazardi, K., Marchan, E., Visbal, G., Aguirre

Kinetic Study of Hydroxyl and Sulfate Radical-Mediated Oxidation of Pharmaceuticals in Wastewater Effluents.

PubMed

Lian, Lushi; Yao, Bo; Hou, Shaodong; Fang, Jingyun; Yan, Shuwen; Song, Weihua

2017-03-07

Advanced oxidation processes (AOPs), such as hydroxyl radical (HO • )- and sulfate radical (SO 4 •- )-mediated oxidation, are alternatives for the attenuation of pharmaceuticals and personal care products (PPCPs) in wastewater effluents. However, the kinetics of these reactions needs to be investigated. In this study, kinetic models for 15 PPCPs were built to predict the degradation of PPCPs in both HO • - and SO 4 •- -mediated oxidation. In the UV/H 2 O 2 process, a simplified kinetic model involving only steady state concentrations of HO • and its biomolecular reaction rate constants is suitable for predicting the removal of PPCPs, indicating the dominant role of HO • in the removal of PPCPs. In the UV/K 2 S 2 O 8 process, the calculated steady state concentrations of CO 3 •- and bromine radicals (Br • , Br 2 •- and BrCl •- ) were 600-fold and 1-2 orders of magnitude higher than the concentrations of SO 4 •- , respectively. The kinetic model, involving both SO 4 •- and CO 3 •- as reactive species, was more accurate for predicting the removal of the 9 PPCPs, except for salbutamol and nitroimidazoles. The steric and ionic effects of organic matter toward SO 4 •- could lead to overestimations of the removal efficiencies of the SO 4 •- -mediated oxidation of nitroimidazoles in wastewater effluents.

Trichomonas vaginalis Genital Infections: Progress and Challenges

PubMed Central

Hobbs, Marcia M.; Seña, Arlene C.; Sobel, Jack D.; Schwebke, Jane R.; Krieger, John N.; McClelland, R. Scott; Workowski, Kimberly A.

2011-01-01

Trichomonas vaginalis (TV) infection is the most prevalent curable sexually transmitted infection in the United States and worldwide. Most TV infections are asymptomatic, and the accurate diagnosis of this infection has been limited by lack of sufficiently sensitive and specific diagnostic tests, particularly for men. To provide updates for the 2010 Centers for Disease Control and Prevention’s Sexually Transmitted Diseases Treatment Guidelines, a PubMed search was conducted of all TV literature published from 9 January 2004 through 24 September 2008. Approximately 175 pertinent abstracts and articles were reviewed and discussed with national experts. This article describes advances in TV diagnostics which have led to an improved understanding of the epidemiology of this pathogen, as well as potential biologic and epidemiological interactions between TV and human immunodeficiency virus (HIV). New data on treatment outcomes, metronidazole-resistant TV, management of nitroimidazole-allergic patients, frequency of recurrent TV infection following treatment, and screening considerations for TV in certain populations are also presented. PMID:22080269

Development of a monoclonal antibody-based indirect competitive enzyme-linked immunosorbent assay for nitroimidazoles in edible animal tissues and feeds.

PubMed

Han, Wei; Pan, Yuanhu; Wang, Yulian; Chen, Dongmei; Liu, Zhenli; Zhou, Qi; Feng, Liang; Peng, Dapeng; Yuan, Zonghui

2016-02-20

The misuse of nitroimidazoles (NDZs) can lead to NDZs residues in edible animal tissues, which would be harmful to consumer health. To quickly monitor NDZs residues in edible animal tissues and feed, a monoclonal antibody-based indirect competitive enzyme-linked immunosorbent assay (ic-ELISA) with a simple sample preparation method and clean-up was developed in the present study. At first, a broad-specificity monoclonal antibody, 1D5, against NDZs has been produced, which the IC50 values of the NDZs, dimetridazole, ipronidazole, ronidazole hydroxydimetridazole, and hydroxyipronidazole, were 4.79μgL(-1), 0.47μgL(-1), 5.97μgL(-1), 23.48μgL(-1), and 15.03μgL(-1), respectively. The limit of detection of the method for the NDZ matrix calibration ranged from 4.2μgkg(-1) to 50.3μgkg(-1) in the feed matrices and from 0.11μgkg(-1) to 4.11μgkg(-1) in the edible animal tissues matrices. The recoveries of the NDZs were in the range of 75.5-111.8%. The CVs were less than 14.4%. A good correlation (r=0.9905) between the ELISA and HPLC-MS results of the tissues demonstrated the reliability of the developed ic-ELISA, which makes it a useful tool for screening of NDZs in animal edible tissue and feed. Copyright © 2015 Elsevier B.V. All rights reserved.

Resistance of Trichomonas vaginalis to Metronidazole: Report of the First Three Cases from Finland and Optimization of In Vitro Susceptibility Testing under Various Oxygen Concentrations

PubMed Central

Meri, Taru; Jokiranta, T. Sakari; Suhonen, Lauri; Meri, Seppo

2000-01-01

Trichomonas vaginalis is a globally common sexually transmitted human parasite. Many strains of T. vaginalis from around the world have been described to be resistant to the current drug of choice, metronidazole. However, only a few cases of metronidazole resistance have been reported from Europe. The resistant strains cause prolonged infections which are difficult to treat. T. vaginalis infection also increases the risk for human immunodeficiency virus transmission. We present a practical method for determining the resistance of T. vaginalis to 5-nitroimidazoles. The suggested method was developed by determining the MICs and minimal lethal concentrations (MLCs) of metronidazole and ornidazole for T. vaginalis under various aerobic and anaerobic conditions. Using this assay we have found the first three metronidazole-resistant strains from Finland, although the origin of at least one of the strains seems to be Russia. Analysis of the patient-derived and previously characterized isolates showed that metronidazole-resistant strains were also resistant to ornidazole, and MLCs for all strains tested correlated well with the MICs. The suggested MICs of metronidazole for differentiation of sensitive and resistant isolates are >75 μg/ml in an aerobic 24-h assay and >15 μg/ml in an anaerobic 48-h assay. PMID:10655382

Use of High-Pressure Liquid Chromatography to Determine Plasma Levels of Metronidazole and Metabolites After Intravenous Administration

PubMed Central

Wheeler, L. A.; De Meo, M.; Halula, M.; George, L.; Heseltine, P.

1978-01-01

A rapid and sensitive high-pressure liquid chromatography assay for metronidazole and its two principle metabolites, 1-(2-hydroxyethyl-2-hydroxymethyl)-5-nitro-imidazole [hydroxy metabolite] and 1-acetic acid-2-methyl-5-metronidazole [acid metabolite], was developed. The retention times observed were 5.7, 3.3, and 4.5 min, respectively. A reverse-phase μC18 Bondapak column using a solvent system of methanol, acetonitrile, and 0.005 M pH 4 potassium dihydrogen phosphate (4:3:93, vol/vol) was used to achieve separation of the three compounds. Patients receiving metronidazole therapy were given a loading dose of 13.6 mg of drug per kg intravenously over 1 h, followed by a maintenance dose of 1.43 mg/kg per h. The range of metronidazole concentrations observed was 6.8 to 47.5 μg/ml. These levels are well above the minimal inhibitory concentrations of most clinically significant anaerobic bacteria including Bacteroides fragilis. Little of the acid metabolite was observed in the plasma. The concentration of hydroxy metabolite ranged from 1.6 to 16 μg/ml. The latter may represent an additional source of antimicrobial activity since the hydroxy metabolite has approximately 30% the biological activity of metronidazole. PMID:646342

In vitro resistance to 5-nitroimidazoles and benzimidazoles in Giardia duodenalis: variability and variation in gene expression.

PubMed

Argüello-García, Raúl; Cruz-Soto, Maricela; Romero-Montoya, Lydia; Ortega-Pierres, Guadalupe

2009-12-01

The susceptibility of Giardia duodenalis trophozoites exposed in vitro to sublethal concentrations of metronidazole (MTZ) and albendazole (ABZ) may exhibit inter-culture (variability) and intra-culture (variation) differences in drug susceptibility. It was previously reported that MTZ-resistant trophozoites may display changes in pyruvate:ferredoxin oxidoreductase (PFOR) expression while changes at the beta-tubulin molecule are apparently absent in ABZ-resistant cultures. To assess the levels of gene expression of these molecules, we obtained cloned cultures growing at concentrations up to 23 microM MTZ (WBRM23) and up to 8muM ABZ (WBRA8) and gene sequence and expression of pfor and beta-tubulin loci were compared with these of drug-susceptible clone WB1. Neither the pfor nor the beta-tubulin genes showed changes at sequence level but the MTZ-resistant clones WBRM21 and WBRM23 showed up-regulation of the pfor RNA using the gdh gene as reference. By using WB1 and WBRA8 clones in representational difference analyses of gene expression (RDA) an insert referred to as ARR-VSP was selected and sequenced. It showed the highest homology to one VSP molecule in the Giardia Genome Database (orf GL50803_101765). This isogene was up-regulated in five ABZ-resistant clones and the clone WBRA8 exhibited the highest RNA expression level. When successive progenies of clones WB1, WBRM23 and WBRA8 were analyzed in Northern blot assays to detect pfor and ARR-VSP RNAs respectively, the expression patterns showed variation for both genes but it was much lower in the clone WBRA8. These results suggest that G. duodenalis cultures either susceptible or resistant to MTZ and ABZ may display variability and variation at RNA expression levels albeit these were more marked in the MTZ-resistant parasites. These data might have further implications defining major mechanisms involved in drug resistance of Giardia.

Synthesis and antimicrobial studies of some Mannich bases carrying imidazole moiety.

PubMed

Frank, Priya V; Manjunatha Poojary, Mahesha; Damodara, Naral; Chikkanna, Chandrashekhar

2013-06-01

3 Starting from 2-methyl-4-nitro-imidazole, new 5-(2-methyl- 4-nitro-1-imidazomethyl)-1,3,4-oxadiazole-2-thione () was synthesized and was subjected to Mannich reaction with appropriate amines to yield a new series of 3-substituted aminomethyl-5-(2-methyl-4-nitro-1-imidazomethyl)- 1,3,4-oxadiazole-2-thiones (4a-j). The structure of the title compounds was elucidated by elemental analysis and spectral data. The newly synthesized Mannich bases were screened for their antibacterial and antifungal activity. Many of these compounds exhibited potent antifungal activity.

Clinical and Microbiological Aspects of Trichomonas vaginalis

PubMed Central

Petrin, Dino; Delgaty, Kiera; Bhatt, Renuka; Garber, Gary

1998-01-01

Trichomonas vaginalis, a parasitic protozoan, is the etiologic agent of trichomoniasis, a sexually transmitted disease (STD) of worldwide importance. Trichomoniasis is the most common nonviral STD, and it is associated with many perinatal complications, male and female genitourinary tract infections, and an increased incidence of HIV transmission. Diagnosis is difficult, since the symptoms of trichomoniasis mimic those of other STDs and detection methods lack precision. Although current treatment protocols involving nitroimidazoles are curative, metronidazole resistance is on the rise, outlining the need for research into alternative antibiotics. Vaccine development has been limited by a lack of understanding of the role of the host immune response to T. vaginalis infection. The lack of a good animal model has made it difficult to conduct standardized studies in drug and vaccine development and pathogenesis. Current work on pathogenesis has focused on the host-parasite relationship, in particular the initial events required to establish infection. These studies have illustrated that the pathogenesis of T. vaginalis is indeed very complex and involves adhesion, hemolysis, and soluble factors such as cysteine proteinases and cell-detaching factor. T. vaginalis interaction with the members of the resident vaginal flora, an advanced immune evasion strategy, and certain stress responses enable the organism to survive in its changing environment. Clearly, further research and collaboration will help elucidate these pathogenic mechanisms, and with better knowledge will come improved disease control. PMID:9564565

Second-line rescue triple therapy with levofloxacin after failure of non-bismuth quadruple "sequential" or "concomitant" treatment to eradicate H. pylori infection.

PubMed

Gisbert, Javier P; Molina-Infante, Javier; Marin, Alicia C; Vinagre, Gemma; Barrio, Jesus; McNicholl, Adrian Gerald

2013-06-01

Non-bismuth quadruple "sequential" and "concomitant" regimens, including a proton pump inhibitor (PPI), amoxicillin, clarithromycin and a nitroimidazole, are increasingly used as first-line treatments for Helicobacter pylori infection. Eradication with rescue regimens may be challenging after failure of key antibiotics such as clarithromycin and nitroimidazoles. To evaluate the efficacy and tolerability of a second-line levofloxacin-containing triple regimen (PPI-amoxicillin-levofloxacin) in the eradication of H. pylori after non-bismuth quadruple-containing treatment failure. prospective multicenter study. in whom a non-bismuth quadruple regimen, administered either sequentially (PPI + amoxicillin for 5 days followed by PPI + clarithromycin + metronidazole for 5 more days) or concomitantly (PPI + amoxicillin + clarithromycin + metronidazole for 10 days) had previously failed. levofloxacin (500 mg b.i.d.), amoxicillin (1 g b.i.d.) and PPI (standard dose b.i.d.) for 10 days. eradication was confirmed with (13)C-urea breath test 4-8 weeks after therapy. Compliance and tolerance: compliance was determined through questioning and recovery of empty medication envelopes. Incidence of adverse effects was evaluated by means of a questionnaire. 100 consecutive patients were included (mean age 50 years, 62% females, 12% peptic ulcer and 88% dyspepsia): 37 after "sequential", and 63 after "concomitant" treatment failure. All patients took all medications correctly. Overall, per-protocol and intention-to-treat H. pylori eradication rates were 75.5% (95% CI 66-85%) and 74% (65-83%). Respective intention-to-treat cure rates for "sequential" and "concomitant" failure regimens were 74.4% and 71.4%, respectively. Adverse effects were reported in six (6%) patients; all of them were mild. Ten-day levofloxacin-containing triple therapy constitutes an encouraging second-line strategy in patients with previous non-bismuth quadruple "sequential" or "concomitant" treatment failure.

Intravaginal boric acid: is it an alternative therapeutic option for vaginal trichomoniasis?

PubMed

Thorley, Nicola; Ross, Jonathan

2017-12-09

Trichomoniasis, caused by Trichomonas vaginalis (TV), is the most common curable sexually transmitted infection worldwide. Current guidance in the UK is to treat TV with a nitroimidazole antibiotic. The high prevalence of TV, high rate of antibiotic resistance and limited tolerability to nitroimidazoles suggest that alternative treatment regimens are needed. Intravaginal boric acid (BA) has been used safely for the treatment of candida vulvovaginitis and bacterial vaginosis, and in vitro studies suggest BA is active against TV. We review the evidence for the efficacy of BA in patients with TV. MEDLINE, EMBASE, CINAHL, AMED, HMIC and BNI and Grey literature databases, The Cochrane Library, Trial Registers, conference abstracts and proceedings were searched. Inclusion criteria were women aged 16 years or over with microbiological confirmation of TV infection and using BA as treatment. There were no restrictions on language, publication date or study design. The in vitro evidence for BA activity against TV was also reviewed. No randomised controlled trials or case series were found. Four case reports demonstrated TV clearance with BA using a variety of dose regimens (dose 600 mg alternate nights to 600 mg two times per day; duration 1-5 months). In vitro studies suggest that BA has activity against TV which is independent of its effect on pH. Further evaluation of BA for the treatment of uncomplicated TV is required, but it may be useful when therapeutic options are limited. If shown to be safe and effective, intravaginal BA might provide a well-tolerated alternative anti-infective treatment which reduces community exposure to systemic antibiotics. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Response of murine tumours to combinations of CCNU with misonidazole and other radiation sensitizers.

PubMed Central

Siemann, D. W.

1982-01-01

The effect of combinations of the conventional chemotherapeutic agent 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) and nitroimidazole radiation sensitizers was evaluated in female C3H mice. Tumour response to single-agent or combination therapy was assessed in a tumour growth-delay assay. In the KHT sarcoma the simultaneous addition of misonidazole (MISO) was found to increase significantly the tumour growth delay resulting from CCNU treatment. The observed enhancement ratios (ER) increased with MISO dose, and ranged from 1.3 to 1.9 for sensitizer doses of 0.25-1.0 mg/g. The combination of CCNU and 1.0 or 0.5 mg/g MISO in the RIF-1 tumour or the MT-1 tumour produced ERs of approximately 2.0 and approximately 1.5 respectively. In the KHT sarcoma a series of other nitroimidazole sensitizers, including Ro-05-9963, SR-2555, SR-2508 and metronidazole (METRO), were also evaluated at equimolar doses (5 mmol/kg) in combination with a 20mg/kg dose of CCNU. Unlike MISO, these compounds in general failed to enhance the CCNU cytotoxicity in this tumour model. However, SR-2508 did enhance the response of the RIF-1 tumour to large single doses of CCNU, though not as much as MISO. Normal-tissue toxicity was determined using peripheral white blood cell (WBC) counts 3 days after treatment. CCNU doses of 10-50 mg/kg given either alone or in simultaneous combination with 0.5 or 1.0 mg/g MISO were studied. WBC toxicity increased with CCNU dose, but the addition of MISO at either dose did not significantly enhance this normal-tissue toxicity. PMID:6460517

Photodynamic therapy as a new approach to Trichomonas vaginalis inactivation.

PubMed

Silva Fonseca, Thaisa Helena; Alacoque, Marina; Silva Oliveira, Fabrício Marcus; Soares, Betânia Maria; Leite, Henrique Vitor; Caliari, Marcelo Vidigal; Gomes, Maria Aparecida; Busatti, Haendel

2018-06-01

The emergence of nitroimidazole resistant isolates has been an aggravating factor in the treatment of trichomoniasis, the most common non-viral sexually transmitted disease in the world. This highlights the importance of new technologies that are safe, effective, and have minor side effects or resistance. Hence, we evaluated the effectiveness of photodynamic therapy on the inactivation of Trichomonas vaginalis in vitro. We used methylene blue as a photosensitizing substance, and a light-emitting diode (LED) for irradiation of metronidazole sensitive and resistant strains. Our results showed that only the presence of light did not interfere with parasite growth; however, methylene blue isolated or associated with light inhibited 31.78% ± 7.18 and 80.21% ± 7.11 of the sensitive strain, respectively, and 31.17% ± 4.23 and 91.13% ± 2.31 of the resistant strain, respectively. The high trichomonicidal activity of the photodynamic therapy, associated with low cost and ease of application, signalize its great therapeutic potential not only when conventional treatment fails, but also routinely in women with trichomoniasis. Copyright © 2018 Elsevier B.V. All rights reserved.

A Review of Evidence-Based Care of Symptomatic Trichomoniasis and Asymptomatic Trichomonas vaginalis Infections

PubMed Central

Meites, Elissa; Gaydos, Charlotte A.; Hobbs, Marcia M.; Kissinger, Patricia; Nyirjesy, Paul; Schwebke, Jane R.; Secor, W. Evan; Sobel, Jack D.; Workowski, Kimberly A.

2015-01-01

Trichomonas vaginalis is the most prevalent nonviral sexually transmitted infection, affecting an estimated 3.7 million women and men in the United States. Health disparities are prominent in the epidemiology of this infection, which affects 11% of women aged ≥40 years and a disproportionately high percentage of black women. Particularly high prevalences have been identified among sexually transmitted disease (STD) clinic patients and incarcerated individuals. This article reviews and updates scientific evidence in key topic areas used for the development of the 2015 STD Treatment Guidelines published by the Centers for Disease Control and Prevention. Current evidence is presented regarding conditions associated with Trichomonas vaginalis infection, including human immunodeficiency virus (HIV) and pregnancy complications such as preterm birth. Nucleic acid amplification tests and point-of-care tests are newly available diagnostic methods that can be conducted on a variety of specimens, potentially allowing highly sensitive testing and screening of both women and men at risk for infection. Usually, trichomoniasis can be cured with single-dose therapy of an appropriate nitroimidazole antibiotic, but women who are also infected with HIV should receive therapy for 7 days. Antimicrobial resistance is an emerging concern. PMID:26602621

Anti-Trichomonas vaginalis properties of the oil of Amomum tsao-ko and its major component, geraniol.

PubMed

Dai, Min; Peng, Cheng; Peng, Fu; Xie, Chengbin; Wang, Pinjia; Sun, Fenghui

2016-01-01

Trichomonosis, caused by the flagellate protozoan Trichomonas vaginalis, is the most common non-viral sexually transmitted disease (STD) and 5-nitroimidazole drugs are used for the treatment. However, a growing number of T. vaginalis isolates are resistant to these drugs, which make it becomes an urgent issue. The current study was designed to evaluate the anti-T. vaginalis activity of the essential oil from A. tsao-ko used in traditional Chinese medicine and as a spice and its main component, geraniol. The anti-T. vaginalis activities of A. tsao-ko essential oil and geraniol were evaluated by the minimum lethal concentration (MLC) and 50% inhibitory concentration (IC50) in vitro. The morphological changes of T. vaginalis were observed by transmission electron microscopy (TEM). Additionally, sub-MLC concentration treatment with sub-MLC A. tsao-ko essential oil and geraniol was also performed. This study shows that MLC/IC50 of A. tsao-ko essential oil was 44.97 µg/ml/22.49 µg/ml for T. vaginalis isolate Tv1, and 89.93 µg/ml/44.97 µg/ml for T. vaginalis isolate Tv2. Those of geraniol were 342.96 µg/ml/171.48 µg/ml, respectively. After A. tsao-ko essential oil or geraniol treatment, obvious similar morphological changes of T. vaginalis were observed by TEM: the nuclear membrane was damaged, nuclei were dissolved, and the chromatin was accumulated; in the cytoplasm, numerous vacuoles appeared, rough endoplasmic reticulum dilated, the number of ribosomes were reduced, organelles disintegrated, the cell membrane was partially damaged, with cytoplasmic leakage, and cell disintegration was observed. The action time did not increase the effect of A. tsao-ko essential oil or geraniol against T. vaginalis, as no significant difference was observed after sub-MLC concentration treatment for 1, 3, and 5 h with A. tsao-ko essential oil and geraniol. The study describes the first report on the activity and morphological changes of A. tsao-ko essential oil and geraniol against T. vaginalis. The results obtained herein presented new opportunities for antitrichomonal drugs.

Mutagenicity testing of the antiparasitic drug entizol (polfa) in the detection system of Salmonella typhimurium mutants.

PubMed

Dobiás, L

1980-02-01

The mutagenic activity was tested of a clinically used drug Entizol (Polfa) which contains metronidazole as an active substance. The mutagenicity of the compound was detected for Salmonella typhimurium indicator strains TA100, TA1535, TA1950, and TA1538 in tests in vitro without metabolic activation at the concentration range of 180 to 1600 microgram per plate. Metabolic conversion of the preparation studied in vivo gave rise to mutagenic metabolites detectable in the blood of mice after both intraperitoneal and per-oral application. The presence of the products of drug metabolism in the blood of experimental animals was tested at 1-40 h intervals after application. Blood samples of mice treated intraperitoneally with single doses of 1470 and 35 mg/kg were tested in strains TA100 and TA98. There were differences in the times of occurrence of mutagenic metabolites. The development of two mutagenicity maxima, detected in the blood withdrawn within the interval of 60-120 min (Rt/Rc 3.1) and 19 h (Rt/Rc 24.8) after the application of a dose of 1470 mg/kg in the strain TA100, is characteristic. The mutagenic effect of the blood of animals treated with a dose of 35 mg/kg, which approximately corresponds to standard therapeutic values, also had an analogous character. The highest mutagenic effect was detected in blood samples withdrawn 19 h after application (Rt/Rc 15.8). The frameshift mutation-detecting strain TA98 reverted at a lower frequency (about 5 times) under the above conditions, but only during analysis of the blood samples of animals treated with a dose of 1470 mg/kg. These results indicate that, for assessing the mutagenicity of 5-nitroimidazole compounds and their metabolites in blood, it is necessary to analyse blood samples withdrawn at least up to 24 h after application of the compound. This relationship was not proved to exist between the frequencies of induced revertants during the testing of blood withdrawn within 1-24 h after single per-oral administration of the drug in a dose range of 500-62.5 mg/kg. However, the mutagenicity of blood metabolites for strain TA100 was demonstrated not earlier than 24 h after the application of Entizol at 500 and 250 mg/kg.

Should male consorts of women with bacterial vaginosis be treated?

PubMed Central

Moi, H; Erkkola, R; Jerve, F; Nelleman, G; Bymose, B; Alaksen, K; Tornqvist, E

1989-01-01

Nitroimidazoles have been shown to be the drugs of choice to treat women with bacterial vaginosis, but the recurrence rate is high. Some workers have suggested that the recurrence of symptoms may in fact be reinfection by male consorts, but no controlled studies have been undertaken to confirm this. In an international, multicentre, randomised, double blind trial, the recurrence rate was studied in 241 women with a clinical diagnosis of bacterial vaginosis. All women were treated with 2 g metronidazole twice at an interval of two days. The patients were randomly allocated to two groups, one contained 123 women, whose consorts were given the same dose of metronidazole, the other consisted of 118 women whose consorts were given inert but identical placebo tablets. The women were evaluated at weeks 1, 4, and 12 after treatment. At week 1, the cure rate was 97% (115/119) in women whose consorts had been treated and 98% (111/113) in the others. At week 4 bacterial vaginosis had recurred in 17% (19/112) of women whose consorts had been treated and in 13% (14/106) of those whose consorts had received placebo. At week 12 the recurrence rates were 21% (20/95) in women with treated consorts, and 16% (15/95) in the others. The differences in recurrence rates between the two groups of women were not significant. In conclusion, treating the sexual partners of women with bacterial vaginosis does not seem to increase the cure rate. PMID:2680896

Metronidazole-induced encephalopathy: not always a reversible situation.

PubMed

Hobbs, Kyle; Stern-Nezer, Sara; Buckwalter, Marion S; Fischbein, Nancy; Finley Caulfield, Anna

2015-06-01

Metronidazole is a nitroimidazole antimicrobial drug prescribed to treat infections caused by anaerobic bacteria and protozoa. Uncommonly, it causes central nervous system (CNS) toxicity manifesting as metronidazole-induced encephalopathy (MIE). Case report. A 65-year-old woman with hepatitis B cirrhosis (Child-Pugh class C, MELD 21) developed progressive encephalopathy to GCS 4 during a 3-week course of metronidazole for cholecystitis. Initial MRI was consistent with CNS metronidazole toxicity, with symmetrical T2 hyperintensity and generally restricted diffusion in bilateral dentate nuclei, corpus callosum, midbrain, superior cerebellar peduncles, internal capsules, and cerebral white matter. Laboratory values did not demonstrate significant electrolyte shifts, and continuous EEG was without seizure. High-dose thiamine was empirically administered. Lumbar puncture was not performed due to coagulopathy and thrombocytopenia. Despite discontinuation of metronidazole and keeping ammonia levels near normal, the patient did not improve. MRI was repeated 1 week after discontinuation of metronidazole. Although there was decreased DWI hyperintensity in the dentate nuclei, diffuse T2 hyperintensity persisted and even progressed in the brainstem, basal ganglia, and subcortical white matter. Petechial hemorrhages developed in bilateral corticospinal tracts and subcortical white matter. T1 hypointensity appeared in the corpus callosum. She was transitioned to comfort measures only and died 12 days later. MIE is an uncommon adverse effect of treatment with metronidazole that characteristically affects the dentate nuclei but may also involve the brainstem, corpus callosum, subcortical white matter, and basal ganglia. While the clinical symptoms and neuroimaging changes are usually reversible, persistent encephalopathy with poor outcome may occur.

OH Radical Reactions with Nitroimidazole and Nitrotriazole Derivatives

NASA Astrophysics Data System (ADS)

Gümüş, Selçuk

2012-04-01

The reactions between hydroxyl radical and 5-nitro-1H-imidazole (A), 2-nitro-1H-imidazole (B), and 3-nitro-4H-1,2,4-triazole (C) were theoretically investigated using B3LYP/6-31G(d,p) level of theory. The OH radical additions to double bonds were explored in bulk solvent (water). The data presented show that the barriers to reaction were very low, 3-7 kcal/mol, indicating fast reactions. Thermodynamically, OH addition to position 2 of structure A leads to the most stable radical product. The main geometrical parameters are reported for reactants, transition states, and radical products together with some energetic data of the nitro-imidazolone-type final compounds.

The Primary Resistance of Helicobacter pylori in Taiwan after the National Policy to Restrict Antibiotic Consumption and Its Relation to Virulence Factors—A Nationwide Study

PubMed Central

Chen, Mei-Jyh; Chen, Chieh-Chang; Fang, Yu-Jen; Lee, Ji-Yuh; Wu, Jeng-Yih; Luo, Jiing-Chyuan; Liou, Tai-Cherng; Chang, Wen-Hsiung; Tseng, Cheng-Hao; Wu, Chun-Ying; Yang, Tsung-Hua; Chang, Chun-Chao; Wang, Hsiu‐Po; Sheu, Bor-Shyang; Lin, Jaw-Town; Bair, Ming-Jong; Wu, Ming-Shiang

2015-01-01

Objective The Taiwan Government issued a policy to restrict antimicrobial usage since 2001. We aimed to assess the changes in the antibiotic consumption and the primary resistance of H. pylori after this policy and the impact of virulence factors on resistance. Methods The defined daily dose (DDD) of antibiotics was analyzed using the Taiwan National Health Insurance (NHI) research database. H. pylori strains isolated from treatment naïve (N=1395) and failure from prior eradication therapies (N=360) from 9 hospitals between 2000 and 2012 were used for analysis. The minimum inhibitory concentration was determined by agar dilution test. Genotyping for CagA and VacA was determined by PCR method. Results The DDD per 1000 persons per day of macrolides reduced from 1.12 in 1997 to 0.19 in 2008, whereas that of fluoroquinolones increased from 0.12 in 1997 to 0.35 in 2008. The primary resistance of amoxicillin, clarithromycin, metronidazole, and tetracycline remained as low as 2.2%, 7.9%, 23.7%, and 1.9% respectively. However, the primary levofloxacin resistance rose from 4.9% in 2000–2007 to 8.3% in 2008–2010 and 13.4% in 2011–2012 (p=0.001). The primary resistance of metronidazole was higher in females than males (33.1% vs. 18.8%, p<0.001), which was probably attributed to the higher consumption of nitroimidazole. Neither CagA nor VacA was associated with antibiotic resistance. Conclusions The low primary clarithromycin and metronidazole resistance of H. pylori in Taiwan might be attributed to the reduced consumption of macrolides and nitroimidazole after the national policy to restrict antimicrobial usage. Yet, further strategies are needed to restrict the consumption of fluoroquinolones in the face of rising levofloxacin resistance. PMID:25942450

A Hypoxia-Targeted Boron Neutron Capture Therapy Agent for the Treatment of Glioma.

PubMed

Luderer, Micah John; Muz, Barbara; de la Puente, Pilar; Chavalmane, Sanmathi; Kapoor, Vaishali; Marcelo, Raymundo; Biswas, Pratim; Thotala, Dinesh; Rogers, Buck; Azab, Abdel Kareem

2016-10-01

Boron neutron capture therapy (BNCT) has the potential to become a viable cancer treatment modality, but its clinical translation has been limited by the poor tumor selectivity of agents. To address this unmet need, a boronated 2-nitroimidazole derivative (B-381) was synthesized and evaluated for its capability of targeting hypoxic glioma cells. B-381 has been synthesized from a 1-step reaction. Using D54 and U87 glioma cell lines, the in vitro cytotoxicity and cellular accumulation of B-381 has been evaluated under normoxic and hypoxic conditions compared to L-boronophenylalanine (BPA). Furthermore, tumor retention of B-381 was evaluated in vivo. B-381 had low cytotoxicity in normal and cancer cells. Unlike BPA, B-381 illustrated preferential retention in hypoxic glioma cells compared to normoxic glioma cells and normal tissues in vitro. In vivo, B-381 illustrated significantly higher long-term tumor retention compared to BPA, with 9.5-fold and 6.5-fold higher boron levels at 24 and 48 h, respectively. B-381 represents a new class of BNCT agents in which their selectivity to tumors is based on hypoxic tumor metabolism. Further studies are warranted to evaluate B-381 and similar compounds as preclinical candidates for future BNCT clinical trials for the treatment of glioma.

Caatinga plants: Natural and semi-synthetic compounds potentially active against Trichomonas vaginalis.

PubMed

Vieira, Patrícia de Brum; Silva, Nícolas Luiz Feijó; da Silva, Gloria Narjara Santos; Silva, Denise Brentan; Lopes, Norberto Peporine; Gnoatto, Simone Cristina Baggio; da Silva, Márcia Vanusa; Macedo, Alexandre José; Bastida, Jaume; Tasca, Tiana

2016-05-01

Trichomonas vaginalis causes trichomoniasis; the most common but overlooked non-viral sexually transmitted disease worldwide. The treatment is based at 5'-nitroimidazoles, however, failure are related to resistance of T. vaginalis to chemotherapy. Caatinga is a uniquely Brazilian region representing a biome with type desert vegetation and plants present diverse biological activity, however, with few studies. The aim of this study was to investigate the activity against T. vaginalis of different plants from Caatinga and identify the compounds responsible by the activity. A bioguided fractionation of Manilkara rufula was performed and four major compounds were identified: caproate of α-amyrin (1b), acetate of β-amyrin (2a), caproate of β-amyrin (2b), and acetate of lupeol (3a). In addition, six derivatives of α-amyrin (1), β-amyrin (2) and lupeol (3) were synthesized and tested against the parasite. Ursolic acid (5) reduced about 98% of parasite viability after 2h of incubation and drastic ultrastructural alterations were observed by scanning electron microscopy. Moreover, 5 presented high cytotoxicity to HMVII and HeLa cell line and low cytotoxicity against Vero line at 50 μM (MIC against the parasite). Metronidazole effect against T. vaginalis resistant isolate was improved when in association with 5. Copyright © 2016 Elsevier Ltd. All rights reserved.

Experimental and molecular docking investigation on metal-organic framework MIL-101(Cr) as a sorbent for vortex assisted dispersive micro-solid-phase extraction of trace 5-nitroimidazole residues in environmental water samples prior to UPLC-MS/MS analysis.

PubMed

Lu, Nan; Wang, Ting; Zhao, Pan; Zhang, Lianjun; Lun, Xiaowen; Zhang, Xueli; Hou, Xiaohong

2016-11-01

In the presented work, metal-organic framework (MOF) material MIL-101(Cr) (MIL, Matérial Institute Lavoisier) was used as a sorbent for vortex assisted dispersive micro-solid-phase extraction (VA-D-μ-SPE) of trace amount of metronidazole (MNZ), ronidazole (RNZ), secnidazole (SNZ), dimetridazole (DMZ), tinidazole (TNZ), and ornidazole (ONZ) in different environmental water samples. Ultra-high-performance liquid chromatography coupled with tandem mass spectrometry (UPLC-MS/MS) was used to quantify the target analytes. The extraction conditions, including type of sorbents, amount of MIL-101(Cr), solution pH, extraction method, extraction time, effect of salt, and elution conditions were investigated. Upon the optimal conditions, the developed method showed an excellent extraction performance with the average recovery ranging from 75.2 to 98.8 %. Good sensitivity levels were achieved with the detection limits of 0.03∼0.06 μg/L and the quantitation limits of 0.09∼0.20 μg/L. The linear ranges were varied from 0.1 to 20 for SNZ and ONZ and from 0.2 to 40 μg/L for MNZ, RNZ, DMZ, and TNZ (r 2  > 0.992), and repeatability of the method was satisfactory with the relative standard deviations (RSD) <8 %. Ultimately, the applicability of the method was successfully confirmed by the extraction and determination of 5-nitroimidazoles (5-NDZs) in 12 real water samples, showing the positive findings of MNZ and TNZ ranging from 0.3 to 1.0 μg/L. Furthermore, molecular docking was applied to explain the molecular interactions and free binding energies between MIL-101(Cr) and 5-NDZs, providing a deep insight into the adsorption mechanism. The proposed method exhibited the advantages of simplicity, rapidly, less solvent consumption, ease of operation, higher sensitivity, and lower matrix effect. Graphical abstract Schematic diagram of the extraction process and molecular docking investigation.

A Hypoxia-Targeted Boron Neutron Capture Therapy Agent for the Treatment of Glioma

PubMed Central

Luderer, Micah John; Muz, Barbara; de la Puente, Pilar; Chavalmane, Sanmathi; Kapoor, Vaishali; Marcelo, Raymundo; Biswas, Pratim; Thotala, Dinesh; Rogers, Buck; Azab, Abdel Kareem

2016-01-01

Purpose Boron neutron capture therapy (BNCT) has the potential to become a viable cancer treatment modality, but its clinical translation has been limited by the poor tumor selectivity of agents. To address this unmet need, a boronated 2-nitroimidazole derivative (B-381) was synthesized and evaluated for its capability of targeting hypoxic glioma cells. Methods B-381 has been synthesized from a 1-step reaction. Using D54 and U87 glioma cell lines, the in vitro cytotoxicity and cellular accumulation of B-381 has been evaluated under normoxic and hypoxic conditions compared to L-boronophenylalanine (BPA). Furthermore, tumor retention of B-381 was evaluated in vivo. Results B-381 had low cytotoxicity in normal and cancer cells. Unlike BPA, B-381 illustrated preferential retention in hypoxic glioma cells compared to normoxic glioma cells and normal tissues in vitro. In vivo, B-381 illustrated significantly higher long-term tumor retention compared to BPA, with 9.5-fold and 6.5-fold higher boron levels at 24 and 48 h, respectively. Conclusions B-381 represents a new class of BNCT agents in which their selectivity to tumors is based on tumor hypoxic metabolism, and further studies are warranted to evaluate this compound and similar compounds as preclinical candidates for future BNCT clinical trials for the treatment of glioma. PMID:27401411

A Review of Evidence-Based Care of Symptomatic Trichomoniasis and Asymptomatic Trichomonas vaginalis Infections.

PubMed

Meites, Elissa; Gaydos, Charlotte A; Hobbs, Marcia M; Kissinger, Patricia; Nyirjesy, Paul; Schwebke, Jane R; Secor, W Evan; Sobel, Jack D; Workowski, Kimberly A

2015-12-15

Trichomonas vaginalis is the most prevalent nonviral sexually transmitted infection, affecting an estimated 3.7 million women and men in the United States. Health disparities are prominent in the epidemiology of this infection, which affects 11% of women aged ≥40 years and a disproportionately high percentage of black women. Particularly high prevalences have been identified among sexually transmitted disease (STD) clinic patients and incarcerated individuals. This article reviews and updates scientific evidence in key topic areas used for the development of the 2015 STD Treatment Guidelines published by the Centers for Disease Control and Prevention. Current evidence is presented regarding conditions associated with Trichomonas vaginalis infection, including human immunodeficiency virus (HIV) and pregnancy complications such as preterm birth. Nucleic acid amplification tests and point-of-care tests are newly available diagnostic methods that can be conducted on a variety of specimens, potentially allowing highly sensitive testing and screening of both women and men at risk for infection. Usually, trichomoniasis can be cured with single-dose therapy of an appropriate nitroimidazole antibiotic, but women who are also infected with HIV should receive therapy for 7 days. Antimicrobial resistance is an emerging concern. Published by Oxford University Press for the Infectious Diseases Society of America 2015. This work is written by (a) US Government employee(s) and is in the public domain in the US.

Prevalence of β-lactam (blaTEM) and Metronidazole (nim) Resistance Genes in the Oral Cavity of Greek Subjects

PubMed Central

Koukos, Georgios; Konstantinidis, Antonios; Tsalikis, Lazaros; Arsenakis, Minas; Slini, Theodora; Sakellari, Dimitra

2016-01-01

Objectives: The aim of this study is to investigate the prevalence of blaTEM and nim genes that encode resistance to β-lactams and nitroimidazoles, respectively, in the oral cavity of systemically healthy Greek subjects. Materials and Methodology: After screening 720 potentially eligible subjects, 154 subjects were recruited for the study, including 50 periodontally healthy patients, 52 cases of gingivitis and 52 cases of chronic periodontitis. The clinical parameters were assessed with an automated probe. Various samples were collected from the tongue, first molars and pockets >6mm, and analysed by polymerase chain reaction-amplification of the blaTEM and nim genes, using primers and conditions previously described in the literature. Results: There was a high rate of detection of blaTEM in plaque and tongue samples alike in all periodontal conditions (37% of plaque and 60% of tongue samples, and 71% of participants). The blaTEM gene was detected more frequently in the tongue samples of the periodontally healthy (56%) and chronic periodontitis (62%) groups compared to the plaque samples from the same groups (36% and 29%, respectively; z-test with Bonferroni corrections-tests, P<0.05). The nim gene was not detected in any of the 343 samples analysed. Conclusion: The oral cavity of Greek subjects often harbours blaTEM but not nim genes, and therefore the antimicrobial activity of β-lactams might be compromised. PMID:27099637

PHARMACOKINETICS OF A SINGLE DOSE OF METRONIDAZOLE AFTER RECTAL ADMINISTRATION IN CAPTIVE ASIAN ELEPHANTS (ELEPHAS MAXIMUS).

PubMed

Sander, Samantha J; Siegal-Willott, Jessica L; Ziegler, Jessie; Lee, Elizabeth; Tell, Lisa; Murray, Suzan

2016-03-01

Metronidazole is a nitroimidazole antibacterial and antiprotozoal drug with bacteriocidal activity against a broad range of anaerobic bacteria. It is a recognized treatment for elephants diagnosed with anaerobic bacterial infection or protozoal disease or exhibiting signs of colonic impaction, diarrhea, and colic. This study evaluated the pharmacokinetics of rectally administered metronidazole (15 mg/kg) in five adult female Asian elephants (Elephas maximus). Serum samples were collected from each animal for 96 hr after rectal administration of metronidazole. Serum concentrations of metronidazole and its primary metabolite, hydroxymetronidazole, were measured via ultraperformance liquid chromatography. Data were analyzed via a noncompartmental pharmacokinetic approach. Results indicated that serum levels of metronidazole were quantifiable at the 0.25 hr time point and absent in all elephants by the 96 hr time point. The serum peak concentration (mean ± SD, 13.15 ± 2.59 μg/ml) and area under the curve from time 0 to infinity (mean ± SD, 108.79 ± 24.77 hr × μg/ml) were higher than that reported in domestic horses after similar usage. Concurrently, the time of maximum serum concentration (mean ± SD, 1.2 ± 0.45 hr) and terminal elimination half-life (harmonic mean ± pseudo-SD, 7.85 ± 0.93 hr) were longer when compared to equine reports. Rectal administration of metronidazole was well tolerated and rapidly absorbed in all study elephants. Based on the findings in this study, metronidazole administered at a single dose of 15 mg/kg per rectum in the Asian elephant is likely to result in serum concentrations above 4 μg/ml for 8 hr and above 2 μg/ml for 24 hr after treatment is administered. Dosing recommendations should reflect the mean inhibitory concentration of metronidazole for each pathogen.

Development of "one-pot" method for multi-class compounds in porcine formula feed by multi-function impurity adsorption cleaning followed ultra-performance liquid chromatography-tandem mass spectrometry detection.

PubMed

Wang, Peilong; Wang, Xiao; Zhang, Wei; Su, Xiaoou

2014-02-01

A novel and efficient determination method for multi-class compounds including β-agonists, sedatives, nitro-imidazoles and aflatoxins in porcine formula feed based on a fast "one-pot" extraction/multifunction impurity adsorption (MFIA) clean-up procedure has been developed. 23 target analytes belonging to four different class compounds could be determined simultaneously in a single run. Conditions for "one-pot" extraction were studied in detail. Under the optimized conditions, the multi-class compounds in porcine formula feed samples were extracted and purified with methanol contained ammonia and absorbents by one step. The compounds in extracts were purified by using multi types of absorbent based on MFIA in one pot. The multi-walled carbon nanotubes were employed to improved clean-up efficiency. Shield BEH C18 column was used to separate 23 target analytes, followed by tandem mass spectrometry (MS/MS) detection using an electro-spray ionization source in positive mode. Recovery studies were done at three fortification levels. Overall average recoveries of target compounds in porcine formula feed at each levels were >51.6% based on matrix fortified calibration with coefficients of variation from 2.7% to 13.2% (n=6). The limit of determination (LOD) of these compounds in porcine formula feed sample matrix was <5.0 μg/kg. This method was successfully applied in screening and confirmation of target drugs in >30 porcine formula feed samples. It was demonstrated that the integration of the MFIA protocol with the MS/MS instrument could serve as a valuable strategy for rapid screening and reliable confirmatory analysis of multi-class compounds in real samples. Copyright © 2013 Elsevier B.V. All rights reserved.

A case of metronidazole-resistant Trichomonas vaginalis in pregnancy.

PubMed

Forbes, Georgina L; Drayton, Rachel; Forbes, Gavin D

2016-09-01

Trichomonas vaginalis is a sexually transmitted protozoan infection resulting in vulvo-vaginitis and altered vaginal discharge in symptomatic women. Trichomoniasis has been implicated in causing adverse pregnancy outcomes such as low birth weight and pre-term labour. Metronidazole is the recommended first-line treatment for trichomonal infection. Other nitroimidazoles, such as tinidazole, are used as alternative regimens with similar activity but at a greater expense. Treatment failure usually represents patient non-compliance or re-infection, although metronidazole resistance has previously been documented. Antimicrobial susceptibility testing for T. vaginalis is currently not available in the UK. Patients with disease unresponsive to first-line treatments pose a major challenge, as therapeutic options are limited. We present the case of a patient with presumed resistant infection during pregnancy, and the additional treatment issues that this presented. © The Author(s) 2015.

[Tetracyclines, sulfonamides and metronidazole].

PubMed

Pérez-Trallero, Emilio; Iglesias, Luis

2003-11-01

Tetracyclines form a group of natural and semisynthetic products that acts inhibiting the bacterial protein synthesis. They are bacteriostatic agents, exhibiting activity against a wide range of organisms, but they are at the present of limited use because of their acquired resistance. Doxycycline is currently the most frequently used tetracycline in human medicine and it is included in the List of Essential Medicines of the World Health Organization. Sulfonamides are synthetic, broad-spectrum bacteriostatic antibiotics. They were the first effective systemic antimicrobial agents. Their mode of action is based on the inhibition of DNA synthesis. Due to their toxicity and high adquired resistance their use is currently very low. Metronidazole is the main compound of 5-nitroimidazole family. It is a very active bactericidal antibiotic against anaerobic and some microaerophilic bacteria and it is still very useful in the treatment of bacterian and parasitic infections.

Simultaneous determination of ornidazole and its main metabolites in human plasma by LC-MS/MS: application to a pharmacokinetic study.

PubMed

Du, Jiangbo; Ma, Zhiyu; Zhang, Yifan; Wang, Ting; Chen, Xiaoyan; Zhong, Dafang

2014-09-01

Ornidazole is a 5-nitroimidazole antimicrobial agent used for almost 40 years. A novel LC-MS/MS assay was developed and validated for the simultaneous determination of ornidazole and its main metabolites (M3, M6, M16-1, and M16-2) in human plasma. After extraction from 100 μl of plasma by protein precipitation with acetonitrile, all the analytes were separated on a Capcell PAK MG C18 column (100 × 4.6 mm, 5 μm) within 5.0 min and detected by ESI-MS/MS in the positive mode. The validation results met the acceptance criteria as per the US FDA and EMA guidelines. The validated method was successfully applied to a pharmacokinetic study after oral administration of 1000 mg ornidazole to six healthy Chinese volunteers.

Survey of Chemical Compounds Tested In Vitro against Rumen Protozoa for Possible Control of Bloat

PubMed Central

Willard, F. L.; Kodras, Rudolph

1967-01-01

Over 170 chemical agents were screened for antiprotozoal action in bovine ruminal fluid. Compounds were tested at 0.1 and 0.05% concentrations. Tested compounds included inorganic compounds, antibiotics, biocides, neuromuscular agents, arsenicals, plant and animal hormones, antimalarials, surface-active agents, anthelmintics, and many others. The most active compounds were cupric sulfate, nickel sulfate, nitrofurazone, hydrogen peroxide, dodecyl sodium sulfate, pelargonic acid, iodoacetic acid, 1-diethylaminoethylamino-4-methylthiaxanthrone, sodium arsanilate, sodium arsenate, bismuth glycolyl arsanilate, 1-β-hydroxyethyl-2-methyl-5-nitroimidazole, and p-nitroaniline. Copper ion was not particularly effective against entodinia; nickel ion had no effect on holotrichs. Hydrogen peroxide and iodoacetic acid were effective at a concentration of 0.005%. Anionic surface-active agents were very effective, especially long-chain sulfates and phosphates. These antiprotozoal agents warrant further in vivo studies for possible use in treating or curing bloat in ruminants. PMID:6077407

Survey of chemical compounds tested in vitro against rumen protozoa for possible control of bloat.

PubMed

Willard, F L; Kodras, R

1967-09-01

Over 170 chemical agents were screened for antiprotozoal action in bovine ruminal fluid. Compounds were tested at 0.1 and 0.05% concentrations. Tested compounds included inorganic compounds, antibiotics, biocides, neuromuscular agents, arsenicals, plant and animal hormones, antimalarials, surface-active agents, anthelmintics, and many others. The most active compounds were cupric sulfate, nickel sulfate, nitrofurazone, hydrogen peroxide, dodecyl sodium sulfate, pelargonic acid, iodoacetic acid, 1-diethylaminoethylamino-4-methylthiaxanthrone, sodium arsanilate, sodium arsenate, bismuth glycolyl arsanilate, 1-beta-hydroxyethyl-2-methyl-5-nitroimidazole, and p-nitroaniline. Copper ion was not particularly effective against entodinia; nickel ion had no effect on holotrichs. Hydrogen peroxide and iodoacetic acid were effective at a concentration of 0.005%. Anionic surface-active agents were very effective, especially long-chain sulfates and phosphates. These antiprotozoal agents warrant further in vivo studies for possible use in treating or curing bloat in ruminants.

Inner reorganization limiting electron transfer controlled hydrogen bonding: intra- vs. intermolecular effects.

PubMed

Martínez-González, Eduardo; Frontana, Carlos

2014-05-07

In this work, experimental evidence of the influence of the electron transfer kinetics during electron transfer controlled hydrogen bonding between anion radicals of metronidazole and ornidazole, derivatives of 5-nitro-imidazole, and 1,3-diethylurea as the hydrogen bond donor, is presented. Analysis of the variations of voltammetric EpIcvs. log KB[DH], where KB is the binding constant, allowed us to determine the values of the binding constant and also the electron transfer rate k, confirmed by experiments obtained at different scan rates. Electronic structure calculations at the BHandHLYP/6-311++G(2d,2p) level for metronidazole, including the solvent effect by the Cramer/Truhlar model, suggested that the minimum energy conformer is stabilized by intramolecular hydrogen bonding. In this structure, the inner reorganization energy, λi,j, contributes significantly (0.5 eV) to the total reorganization energy of electron transfer, thus leading to a diminishment of the experimental k.

Oxidative generation of guanine radicals by carbonate radicals and their reactions with nitrogen dioxide to form site specific 5-guanidino-4-nitroimidazole lesions in oligodeoxynucleotides.

PubMed

Joffe, Avrum; Mock, Steven; Yun, Byeong Hwa; Kolbanovskiy, Alexander; Geacintov, Nicholas E; Shafirovich, Vladimir

2003-08-01

A simple photochemical approach is described for synthesizing site specific, stable 5-guanidino-4-nitroimidazole (NIm) adducts in single- and double-stranded oligodeoxynucleotides containing single and multiple guanine residues. The DNA sequences employed, 5'-d(ACC CG(1)C G(2)TC CG(3)C G(4)CC) and 5'-d(ACC CG(1)C G(2)TC C), were a portion of exon 5 of the p53 tumor suppressor gene, including the codons 157 (G(2)) and 158 (G(3)) mutation hot spots in the former sequence with four Gs and the codon 157 (G(2)) mutation hot spot in the latter sequence with two Gs. The nitration of oligodeoxynucleotides was initiated by the selective photodissociation of persulfate anions to sulfate radicals induced by UV laser pulses (308 nm). In aqueous solutions, of bicarbonate and nitrite anions, the sulfate radicals generate carbonate anion radicals and nitrogen dioxide radicals by one electron oxidation of the respective anions. The guanine residue in the oligodeoxynucleotide is oxidized by the carbonate anion radical to form the neutral guanine radical. While the nitrogen dioxide radicals do not react with any of the intact DNA bases, they readily combine with the guanine radicals at either the C8 or the C5 positions. The C8 addition generates the well-known 8-nitroguanine (8-nitro-G) lesions, whereas the C5 attack produces unstable adducts, which rapidly decompose to NIm lesions. The maximum yields of the nitro products (NIm + 8-nitro-G) were typically in the range of 20-40%, depending on the number of guanine residues in the sequence. The ratio of the NIm to 8-nitro-G lesions gradually decreases from 3.4 in the model compound, 2',3',5'-tri-O-acetylguanosine, to 2.1-2.6 in the single-stranded oligodeoxynucleotides and to 0.8-1.1 in the duplexes. The adduct of the 5'-d(ACC CG(1)C G(2)TC C) oligodeoxynucleotide containing the NIm lesion in codon 157 (G(2)) was isolated in HPLC-pure form. The integrity of this adduct was established by a detailed analysis of exonuclease digestion ladders by matrix-assisted laser desorption ionization with time-of-flight detection MS techniques.

Potential drug-drug interactions between anti-cancer agents and community pharmacy dispensed drugs.

PubMed

Voll, Marsha L; Yap, Kim D; Terpstra, Wim E; Crul, Mirjam

2010-10-01

To identify the prevalence of potential drug-drug interactions between hospital pharmacy dispensed anti-cancer agents and community pharmacy dispensed drugs. A retrospective cohort study was conducted on the haematology/oncology department of the internal medicine ward in a large teaching hospital in Amsterdam, the Netherlands. Prescription data from the last 100 patients treated with anti-cancer agents were obtained from Paracelsus, the chemotherapy prescribing system in the hospital. The community pharmacy dispensed drugs of these patients were obtained by using OZIS, a system that allows regionally linked pharmacies to call up active medication on any patient. Both medication lists were manually screened for potential drug-drug interactions by using several information sources on interactions, e.g. Pubmed, the Flockhart P450 table, Micromedex and Dutch reference books. Prevalence of potential drug-drug interactions between anti-cancer agents provided by the hospital pharmacy and drugs dispensed by the community pharmacy. Ninety-one patients were included in the study. A total of 31 potential drug-drug interactions were found in 16 patients, of which 15 interactions were clinically relevant and would have required an intervention. Of these interactions 1 had a level of severity ≥ D, meaning the potential drug-drug interaction could lead to long lasting or permanent damage, or even death. The majority of the interactions requiring an intervention (67%) had a considerable level of evidence (≥ 2) and were based on well-documented case reports or controlled interaction studies. Most of the potential drug-drug interactions involved the antiretroviral drugs (40%), proton pump inhibitors (20%) and antibiotics (20%). The anti-cancer drug most involved in the drug-drug interactions is methotrexate (33%). This study reveals a high prevalence of potential drug-drug interactions between anti-cancer agents provided by the hospital pharmacy and drugs dispensed by the community pharmacy. It shows us there is need for an optimal medication surveillance mechanism to detect potential drug-drug interactions between these two groups of medication, especially because of the high toxicity of anticancer drugs and thus the severe consequences these interactions can have for the patient.

Potential drug interactions in patients given antiretroviral therapy

PubMed Central

dos Santos, Wendel Mombaque; Secoli, Silvia Regina; Padoin, Stela Maris de Mello

2016-01-01

ABSTRACT Objective: to investigate potential drug-drug interactions (PDDI) in patients with HIV infection on antiretroviral therapy. Methods: a cross-sectional study was conducted on 161 adults with HIV infection. Clinical, socio demographic, and antiretroviral treatment data were collected. To analyze the potential drug interactions, we used the software Micromedex(r). Statistical analysis was performed by binary logistic regression, with a p-value of ≤0.05 considered statistically significant. Results: of the participants, 52.2% were exposed to potential drug-drug interactions. In total, there were 218 potential drug-drug interactions, of which 79.8% occurred between drugs used for antiretroviral therapy. There was an association between the use of five or more medications and potential drug-drug interactions (p = 0.000) and between the time period of antiretroviral therapy being over six years and potential drug-drug interactions (p < 0.00). The clinical impact was prevalent sedation and cardiotoxicity. Conclusions: the PDDI identified in this study of moderate and higher severity are events that not only affect the therapeutic response leading to toxicity in the central nervous and cardiovascular systems, but also can interfere in tests used for detection of HIV resistance to antiretroviral drugs. PMID:27878224

A regulatory perspective on the abuse potential evaluation of novel stimulant drugs in the United States.

PubMed

Calderon, Silvia N; Klein, Michael

2014-12-01

In the United States of America (USA), the abuse potential assessment of a drug is performed as part of the safety evaluation of a drug under development, and to evaluate if the drug needs to be subject to controls that would minimize the abuse of the drug once on the market. The assessment of the abuse potential of new drugs consists of a scientific and medical evaluation of all data related to abuse of the drug. This paper describes the regulatory framework for evaluating the abuse potential of new drugs, in general, including novel stimulants. The role of the United States Food and Drug Administration (FDA) in the evaluation of the abuse potential of drugs, and its role in drug control are also discussed. A definition of abuse potential, an overview of the currently accepted approaches to evaluating the abuse potential of a drug, as well as a description of the criteria that applies when recommending a specific level of control (i.e., a Schedule) for a drug under the Controlled Substances Act (CSA). This article is part of the Special Issue entitled 'CNS Stimulants'. Published by Elsevier Ltd.

Drug-disease and drug-drug interactions: systematic examination of recommendations in 12 UK national clinical guidelines.

PubMed

Dumbreck, Siobhan; Flynn, Angela; Nairn, Moray; Wilson, Martin; Treweek, Shaun; Mercer, Stewart W; Alderson, Phil; Thompson, Alex; Payne, Katherine; Guthrie, Bruce

2015-03-11

To identify the number of drug-disease and drug-drug interactions for exemplar index conditions within National Institute of Health and Care Excellence (NICE) clinical guidelines. Systematic identification, quantification, and classification of potentially serious drug-disease and drug-drug interactions for drugs recommended by NICE clinical guidelines for type 2 diabetes, heart failure, and depression in relation to 11 other common conditions and drugs recommended by NICE guidelines for those conditions. NICE clinical guidelines for type 2 diabetes, heart failure, and depression Potentially serious drug-disease and drug-drug interactions. Following recommendations for prescription in 12 national clinical guidelines would result in several potentially serious drug interactions. There were 32 potentially serious drug-disease interactions between drugs recommended in the guideline for type 2 diabetes and the 11 other conditions compared with six for drugs recommended in the guideline for depression and 10 for drugs recommended in the guideline for heart failure. Of these drug-disease interactions, 27 (84%) in the type 2 diabetes guideline and all of those in the two other guidelines were between the recommended drug and chronic kidney disease. More potentially serious drug-drug interactions were identified between drugs recommended by guidelines for each of the three index conditions and drugs recommended by the guidelines for the 11 other conditions: 133 drug-drug interactions for drugs recommended in the type 2 diabetes guideline, 89 for depression, and 111 for heart failure. Few of these drug-disease or drug-drug interactions were highlighted in the guidelines for the three index conditions. Drug-disease interactions were relatively uncommon with the exception of interactions when a patient also has chronic kidney disease. Guideline developers could consider a more systematic approach regarding the potential for drug-disease interactions, based on epidemiological knowledge of the comorbidities of people with the disease the guideline is focused on, and should particularly consider whether chronic kidney disease is common in the target population. In contrast, potentially serious drug-drug interactions between recommended drugs for different conditions were common. The extensive number of potentially serious interactions requires innovative interactive approaches to the production and dissemination of guidelines to allow clinicians and patients with multimorbidity to make informed decisions about drug selection. © Dumbreck et al 2015.

Immunohistochemical detection of a hypoxia marker in spontaneous canine tumours.

PubMed Central

Cline, J. M.; Thrall, D. E.; Page, R. L.; Franko, A. J.; Raleigh, J. A.

1990-01-01

An immunoperoxidase technique has been used to detect the in vivo binding of a 2-nitroimidazole hypoxia marker in histochemical sections of a variety of excised canine tumours. The binding occurred 10-12 cell diameters away from tumour blood vessels, consistent with the expected location of hypoxic cells in tissues in which oxygen concentration gradients are established by diffusion. Hypoxic fractions ranging from 4 to 13% have been estimated on the basis of morphometric analysis of multiple tumour sections. The binding of the marker was restricted to the cytoplasm of the cells. The marker appeared in regions adjacent to necrosis but also in regions free of necrosis. As in earlier autoradiography studies, binding was occasionally observed in cells adjacent to tumour blood vessels. Generally, binding to normal tissues was not observed. However, binding to smooth muscle cells surrounding arterioles in some sections of normal tissue and tumour tissue was observed. Images Figure 1 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 PMID:1701659

Insights into the binding mode of sulphamates and sulphamides to hCA II: crystallographic studies and binding free energy calculations.

PubMed

De Simone, Giuseppina; Langella, Emma; Esposito, Davide; Supuran, Claudiu T; Monti, Simona Maria; Winum, Jean-Yves; Alterio, Vincenzo

2017-12-01

Sulphamate and sulphamide derivatives have been largely investigated as carbonic anhydrase inhibitors (CAIs) by means of different experimental techniques. However, the structural determinants responsible for their different binding mode to the enzyme active site were not clearly defined so far. In this paper, we report the X-ray crystal structure of hCA II in complex with a sulphamate inhibitor incorporating a nitroimidazole moiety. The comparison with the structure of hCA II in complex with its sulphamide analogue revealed that the two inhibitors adopt a completely different binding mode within the hCA II active site. Starting from these results, we performed a theoretical study on sulphamate and sulphamide derivatives, demonstrating that electrostatic interactions with residues within the enzyme active site play a key role in determining their binding conformation. These findings open new perspectives in the design of effective CAIs using the sulphamate and sulphamide zinc binding groups as lead compounds.

Enhancement of hypoxia-activated prodrug TH-302 anti-tumor activity by Chk1 inhibition.

PubMed

Meng, Fanying; Bhupathi, Deepthi; Sun, Jessica D; Liu, Qian; Ahluwalia, Dharmendra; Wang, Yan; Matteucci, Mark D; Hart, Charles P

2015-05-21

The hypoxia-activated prodrug TH-302 is reduced at its nitroimidazole group and selectively under hypoxic conditions releases the DNA cross-linker bromo-isophosphoramide mustard (Br-IPM). Here, we have explored the effect of Chk1 inhibition on TH-302-mediated pharmacological activities. We employed in vitro cell viability, DNA damage, cellular signaling assays and the in vivo HT29 human tumor xenograft model to study the effect of Chk1inhibition on TH-302 antitumor activities. TH-302 cytotoxicity is greatly enhanced by Chk1 inhibition in p53-deficient but not in p53-proficient human cancer cell lines. Chk1 inhibitors reduced TH-302-induced cell cycle arrest via blocking TH-302-induced decrease of phosphorylation of histone H3 and increasing Cdc2-Y15 phosphorylation. Employing the single-cell gel electrophoresis (comet) assay, we observed a potentiation of the TH-302 dependent tail moment. TH-302 induced γH2AX and apoptosis were also increased upon the addition of Chk1 inhibitor. Potentiation of TH-302 cytotoxicity by Chk1 inhibitor was only observed in cell lines proficient in, but not deficient in homology-directed DNA repair. We also show that combination treatment led to lowering of Rad51 expression levels as compared to either agent alone. In vivo data demonstrate that Chk1 inhibitor enhances TH-302 anti-tumor activity in p53 mutant HT-29 human tumor xenografts, supporting the hypothesis that these in vitro results can translate to enhanced in vivo efficacy of the combination. TH-302-mediated in vitro and in vivo anti-tumor activities were greatly enhanced by the addition of Chk1 inhibitors. The preclinical data presented in this study support a new approach for the treatment of p53-deficient hypoxic cancers by combining Chk1 inhibitors with the hypoxia-activated prodrug TH-302.

[Development of antituberculous drugs: current status and future prospects].

PubMed

Tomioka, Haruaki; Namba, Kenji

2006-12-01

Worldwide, tuberculosis (TB) remains the most frequent and important infectious disease causing morbidity and death. One-third of the world's population is infected with Mycobacterium tuberculosis (MTB), the etiologic agent of TB. The World Health Organization estimates that about eight to ten million new TB cases occur annually worldwide and the incidence of TB is currently increasing. In this context, TB is in the top three, with malaria and HIV being the leading causes of death from a single infectious agent, and approximately two million deaths are attributable to TB annually. In particular, pulmonary TB, the most common form of TB, is a highly contagious and life-threatening infection. Moreover, enhanced susceptibility to TB in HIV-infected populations is another serious health problem throughout the world. In addition, multidrug-resistant TB (MDR-TB) has been increasing in incidence in many areas, not only in developing countries but industrialized countries as well, during the past decade. These situations, particularly the global resurgence of TB and the rapid emergence of MDR-TB, underscore the importance of the development of new antituberculous drugs and new protocols for efficacious clinical control of TB patients using ordinary antimycobacterial drugs. Concerning the development of new antituberculous drugs, the following points are of particular importance. (1) Development of drugs which display lasting antimycobacterial activity in vivo is desirable, since they can be administered with long intervals and consequently facilitate directly observed therapy and enhance patient compliance. (2) Development of novel antituberculosis compounds to combat MDR-TB is urgently needed. (3) The eradication of slowly metabolizing and, if possible, dormant populations of MTB organisms that cause relapse, using new classes of anti-TB drugs is very promising for prevention of TB incidence, because it will markedly reduce the incidence of active TB from persons who are latently infected with MTB. Unfortunately, no new drugs except rifabutin and rifapentine has been marketed for TB in the US and other countries during the 40 years after release of rifampicin. There are a number of constraints that have deterred companies from investing in new anti-TB drugs. The research is expensive, slow and difficult, and requires specialized facilities for handling MTB. There are few animal models that closely mimic the human TB disease. Development time of any anti-TB drug will be long. In fact, clinical trials will require the minimum six-month therapy, with a follow-up period of one year or more. In addition, it is hard to demonstrate obvious benefit of a new anti-TB agents over pre-existing drugs, since clinical trials involve multidrug combination therapy using highly effective ordinary anti-TB drugs. Finaly, there is the perceived lack of commercial return to companies engaged in the development of new anti-TB drugs, because over 95% of TB cases worldwide are in developing countries. In this symposium, we reviewed the following areas. 1. Critical new information on the entire genome of MTB recently obtained and increasing knowledge of various mycobacterial virulence genes are greatly promoting the identification of genes that code for new drug targets. In this context, Dr. Namba reviewed the status of new types of compounds which are being developed as anti-TB drug. He also discussed the development of new antimycobacterial drugs according to new and potential pharmacological targets and the best clinical development plans for new-TB drugs in relation to corporate strategy. 2. Using such findings for mycobacterial genomes, bioinformatics/genomics/proteomics-based drug design and drug development using quantitative structure-activity relationships may be possible in the near future. In this context, Dr. Suwa and Dr. Suzuki reviewed the usefulness of chemical genomics in searching novel drug targets for development of new antituberculous drugs. The authors reviewed (1) the history and present status of chemical genomics that is defined as the systemic search for a selective small molecular modulator for each function of all gene products, (2) recent studies of the authors on profiles of the interactions between various kinds of human proteins and small molecule modulators using the new technology devised by Reverse Proteomics Research Institute, and (3) future prospects of the development of new antituberculous drugs based on chemical genomics. 3. It appears also promising to develop new types of drug administration systems using drug vehicles, which enable efficacious drug delivery to their target in vivo. Dr. Izumikawa, Dr. Ohno and Dr. Kohno reviewed the usefulness of liposome- and polymer-based technologies, which enable efficacious delivery of encapsulated drugs at required doses for prolonged periods of time with only a single shot without toxicity, and also enable highly targeted delivery of drugs to their target in vivo. They indicated that the applications of drug delivery system using conventional anti-mycobacterial agents are challenging to improve the compliance of treatment and better clinical outcome. 4. Immunoadjunctive therapy appears to be promising in improving outcome of clinical control of refractory mycobacterial infections, including MDR-TB and M. avium complex infection. Dr. Shimizu, Dr. Sato and Dr. Tomioka reviewed the present status of immunotherapy of mycobacterial infections in combination with antimycobacterial drugs. They indicated that the development of new classes of immunomodulators other than cytokines (IL-2, IFN-gamma, GM-CSF, IL-12, etc.) particularly those with no severe side-effects, are urgently needed. Their review dealed with some promising immunoadjunctive agents, especially ATP and its analogues, which potentiate macrophage antimycobacterial activity via purinergic P2 receptors. The aim of this symposium is to address the future prospects of the development of new drugs and drug regimens for anti-TB chemotherapy. There are a number of difficulties in drug-design for the development of new drug formulations with increased potential for antimycobacterial effects, excellent pharmacokinetics, and tolerability. It should be emphasized that the most urgent goal of chemotherapy of TB and MAC infections, especially that associated with HIV infection, is to develop highly active, low-cost drugs which can be used not only in industrialized countries but also in developing countries, since the incidences of AIDS-associated intractable TB and MAC infections are rapidly increasing in the latter. We strongly wish a great advance of fundametal and practical studies in developing such kinds of new anti-TB drugs in the near future. 1. Prospects for non-clinical or clinical development of new antituberculous drugs in relation to corporate strategy: Kenji NAMBA (New Product Research Laboratories I, Daiichi Pharmaceutical Co., Ltd.) Tuberculosis (TB) remains one of the deadliest threats to public health. No new anti-TB drugs have been brought into the clinic in the past 40 years. Current non-clinical works with progressed technology and Global Alliance for TB Drug Development, a non-profit organization established in 2000, accelerate research and development of faster-acting anti-TB compounds. We reviewed the status of new types of compounds which are being developed as anti-TB drug, such as diarylquinoline (TMC 207), nitroimidazole (PA-824 and OPC-67683), and moxifloxacin (MFLX). We also discussed the best clinical development plans for new-TB drugs in relation to corporate strategy. 2. Exploring novel drug targets through the chemical genomics approach and its possible application to the development of anti-tuberculosis drugs: Yorimasa SUWA (Reverse Proteomics Research Institute Co., Ltd.), Yohji SUZUKI (Teijin Ltd.) Recently, chemical genomics approach has been focused as an emerging technology for the drug discovery. In advance to a very large scale national project in US started last year, Reverse Proteomics Research Institute Co., Ltd. (REPRORI) has developed the core technologies for chemical genomics. Here we describe the outline of chemical genomics study, especially that of REPRORI, and discuss about its possible application to the development of anti-tuberculosis drugs. 3. Anti-mycobacterial agents and drug delivery: Koichi IZUMIKAWA, Hideaki OHNO, Shigeru KOHNO (Second Department of Internal Medicine, Nagasaki University School of Medicine) Mycobacterium infection is a major clinical concern in whole world. Since the newly developed anti-mycobacterial agents are few and still unavailable in clinical settings, the applications of drug delivery system using conventional anti-mycobacterial agents are challenging to improve the compliance of treatment and better efficacy. The efficacy of anti-mycobacterial agents modified by liposome or polymer based technology have been investigated and reported using various animal models. Drug delivery system increased and prolonged the drug concentrations at the blood and targeted organs and the duration of sustained drug release, respectively. These effects lead to decrease in the frequency of drug administrations dramatically and better efficacy rates. The studies, however, were performed only in animal models, the further investigations and evaluations in human are required for practical use. 4. Adjunctive immunotherapy of mycobacterial infections: Toshiaki SHIMIZU, Katsumasa SATO, Haruaki TOMIOKA (Department of Microbiology and Immunology, Shimane University School of Medicine) There is an urgent need to develop new antimicrobials and protocols for the administration of drugs that are potently efficacious against intractable mycobacterial infections. Unfortunately, development of the new drugs for solving this problem is not progressing. (ABSTRACT TRUNCATED)

A regulatory perspective on the evaluation of hallucinogen drugs for human use.

PubMed

Calderon, Silvia N; Hunt, Joshua; Klein, Michael

2017-11-24

In recent years, there is renewed interest in the study of various hallucinogens for their potential therapeutic effects. In the United States of America (USA), the abuse potential assessment of a drug is carried out as part of the general safety and efficacy evaluation of a drug. Additionally, the abuse potential assessment is taken under consideration in determining if a drug needs to be subject to controls to minimize the abuse of the drug once on the market. This assessment is conducted for all new drugs with central nervous system (CNS) activity, that are chemically or pharmacologically similar to other drugs with known abuse potential, or drugs that produce psychoactive effects predictive of abuse, such as euphoria and hallucinations. This paper describes the regulatory framework for evaluating the abuse potential of new drugs, with emphasis on hallucinogens. The paper discusses the role of the United States Food and Drug Administration (FDA) in the evaluation of the abuse potential of drugs and its role in drug control, and provides an overview of the controlled status of hallucinogens and the requirements to conduct research with Schedule I substances in the USA. Published by Elsevier Ltd.

Identification of polycystic ovary syndrome potential drug targets based on pathobiological similarity in the protein-protein interaction network

PubMed Central

Li, Wan; Wei, Wenqing; Li, Yiran; Xie, Ruiqiang; Guo, Shanshan; Wang, Yahui; Jiang, Jing; Chen, Binbin; Lv, Junjie; Zhang, Nana; Chen, Lina; He, Weiming

2016-01-01

Polycystic ovary syndrome (PCOS) is one of the most common endocrinological disorders in reproductive aged women. PCOS and Type 2 Diabetes (T2D) are closely linked in multiple levels and possess high pathobiological similarity. Here, we put forward a new computational approach based on the pathobiological similarity to identify PCOS potential drug target modules (PPDT-Modules) and PCOS potential drug targets in the protein-protein interaction network (PPIN). From the systems level and biological background, 1 PPDT-Module and 22 PCOS potential drug targets were identified, 21 of which were verified by literatures to be associated with the pathogenesis of PCOS. 42 drugs targeting to 13 PCOS potential drug targets were investigated experimentally or clinically for PCOS. Evaluated by independent datasets, the whole PPDT-Module and 22 PCOS potential drug targets could not only reveal the drug response, but also distinguish the statuses between normal and disease. Our identified PPDT-Module and PCOS potential drug targets would shed light on the treatment of PCOS. And our approach would provide valuable insights to research on the pathogenesis and drug response of other diseases. PMID:27191267

Drug Scene Syllabus, A Manual on Drugs and Volatile Chemical of Potential Abuse.

ERIC Educational Resources Information Center

Johnson, Robert B.; And Others

A brief historical review of attempts to control the abuse of drugs introduces a series of tables listing pertinent information about drugs of potential abuse. Each table provides the common commercial and slang names for the drugs, their medical and legal classification, their potential for emotional and physical dependence, whether the user…

Drug discrimination: A versatile tool for characterization of CNS safety pharmacology and potential for drug abuse.

PubMed

Swedberg, Michael D B

2016-01-01

Drug discrimination studies for assessment of psychoactive properties of drugs in safety pharmacology and drug abuse and drug dependence potential evaluation have traditionally been focused on testing novel compounds against standard drugs for which drug abuse has been documented, e.g. opioids, CNS stimulants, cannabinoids etc. (e.g. Swedberg & Giarola, 2015), and results are interpreted such that the extent to which the test drug causes discriminative effects similar to those of the standard training drug, the test drug would be further characterized as a potential drug of abuse. Regulatory guidance for preclinical assessment of abuse liability by the European Medicines Agency (EMA, 2006), the U.S. Food and Drug Administration (FDA, 2010), the International Conference of Harmonization (ICH, 2009), and the Japanese Ministry of Health Education and Welfare (MHLW, 1994) detail that compounds with central nervous system (CNS) activity, whether by design or not, need abuse and dependence liability assessment. Therefore, drugs with peripheral targets and a potential to enter the CNS, as parent or metabolite, are also within scope (see Swedberg, 2013, for a recent review and strategy). Compounds with novel mechanisms of action present a special challenge due to unknown abuse potential, and should be carefully assessed against defined risk criteria. Apart from compounds sharing mechanisms of action with known drugs of abuse, compounds intended for indications currently treated with drugs with potential for abuse and or dependence are also within scope, regardless of mechanism of action. Examples of such compounds are analgesics, anxiolytics, cognition enhancers, appetite control drugs, sleep control drugs and drugs for psychiatric indications. Recent results (Swedberg et al., 2014; Swedberg & Raboisson, 2014; Swedberg, 2015) on the metabotropic glutamate receptor type 5 (mGluR5) antagonists demonstrate that compounds causing hallucinatory effects in humans did not exhibit clear discriminative effects when tested against classical drugs of abuse in drug discrimination studies, and were not self-administered by rats. However, these compounds did cause salient discriminative effects of their own in animals trained to discriminate them from no drug. Therefore, from a safety pharmacology perspective, novel compounds that do not cause discriminative effects similar to classical drugs of abuse, may still cause psychoactive effects in humans and carry the potential to maintain drug abuse, suggesting that proactive investigation of drug abuse potential is warranted (Swedberg, 2013). These and other findings will be discussed, and the application of drug discrimination procedures beyond the typical standard application of testing novel compounds against known and well characterized reference drugs will be addressed. Copyright © 2016 Elsevier Inc. All rights reserved.

Potential drug related problems detected by electronic expert support system in patients with multi-dose drug dispensing.

PubMed

Tora, Hammar; Bo, Hovstadius; Bodil, Lidström; Göran, Petersson; Birgit, Eiermann

2014-10-01

Background Drug related problems (DRPs) are frequent and cause suffering for patients and substantial costs for society. Multi-dose drug dispensing (MDDD) is a service by which patients receive their medication packed in bags with one unit for each dose occasion. The clinical decision support system (CDSS) electronic expert support (EES) analyses patients' prescriptions in the Swedish national e-prescription repository and provides alerts if potential DRPs are detected, i.e. drug-drug interactions, duplicate therapy, drug-disease contraindications, high dose, gender warnings, geriatric, and paediatric alerts. Objective To analyse potential DRPs in patients with MDDD, detected by means of EES. Setting A register study of all electronically stored prescriptions for patients with MDDD in Sweden (n = 180,059) March 5-June 5, 2013. Method Drug use and potential DRPs detected in the study population during the 3 month study period by EES were analysed. The potential DRPs were analysed in relation to patients' age, gender, number of drugs, and type of medication. Main outcome measure Prevalence of potential DRPs measured as EES alerts. Results The study population was on average 75.8 years of age (± 17.5, range 1-110) and had 10.0 different medications (± 4.7, range 1-53). EES alerted for potential DRPs in 76 % of the population with a mean of 2.2 alerts per patient (± 2.4, range 0-27). The older patients received a lower number of alerts compared to younger patients despite having a higher number of drugs. The most frequent alert categories were drug-drug interactions (37 % of all alerts), duplicate therapy (30 %), and geriatric warnings for high dose or inappropriate drugs (23 %). Psycholeptics, psychoanaleptics, antithrombotic agents, anti-epileptics, renin-angiotensin system agents, and analgesics represented 71 % of all drugs involved in alerts. Conclusions EES detected potential DRPs in the majority of patients with MDDD. The number of potential DRPs was associated with the number of drugs, age, gender, and type of medication. A CDSS such as EES might be a useful tool for physicians and pharmacists to assist in the important task of monitoring patients with MDDD for potential DRPs.

Using Statistics and Data Mining Approaches to Analyze Male Sexual Behaviors and Use of Erectile Dysfunction Drugs Based on Large Questionnaire Data.

PubMed

Qiao, Zhi; Li, Xiang; Liu, Haifeng; Zhang, Lei; Cao, Junyang; Xie, Guotong; Qin, Nan; Jiang, Hui; Lin, Haocheng

2017-01-01

The prevalence of erectile dysfunction (ED) has been extensively studied worldwide. Erectile dysfunction drugs has shown great efficacy in preventing male erectile dysfunction. In order to help doctors know drug taken preference of patients and better prescribe, it is crucial to analyze who actually take erectile dysfunction drugs and the relation between sexual behaviors and drug use. Existing clinical studies usually used descriptive statistics and regression analysis based on small volume of data. In this paper, based on big volume of data (48,630 questionnaires), we use data mining approaches besides statistics and regression analysis to comprehensively analyze the relation between male sexual behaviors and use of erectile dysfunction drugs for unravelling the characteristic of patients who take erectile dysfunction drugs. We firstly analyze the impact of multiple sexual behavior factors on whether to use the erectile dysfunction drugs. Then, we explore to mine the Decision Rules for Stratification to discover patients who are more likely to take drugs. Based on the decision rules, the patients can be partitioned into four potential groups for use of erectile dysfunction: high potential group, intermediate potential-1 group, intermediate potential-2 group and low potential group. Experimental results show 1) the sexual behavior factors, erectile hardness and time length to prepare (how long to prepares for sexual behaviors ahead of time), have bigger impacts both in correlation analysis and potential drug taking patients discovering; 2) odds ratio between patients identified as low potential and high potential was 6.098 (95% confidence interval, 5.159-7.209) with statistically significant differences in taking drug potential detected between all potential groups.

Establishment of a novel experimental protocol for drug-induced seizure liability screening based on a locomotor activity assay in zebrafish.

PubMed

Koseki, Naoteru; Deguchi, Jiro; Yamashita, Akihito; Miyawaki, Izuru; Funabashi, Hitoshi

2014-08-01

As drug-induced seizures have severe impact on drug development, evaluating seizure induction potential of candidate drugs at the early stages of drug discovery is important. A novel assay system using zebrafish has attracted interest as a high throughput toxicological in vivo assay system, and we tried to establish an experimental method for drug-induced seizure liability on the basis of locomotor activity in zebrafish. We monitored locomotor activity at high-speed movement (> 20 mm/sec) for 60 min immediately after exposure, and assessed seizure liability potential in some drugs using locomotor activity. However this experimental procedure was not sufficient for predicting seizures because the potential of several drugs with demonstrated seizure potential in mammals was not detected. We, therefore, added other parameters for locomotor activity such as extending exposure time or conducting flashlight stimulation (10 Hz) which is a known seizure induction stimulus, and these additional parameters improved seizure potential detection in some drugs. The validation study using the improved methodology was used to assess 52 commercially available drugs, and the prediction rate was approximately 70%. The experimental protocol established in this present study is considered useful for seizure potential screening during early stages of drug discovery.

21 CFR 314.104 - Drugs with potential for abuse.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 5 2013-04-01 2013-04-01 false Drugs with potential for abuse. 314.104 Section 314.104 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS FOR HUMAN USE APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG FDA Action on Applications...

21 CFR 314.104 - Drugs with potential for abuse.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 5 2010-04-01 2010-04-01 false Drugs with potential for abuse. 314.104 Section 314.104 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS FOR HUMAN USE APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG FDA Action on Applications...

21 CFR 314.104 - Drugs with potential for abuse.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 5 2012-04-01 2012-04-01 false Drugs with potential for abuse. 314.104 Section 314.104 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS FOR HUMAN USE APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG FDA Action on Applications...

21 CFR 314.104 - Drugs with potential for abuse.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 5 2011-04-01 2011-04-01 false Drugs with potential for abuse. 314.104 Section 314.104 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS FOR HUMAN USE APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG FDA Action on Applications...

21 CFR 314.104 - Drugs with potential for abuse.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 5 2014-04-01 2014-04-01 false Drugs with potential for abuse. 314.104 Section 314.104 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS FOR HUMAN USE APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG FDA Action on Applications...

Improving the assessment of prescribing: use of a 'substitution index'.

PubMed

Kunisawa, Susumu; Otsubo, Tetsuya; Lee, Jason; Imanaka, Yuichi

2013-07-01

To analyse the current and potential utilization of generic drugs in Japan, to examine the maximum possible cost savings from generic drug use and to develop a fairer measure to assess the level of generic drug substitution. We conducted a cross-sectional retrospective analysis of nine million dispensing records during January to March 2010 in Kyoto Prefecture. Maximum potential quantity-based shares were defined as the quantity of generic drugs used plus the quantity of branded drugs that could have been replaced by generic drugs divided by the quantity of all drugs dispensed. We developed a 'substitution index', defined as the proportion of generic drugs out of the total drugs substitutable with generic drugs (based on quantity rather than cost). Generic drugs had a quantity-based share of 17.9%, a cost-based share of 8.9% and a maximum potential quantity-based share of 50.1%, which is lower than the actual generic drug shares of some other countries. The maximum possible cost savings as a result of generic drug substitution was 16.5%. We also observed wide variations in maximum potential quantity-based shares between health care sectors and health care institutions. Simple comparisons based on quantity-based shares may misrepresent the actual generic drug use. A substitution index that takes into account the maximum potential quantity-based share of generic drugs as a fairer measure may promote more realistic goals and encourage generic drug usage.

Personal digital assistant-based drug information sources: potential to improve medication safety.

PubMed

Galt, Kimberly A; Rule, Ann M; Houghton, Bruce; Young, Daniel O; Remington, Gina

2005-04-01

This study compared the potential for personal digital assistant (PDA)-based drug information sources to minimize potential medication errors dependent on accurate and complete drug information at the point of care. A quality and safety framework for drug information resources was developed to evaluate 11 PDA-based drug information sources. Three drug information sources met the criteria of the framework: Eprocrates Rx Pro, Lexi-Drugs, and mobileMICROMEDEX. Medication error types related to drug information at the point of care were then determined. Forty-seven questions were developed to test the potential of the sources to prevent these error types. Pharmacists and physician experts from Creighton University created these questions based on the most common types of questions asked by primary care providers. Three physicians evaluated the drug information sources, rating the source for each question: 1=no information available, 2=some information available, or 3 = adequate amount of information available. The mean ratings for the drug information sources were: 2.0 (Eprocrates Rx Pro), 2.5 (Lexi-Drugs), and 2.03 (mobileMICROMEDEX). Lexi-Drugs was significantly better (mobileMICROMEDEX t test; P=0.05; Eprocrates Rx Pro t test; P=0.01). Lexi-Drugs was found to be the most specific and complete PDA resource available to optimize medication safety by reducing potential errors associated with drug information. No resource was sufficient to address the patient safety information needs for all cases.

Theranostic Value of Multimers: Lessons Learned from Trimerization of Neurotensin Receptor Ligands and Other Targeting Vectors

PubMed Central

Maschauer, Simone; Einsiedel, Jürgen; Reich, Dominik; Hübner, Harald; Gmeiner, Peter; Wester, Hans-Jürgen; Prante, Olaf; Notni, Johannes

2017-01-01

Neurotensin receptor 1 (NTS1) is overexpressed on a variety of cancer entities; for example, prostate cancer, ductal pancreatic adenocarcinoma, and breast cancer. Therefore, it represents an interesting target for the diagnosis of these cancers types by positron emission tomography (PET). The metabolically-stabilized neurotensin (NT) derivative peptide Nlys8-Lys9-Pro10-Tyr11-Tle12-Leu13-OH was elongated at the N-terminus with 6-azido norleucine and coupled with the 1,4,7-triazacyclononane-1,4,7-tris[(2-carboxyethyl)methylenephosphinic acid] (TRAP) chelator TRAP(alkyne)3 in order to synthesize a NT trimer with subnanomolar affinity and high stability. The 68Ga-labeled peptide [68Ga]Ga-TRAP(NT4)3 was characterized in vitro using the NTS1-expressing human colorectal adenocarcinoma cell line HT29. It displayed fast and high internalization rates of >90%, but also fast efflux rates of 50% over 15 min. In vivo, [68Ga]Ga-TRAP(NT4)3 showed moderate HT29 tumor uptake values of 1.7 %ID/g at 60 min post-injection (p.i.), but also high uptake and retention in the kidneys and liver. A comparison of data for trimer/monomer pairs of NT ligands and other targeting vectors (peptides and peptoids targeting integrins αvβ3, α5β1, and αvβ6, the PSMA-ligand DUPA (2-[3-(1,3-dicarboxypropyl)-ureido]pentanedioic acid), and nitroimidazoles targeting hypoxia) revealed that multimers always exhibit higher target affinities and tumor uptake, but not necessarily improved tumor-to-tissue ratios. Thus, although in vitro data are not suitable for prediction of in vivo performance, multimers are potentially superior to monomers, particularly for applications where high tumor accumulation is crucial. PMID:28287433

Prevalence of Potential and Clinically Relevant Statin-Drug Interactions in Frail and Robust Older Inpatients.

PubMed

Thai, Michele; Hilmer, Sarah; Pearson, Sallie-Anne; Reeve, Emily; Gnjidic, Danijela

2015-10-01

A significant proportion of older people are prescribed statins and are also exposed to polypharmacy, placing them at increased risk of statin-drug interactions. To describe the prevalence rates of potential and clinically relevant statin-drug interactions in older inpatients according to frailty status. A cross-sectional study of patients aged ≥65 years who were prescribed a statin and were admitted to a teaching hospital between 30 July and 10 October 2014 in Sydney, Australia, was conducted. Data on socio-demographics, comorbidities and medications were collected using a standardized questionnaire. Potential statin-drug interactions were defined if listed in the Australian Medicines Handbook and three international drug information sources: the British National Formulary, Drug Interaction Facts and Drug-Reax(®). Clinically relevant statin-drug interactions were defined as interactions with the highest severity rating in at least two of the three international drug information sources. Frailty was assessed using the Reported Edmonton Frail Scale. A total of 180 participants were recruited (median age 78 years, interquartile range 14), 35.0% frail and 65.0% robust. Potential statin-drug interactions were identified in 10% of participants, 12.7% of frail participants and 8.5% of robust participants. Clinically relevant statin-drug interactions were identified in 7.8% of participants, 9.5% of frail participants and 6.8% of robust participants. Depending on the drug information source used, the prevalence rates of potential and clinically relevant statin-drug interactions ranged between 14.4 and 35.6% and between 14.4 and 20.6%, respectively. In our study of frail and robust older inpatients taking statins, the overall prevalence of potential statin-drug interactions was low and varied significantly according to the drug information source used.

Adverse interactions between herbal and dietary substances and prescription medications: a clinical survey.

PubMed

Bush, Thomas M; Rayburn, Keith S; Holloway, Sandra W; Sanchez-Yamamoto, Deanna S; Allen, Blaine L; Lam, Tiffany; So, Brian K; Tran, De H; Greyber, Elizabeth R; Kantor, Sophia; Roth, Larry W

2007-01-01

Patients often combine prescription medications with herbal and dietary substances (herein referred to as herbal medicines). A variety of potential adverse herb-drug interactions exist based on the pharmacological properties of herbal and prescription medications. To determine the incidence of potential and observed adverse herb-drug interactions in patients using herbal medicines with prescription medications. Consecutive patients were questioned about their use of herbal medicines in 6 outpatient clinics. Patients reporting use of these products provided a list of their prescription medications, which were reviewed for any potential adverse herb-drug interactions using a comprehensive natural medicine database. Any potential adverse herb-drug interactions prompted a review of the patient's chart for evidence of an observed adverse herb-drug interaction. The rate of potential and observed adverse herb-drug interactions. Eight hundred four patients were surveyed, and 122 (15%) used herbal medicines. Eighty-five potential adverse herb-drug interactions were found in 49 patients (40% of herbal medicine users). Twelve possible adverse herb-drug interactions in 8 patients (7% of herbal medicine users) were observed. In all 12 cases, the severity scores were rated as mild, including 8 cases of hypoglycemia in diabetics taking nopal (prickly pear cactus). A substantial number of potential adverse herb-drug interactions were detected and a small number of adverse herb-drug interactions observed, particularly in diabetics taking nopal. Screening for herbal medicine usage in 804 patients did not uncover any serious adverse interactions with prescription medications.

Do systemic antibiotics prevent dry socket and infection after third molar extraction? A systematic review and meta-analysis.

PubMed

Ramos, Eva; Santamaría, Joseba; Santamaría, Gorka; Barbier, Luis; Arteagoitia, Icíar

2016-10-01

The use of antibiotics to prevent dry socket and infection is a controversial but widespread practice. The aim of the study is to assess the efficacy of systemic antibiotics in reducing the frequencies of these complications after extraction. A systematic review and meta-analysis, according to the PRISMA statement, based on randomized double-blind placebo-controlled trials evaluating systemic antibiotics to prevent dry socket and infection after third molar surgery. Databases were searched up to June 2015. Relative risks (RRs) were calculated with inverse variance-weighted, fixed-effect, or random-effect models. We included 22 papers in the qualitative and 21 in the quantitative review (3304 extractions). Overall-RR was 0.43 (95% confidence interval [CI] 0.33-0.56; P < .0001); number needed to treat, 14 (95% CI 11-19). Penicillins-RR: 0.40 (95% CI 0.27-0.59). Nitroimidazoles-RR: 0.56 (95% CI 0.38-0.82). No serious adverse events were reported. Systemic antibiotics significantly reduce the risk of dry socket and infection in third molar extraction. Copyright © 2016 Elsevier Inc. All rights reserved.

Disruptive Potential of the Internet to Transform Illicit Drug Markets and Impact on Future Patterns of Drug Consumption.

PubMed

Griffiths, P; Mounteney, J

2017-02-01

The internet facilitates rapid and covert communication, knowledge transfer, and has the potential to disrupt and transform drug market models and associated consumption patterns. Innovation and new trends diffuse rapidly through this medium and new operational models are emerging. Although the online drug markets currently only account for a small share of all drug transactions, the potential of the surface and deep web to provide a new platform for drug sale and exchanges is considerable. © 2016 American Society for Clinical Pharmacology and Therapeutics.

Intracranial Self-Stimulation to Evaluate Abuse Potential of Drugs

PubMed Central

Miller, Laurence L.

2014-01-01

Intracranial self-stimulation (ICSS) is a behavioral procedure in which operant responding is maintained by pulses of electrical brain stimulation. In research to study abuse-related drug effects, ICSS relies on electrode placements that target the medial forebrain bundle at the level of the lateral hypothalamus, and experimental sessions manipulate frequency or amplitude of stimulation to engender a wide range of baseline response rates or response probabilities. Under these conditions, drug-induced increases in low rates/probabilities of responding maintained by low frequencies/amplitudes of stimulation are interpreted as an abuse-related effect. Conversely, drug-induced decreases in high rates/probabilities of responding maintained by high frequencies/amplitudes of stimulation can be interpreted as an abuse-limiting effect. Overall abuse potential can be inferred from the relative expression of abuse-related and abuse-limiting effects. The sensitivity and selectivity of ICSS to detect abuse potential of many classes of abused drugs is similar to the sensitivity and selectivity of drug self-administration procedures. Moreover, similar to progressive-ratio drug self-administration procedures, ICSS data can be used to rank the relative abuse potential of different drugs. Strengths of ICSS in comparison with drug self-administration include 1) potential for simultaneous evaluation of both abuse-related and abuse-limiting effects, 2) flexibility for use with various routes of drug administration or drug vehicles, 3) utility for studies in drug-naive subjects as well as in subjects with controlled levels of prior drug exposure, and 4) utility for studies of drug time course. Taken together, these considerations suggest that ICSS can make significant contributions to the practice of abuse potential testing. PMID:24973197

[Impact of potentially inappropriate drug usage on health insurance business results].

PubMed

Kirschke, Malin; Böhme, Jacqueline

2014-09-01

In Germany a list was drawn up that included 83 potentially inappropriate drugs. The PRISCUS list published in 2010 was intended to highlight certain problems in the pharmakotherapy of elderly patients and serve as a support for improved medicine safety. Almost a third of the insurance portfolio of the HALLESCHE Krankenversicherung aged over 75 years takes drugs that are on the PRISCUS list. Benzodiazepine and Z-drugs are taken most frequently. The costs per insurant with potentially inappropriate medication are on average higher than for policyholders who do not take drugs on the PRISCUS list. The costs per insurant are rising, with an increase in the number of PRISCUS agents being taken as well. However, there is still no scientific proof that potentially inappropriate drugs lead to adverse drug events.

Adverse events caused by potential drug-drug interactions in an intensive care unit of a teaching hospital

PubMed Central

Alvim, Mariana Macedo; da Silva, Lidiane Ayres; Leite, Isabel Cristina Gonçalves; Silvério, Marcelo Silva

2015-01-01

Objective To evaluate the incidence of potential drug-drug interactions in an intensive care unit of a hospital, focusing on antimicrobial drugs. Methods This cross-sectional study analyzed electronic prescriptions of patients admitted to the intensive care unit of a teaching hospital between January 1 and March 31, 2014 and assessed potential drug-drug interactions associated with antimicrobial drugs. Antimicrobial drug consumption levels were expressed in daily doses per 100 patient-days. The search and classification of the interactions were based on the Micromedex® system. Results The daily prescriptions of 82 patients were analyzed, totaling 656 prescriptions. Antimicrobial drugs represented 25% of all prescription drugs, with meropenem, vancomycin and ceftriaxone being the most prescribed medications. According to the approach of daily dose per 100 patient-days, the most commonly used antimicrobial drugs were cefepime, meropenem, sulfamethoxazole + trimethoprim and ciprofloxacin. The mean number of interactions per patient was 2.6. Among the interactions, 51% were classified as contraindicated or significantly severe. Highly significant interactions (clinical value 1 and 2) were observed with a prevalence of 98%. Conclusion The current study demonstrated that antimicrobial drugs are frequently prescribed in intensive care units and present a very high number of potential drug-drug interactions, with most of them being considered highly significant. PMID:26761473

PREDICTING ABUSE POTENTIAL OF STIMULANTS AND OTHER DOPAMINERGIC DRUGS: OVERVIEW AND RECOMMENDATIONS

PubMed Central

Huskinson, Sally L.; Naylor, Jennifer E.; Rowlett, James K.; Freeman, Kevin B.

2014-01-01

Examination of a drug’s abuse potential at multiple levels of analysis (molecular/cellular action, whole-organism behavior, epidemiological data) is an essential component to regulating controlled substances under the Controlled Substances Act (CSA). We reviewed studies that examined several central nervous system (CNS) stimulants, focusing on those with primarily dopaminergic actions, in drug self-administration, drug discrimination, and physical dependence. For drug self-administration and drug discrimination, we distinguished between experiments conducted with rats and nonhuman primates (NHP) to highlight the common and unique attributes of each model in the assessment of abuse potential. Our review of drug self-administration studies suggests that this procedure is important in predicting abuse potential of dopaminergic compounds, but there were many false positives. We recommended that tests to determine how reinforcing a drug is relative to a known drug of abuse may be more predictive of abuse potential than tests that yield a binary, yes-or-no classification. Several false positives also occurred with drug discrimination. With this procedure, we recommended that future research follow a standard decision-tree approach that may require examining the drug being tested for abuse potential as the training stimulus. This approach would also allow several known drugs of abuse to be tested for substitution, and this may reduce false positives. Finally, we reviewed evidence of physical dependence with stimulants and discussed the feasibility of modeling these phenomena in nonhuman animals in a rational and practical fashion. PMID:24662599

Predicting abuse potential of stimulants and other dopaminergic drugs: overview and recommendations.

PubMed

Huskinson, Sally L; Naylor, Jennifer E; Rowlett, James K; Freeman, Kevin B

2014-12-01

Examination of a drug's abuse potential at multiple levels of analysis (molecular/cellular action, whole-organism behavior, epidemiological data) is an essential component to regulating controlled substances under the Controlled Substances Act (CSA). We reviewed studies that examined several central nervous system (CNS) stimulants, focusing on those with primarily dopaminergic actions, in drug self-administration, drug discrimination, and physical dependence. For drug self-administration and drug discrimination, we distinguished between experiments conducted with rats and nonhuman primates (NHP) to highlight the common and unique attributes of each model in the assessment of abuse potential. Our review of drug self-administration studies suggests that this procedure is important in predicting abuse potential of dopaminergic compounds, but there were many false positives. We recommended that tests to determine how reinforcing a drug is relative to a known drug of abuse may be more predictive of abuse potential than tests that yield a binary, yes-or-no classification. Several false positives also occurred with drug discrimination. With this procedure, we recommended that future research follow a standard decision-tree approach that may require examining the drug being tested for abuse potential as the training stimulus. This approach would also allow several known drugs of abuse to be tested for substitution, and this may reduce false positives. Finally, we reviewed evidence of physical dependence with stimulants and discussed the feasibility of modeling these phenomena in nonhuman animals in a rational and practical fashion. This article is part of the Special Issue entitled 'CNS Stimulants'. Copyright © 2014 Elsevier Ltd. All rights reserved.

78 FR 62427 - TRICARE; Removal of the Prohibition To Use Addictive Drugs in the Maintenance Treatment of...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-10-22

... addictive potential, for a drug of addiction when medically necessary and appropriate as part of a... assisted treatment, to include drug maintenance involving substitution of a therapeutic drug with addiction potential, for a drug of addiction, is now generally accepted by qualified professionals to be reasonable...

[Prevalence of potential drug interactions with azithromycin in Colombia, 2012-2013].

PubMed

Machado-Alba, Jorge E; Martínez-Pulgarín, Dayron F; Gómez-Suta, Daniela

2015-05-01

Objective To determine the prevalence of potential drug interactions between azithromycin and different IA and III antiarrhythmic groups in a national database of drug prescriptions in 2012-2013. Methods Retrospective study based on a population database of medicine dispensation. Data from patients who received azithromycin between January 1, 2012 and June 30, 2013 were extracted along with data from patients who received azithromycin in combination with other medications shown to cause heart arrhythmias when used concomitantly. Frequencies and proportions were established. Results 13 859 patients receiving azithromycin alone or in combination with other drugs were identified. The average time of use was 4.5 ± 0.9 days. A total of 702 patients (5.1 %) received azithromycin plus 19 other potentially risky drugs. The most frequently associated were loratadine (77.1 %), diphenhydramine (16.5 %) and amitriptyline (8.1 %). Combinations with a single drug were the most frequent (n=533, 75.9 %), predominantly azithromycin+loratadine. The maximum number of combined drugs was six (n=2, 0.3 %). Conclusions Identification of drug prescriptions through population databases is an effective way to find potential drug interactions. The frequency of potential interactions between azithromycin and other drugs is common in Colombian patients. Future research should assess the risk of occurrence of adverse cardiac events.

Potential Drug-Drug Interactions in a Cohort of Elderly, Polymedicated Primary Care Patients on Antithrombotic Treatment.

PubMed

Schneider, Katharina Luise; Kastenmüller, Kathrin; Weckbecker, Klaus; Bleckwenn, Markus; Böhme, Miriam; Stingl, Julia Carolin

2018-06-01

Drug-drug interactions (DDIs) are an important risk factor for adverse drug reactions. Older, polymedicated patients are particularly affected. Although antithrombotics have been detected as high-risk drugs for DDIs, data on older patients exposed to them are scarce. Baseline data of 365 IDrug study outpatients (≥ 60 years, use of an antithrombotic and one or more additional long-term drug) were analyzed regarding potential drug-drug interactions (pDDIs) with a clinical decision support system. Data included prescription and self-medication drugs. The prevalence of having one or more pDDI was 85.2%. The median number of alerts per patient was three (range 0-17). For 58.4% of the patients, potential severe/contraindicated interactions were detected. Antiplatelets and non-steroidal anti-inflammatory drugs (NSAIDs) showed the highest number of average pDDI alert involvements per use (2.9 and 2.2, respectively). For NSAIDs, also the highest average number of severe/contraindicated alert involvements per use (1.2) was observed. 91.8% of all pDDI involvements concerned the 25 most frequently used drug classes. 97.5% of the severe/contraindicated pDDIs were attributed to only nine different potential clinical manifestations. The most common management recommendation for severe/contraindicated pDDIs was to intensify monitoring. Number of drugs was the only detected factor significantly associated with increased number of pDDIs (p < 0.001). The findings indicate a high risk for pDDIs in older, polymedicated patients on antithrombotics. As a consequence of patients' frequently similar drug regimens, the variety of potential clinical manifestations was small. Awareness of these pDDI symptoms and the triggering drugs as well as patients' self-medication use may contribute to increased patient safety.

Use of systemic antifungals in daily clinical practice in the haematology and oncology setting: results of a prospective observational analysis.

PubMed

Metzke, Barbara; Neubauer, Werner Christian; Hieke, Stefanie; Jung, Manfred; Wäsch, Ralph; Engelhardt, Monika

2012-09-01

To assess the role of systemic antifungal drugs as well as the frequency of potential drug interactions and adverse drug events of commonly used antifungals in an unselected haematology/oncology patient cohort. A prospective analysis was performed in our haematology/oncology department between October 2006 and September 2009. Data were obtained from 250 consecutive patients who received treatment and/or prophylaxis with fluconazole (n = 191), liposomal amphotericin B (n = 105), voriconazole (n = 62), caspofungin (n = 27) and/or posaconazole (n = 22). We performed detailed reviews of patient charts and laboratory values in close cooperation with treating physicians and nursing staff and participated regularly in ward and chart rounds. Potential drug interactions were assessed using the electronic database Micromedex® 1.0 (Healthcare Series). In terms of adverse drug events, caspofungin (56%) and voriconazole (58%) revealed a slightly more favourable safety profile than liposomal amphotericin B (66%) and posaconazole (64%). We confirmed frequent nephrotoxic effects with the use of liposomal amphotericin B (20%). Regarding potential drug interactions, 97 (66%) of 147 evaluated patients were exposed to at least 1 of 22 different potentially interacting drug combinations involving systemic antifungal agents. Cyclosporine was the most prevalent potentially interacting drug in our cohort. Systemic antifungal drugs are widely used in the haematology/oncology setting and exhibit numerous potential drug interactions and adverse events in cancer patients. Our results highlight the challenges related to antifungal drugs and should valuably contribute to a safe and efficient application of this increasingly important class of drugs. Copyright © 2012 John Wiley & Sons, Ltd.

21 CFR 882.1560 - Skin potential measurement device.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Skin potential measurement device. 882.1560 Section 882.1560 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES NEUROLOGICAL DEVICES Neurological Diagnostic Devices § 882.1560 Skin potential...

Drug-Gut Microbiota Interactions: Implications for Neuropharmacology.

PubMed

Walsh, Jacinta; Griffin, Brendan T; Clarke, Gerard; Hyland, Niall P

2018-05-21

The fate and activity of drugs are frequently dictated not only by the host per se but also by the microorganisms present in the gastrointestinal tract. The gut microbiome is known to, both directly and indirectly, affect drug metabolism. More evidence now hints at the impact that drugs can have on the function and composition of the gut microbiome. Both microbiota-mediated alterations in drug metabolism and drug-mediated alterations in the gut microbiome can have beneficial or detrimental effects on the host. Greater insights into the mechanisms driving these reciprocal drug-gut microbiota interactions are needed, to guide the development of microbiome-targeted dietary or pharmacological interventions, with the potential to enhance drug efficacy or reduce drug side-effects. In this review, we explore the relationship between drugs and the gut microbiome, with a specific focus on potential mechanisms underpinning the drug-mediated alterations on the gut microbiome and the potential implications for psychoactive drugs. This article is protected by copyright. All rights reserved.

Potential drug-drug interactions and their risk factors in pediatric patients admitted to the emergency department of a tertiary care hospital in Mexico

PubMed Central

Reyes-López, Alfonso; Garduño-Espinosa, Juan; Muñoz-Hernández, Onofre

2018-01-01

Background Drug-drug interactions (DDIs) detected in a patient may not be clinically apparent (potential DDIs), and when they occur, they produce adverse drug reactions (ADRs), toxicity or loss of treatment efficacy. In pediatrics, there are only few publications assessing potential DDIs and their risk factors. There are no studies in children admitted to emergency departments (ED). The present study estimates the prevalence and describes the characteristics of potential DDIs in patients admitted to an ED from a tertiary care hospital in Mexico; in addition, potential DDI-associated risk factors are investigated. Methods A secondary analysis of data from 915 patients admitted to the ED of the Hospital Infantil de México “Federico Gómez” was conducted. The Medscape Drug Interaction Checker software was used to identify potential DDIs. The results are expressed as number of cases (%), means (95% CI) and medians (25-75th percentiles). Count data regressions for number of total and severity-stratified potential DDIs were performed adjusting for patient characteristics, number of administered drugs, days of stay, presence of ADRs and diagnoses. Results The prevalence of potential DDIs was 61%, with a median of 4 (2–8). A proportion of 0.2% of potential DDIs was “Contraindicated”, 7.5% were classified as “Serious”, 62.8% as “Significant” and 29.5% as “Minor”. Female gender, age, days of stay, number of administered drugs and diagnoses of Neoplasms (C00-D48), Congenital malformations (Q00-Q99), Diseases of the Blood, Blood-forming Organs and Immunity (D50-D89) and Diseases of the nervous system (G00-G99) were significantly associated with potential DDIs. Conclusion The prevalence of potential DDIs in the ED is high, and strategies should therefore be established to monitor patients’ safety during their stay, in addition to conducting investigations to estimate the real harm potential DDIs inflict on patients. PMID:29304072

Novel Approaches in Formulation and Drug Delivery using Contact Lenses

PubMed Central

Singh, Kishan; Nair, Anroop B; Kumar, Ashok; Kumria, Rachna

2011-01-01

The success of ocular delivery relies on the potential to enhance the drug bioavailability by controlled and extended release of drug on the eye surface. Several new approaches have been attempted to augment the competence and diminish the intrinsic side effects of existing ocular drug delivery systems. In this contest, progress has been made to develop drug-eluting contact lens using different techniques, which have the potential to control and sustain the delivery of drug. Further, the availability of novel polymers have facilitated and promoted the utility of contact lenses in ocular drug delivery. Several research groups have already explored the feasibility and potential of contact lens using conventional drugs for the treatment of periocular and intraocular diseases. Contact lenses formulated using modern technology exhibits high loading, controlled drug release, apposite thickness, water content, superior mechanical and optical properties as compared to commercial lenses. In general, this review discus various factors and approaches designed and explored for the successful delivery of ophthalmic drugs using contact lenses as drug delivery device PMID:24826007

Consumer confusion between prescription drug precautions and side effects.

PubMed

Amoozegar, Jacqueline B; Rupert, Douglas J; Sullivan, Helen W; O'Donoghue, Amie C

2017-06-01

Multiple studies have identified consumers' difficulty correctly interpreting risk information provided about prescription drugs, whether in printed format or online. This study's purpose was to explore whether consumers can distinguish between prescription drug precautions and side effects presented on brand-name drug websites. Participants (n=873) viewed fictitious drug websites that presented both precautions and side effects for one of four drugs, and they completed a survey assessing recall and comprehension. We coded open-ended recall data to identify whether drug precautions were mentioned and, if so, how they were interpreted. Approximately 15% of participants mentioned at least one drug precaution. The majority (59.7%) misinterpreted precautions as potential side effects. Participants who misinterpreted precautions rated the drugs as significantly more likely to cause side effects than participants who accurately interpreted the precautions. Age, education, literacy, and other factors did not appear to predict precaution interpretation. At least some consumers are likely to interpret precautions on drug websites as potential side effects, which might affect consumer preferences, treatment decisions, and medication safety. Healthcare providers should be aware of this potential confusion, assess patients' understanding of precautions and potential side effects, and address any misunderstandings. Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.

Drug efficiency: a new concept to guide lead optimization programs towards the selection of better clinical candidates.

PubMed

Braggio, Simone; Montanari, Dino; Rossi, Tino; Ratti, Emiliangelo

2010-07-01

As a result of their wide acceptance and conceptual simplicity, drug-like concepts are having a major influence on the drug discovery process, particularly in the selection of the 'optimal' absorption, distribution, metabolism, excretion and toxicity and physicochemical parameters space. While they have an undisputable value when assessing the potential of lead series or in evaluating inherent risk of a portfolio of drug candidates, they result much less useful in weighing up compounds for the selection of the best potential clinical candidate. We introduce the concept of drug efficiency as a new tool both to guide the drug discovery program teams during the lead optimization phase and to better assess the developability potential of a drug candidate.

A temporal interestingness measure for drug interaction signal detection in post-marketing surveillance.

PubMed

Ji, Yanqing; Ying, Hao; Tran, John; Dews, Peter; Mansour, Ayman; Massanari, R Michael

2014-01-01

Drug-drug interactions (DDIs) can result in serious consequences, including death. Existing methods for identifying potential DDIs in post-marketing surveillance primarily rely on the FDA's (Food and Drug Administration) spontaneous reporting system. However, this system suffers from severe underreporting, which makes it difficult to timely collect enough valid cases for statistical analysis. In this paper, we study how to signal potential DDIs using patient electronic health data. Specifically, we focus on discovery of potential DDIs by analyzing the temporal relationships between the concurrent use of two drugs of interest and the occurrences of various symptoms using novel temporal association mining techniques we developed. A new interestingness measure called functional temporal interest was proposed to assess the degrees of temporal association between two drugs of interest and each symptom. The measure was employed to screen potential DDIs from 21,405 electronic patient cases retrieved from the Veterans Affairs Medical Center in Detroit, Michigan. The preliminary results indicate the usefulness of our method in finding potential DDIs for further analysis (e.g., epidemiology study) and investigation (e.g., case review) by drug safety professionals.

Prevalence of the prescription of potentially interacting drugs.

PubMed

Tragni, Elena; Casula, Manuela; Pieri, Vasco; Favato, Giampiero; Marcobelli, Alberico; Trotta, Maria Giovanna; Catapano, Alberico Luigi

2013-01-01

The use of multiple medications is becoming more common, with a correspondingly increased risk of untoward effects and drug-related morbidity and mortality. We aimed at estimating the prevalence of prescription of relevant potentially interacting drugs and at evaluating possible predictors of potentially interacting drug exposure. We retrospectively analyzed data on prescriptions dispensed from January 2004 to August 2005 to individuals of two Italian regions with a population of almost 2.1 million individuals. We identified 27 pairs of potentially interacting drugs by examining clinical relevance, documentation, and volume of use in Italy. Subjects who received at least one prescription of both drugs were selected. Co-prescribing denotes "two prescriptions in the same day", and concomitant medication "the prescription of two drugs with overlapping coverage". A logistic regression analysis was conducted to examine the predictors of potential Drug-Drug Interaction (pDDIs). 957,553 subjects (45.3% of study population) were exposed to at least one of the drugs/classes of the 27 pairs. Overall, pDDIs occurred 2,465,819 times. The highest rates of concomitant prescription and of co-prescription were for ACE inhibitors+NSAIDs (6,253 and 4,621/100,000 plan participants). Considering concomitance, the male/female ratio was <1 in 17/27 pairs (from 0.31 for NSAIDs-ASA+SSRI to 0.74 for omeprazole+clopidogrel). The mean age was lowest for methotrexate pairs (+omeprazole, 59.9 years; +NSAIDs-ASA, 59.1 years) and highest for digoxin+verapamil (75.4 years). In 13/27 pairs, the mean ages were ≥70 years. On average, subjects involved in pDDIs received ≥10 drugs. The odds of exposure were more frequently higher for age ≥65 years, males, and those taking a large number of drugs. A substantial number of clinically important pDDIs were observed, particularly among warfarin users. Awareness of the most prevalent pDDIs could help practitioners in preventing concomitant use, resulting in a better quality of drug prescription and potentially avoiding unwanted side effects.

Why trash don't pass? pharmaceutical licensing and safety performance of drugs.

PubMed

Banerjee, Tannista; Nayak, Arnab

2017-01-01

This paper examines how asymmetric information in pharmaceutical licensing affects the safety standards of licensed drugs. Pharmaceutical companies often license potential drug molecules at different stages of drug development from other pharmaceutical or biotechnology companies and complete the remaining of research stages before submitting the new drug application(NDA) to the food and drug administration. The asymmetric information associated with the quality of licensed molecules might result in the molecules which are less likely to succeed to be licensed out, while those with greater potential of success being held internally for development. We identify the NDAs submitted between 1993 and 2004 where new molecular entities were acquired through licensing. Controlling for other drug area specific and applicant firm specific factors, we investigate whether drugs developed with licensed molecules face higher probability of safety based recall and ultimate withdrawal from the market than drugs developed internally. Results suggest the opposite of Akerlof's (Q J Econ 84:488-500, 1970) lemons problem. Licensed molecules rather have less probability of facing safety based recalls and ultimate withdrawal from the market comparing to internally developed drug molecules. This suggests that biotechnology and small pharmaceutical firms specializing in pharmaceutical research are more efficient in developing good potential molecules because of their concentrated research. Biotechnology firms license out good potential molecules because it increases their market value and reputation. In addition, results suggest that both the number of previous approved drugs in the disease area, and also the applicant firms' total number of previous approvals in all disease areas reduce the probability that an additional approved drug in the same drug area will potentially be harmful.

Systems biology-embedded target validation: improving efficacy in drug discovery.

PubMed

Vandamme, Drieke; Minke, Benedikt A; Fitzmaurice, William; Kholodenko, Boris N; Kolch, Walter

2014-01-01

The pharmaceutical industry is faced with a range of challenges with the ever-escalating costs of drug development and a drying out of drug pipelines. By harnessing advances in -omics technologies and moving away from the standard, reductionist model of drug discovery, there is significant potential to reduce costs and improve efficacy. Embedding systems biology approaches in drug discovery, which seek to investigate underlying molecular mechanisms of potential drug targets in a network context, will reduce attrition rates by earlier target validation and the introduction of novel targets into the currently stagnant market. Systems biology approaches also have the potential to assist in the design of multidrug treatments and repositioning of existing drugs, while stratifying patients to give a greater personalization of medical treatment. © 2013 Wiley Periodicals, Inc.

The drug-drug interaction potential of antiviral agents for the treatment of chronic hepatitis C infection.

PubMed

Garrison, Kimberly L; German, Polina; Mogalian, Erik; Mathias, Anita

2018-04-25

Several safe and highly-effective directly-acting antiviral drugs for chronic hepatitis C virus (HCV) have been developed and greatly increase the number of treatment options available to successfully treat HCV infection. However, as treatment regimens contain at least two drugs (e.g., sofosbuvir with daclatasvir, simeprevir, ledipasvir, or velpatasvir; elbasvir and grazoprevir) and up to five drugs (ombitasvir/paritaprevir/ritonavir+dasabuvir+ribavirin), the potential for drug-drug interactions (DDI) becomes an important consideration for HCV-infected individuals with comorbidities that require concomitant medications, such as HIV/HCV co-infection or immunosuppression following liver transplantation. This review details the pharmacokinetics and DDI potential of approved DAAs for the treatment of HCV infection. The American Society for Pharmacology and Experimental Therapeutics.

A systematic study of chemogenomics of carbohydrates.

PubMed

Gu, Jiangyong; Luo, Fang; Chen, Lirong; Yuan, Gu; Xu, Xiaojie

2014-03-04

Chemogenomics focuses on the interactions between biologically active molecules and protein targets for drug discovery. Carbohydrates are the most abundant compounds in natural products. Compared with other drugs, the carbohydrate drugs show weaker side effects. Searching for multi-target carbohydrate drugs can be regarded as a solution to improve therapeutic efficacy and safety. In this work, we collected 60 344 carbohydrates from the Universal Natural Products Database (UNPD) and explored the chemical space of carbohydrates by principal component analysis. We found that there is a large quantity of potential lead compounds among carbohydrates. Then we explored the potential of carbohydrates in drug discovery by using a network-based multi-target computational approach. All carbohydrates were docked to 2389 target proteins. The most potential carbohydrates for drug discovery and their indications were predicted based on a docking score-weighted prediction model. We also explored the interactions between carbohydrates and target proteins to find the pathological networks, potential drug candidates and new indications.

Potential drug delivery approaches for XFS-associated and XFS-associated glaucoma.

PubMed

Kulkarni, Shreya S; Kompella, Uday B

2014-01-01

Key tissue targets in treating exfoliation syndrome (XFS) and the associated glaucoma include lens, iris, and ciliary body, which produce the exfoliative material, and the trabecular meshwork, which may be impaired by the exfoliative material. In addition to antiglaucoma drug therapy, strategies for treating the disease include approaches for preventing formation of exfoliative material as well as those aimed at digesting exfoliative material. A variety of drug molecules including small molecules, protein drugs, and nucleic acids are potential candidates for treating XFS. Potential drug classes include antioxidants, lysyl oxidase-like 1 enhancers, antifibrotics, anti-inflammatory agents, proteases, and chaperones. However, the delivery of these agents to the target tissues in the anterior segment is hindered by protective static and dynamic barriers of the eye. Thus, unique drug delivery approaches are needed for each drug type (small molecules, proteins, and nucleic acids). In addition, there is a need for sustaining drug therapy for treating XFS, which can potentially be addressed by using nanoparticles, microparticles, implants, and contact lens delivery systems. This article provides an overview of drug delivery challenges and opportunities in treating XFS with the focus being on nanomedicines.

Content analysis of false and misleading claims in television advertising for prescription and nonprescription drugs.

PubMed

Faerber, Adrienne E; Kreling, David H

2014-01-01

False and misleading advertising for drugs can harm consumers and the healthcare system, and previous research has demonstrated that physician-targeted drug advertisements may be misleading. However, there is a dearth of research comparing consumer-targeted drug advertising to evidence to evaluate whether misleading or false information is being presented in these ads. To compare claims in consumer-targeted television drug advertising to evidence, in order to evaluate the frequency of false or misleading television drug advertising targeted to consumers. A content analysis of a cross-section of television advertisements for prescription and nonprescription drugs aired from 2008 through 2010. We analyzed commercial segments containing prescription and nonprescription drug advertisements randomly selected from the Vanderbilt Television News Archive, a census of national news broadcasts. For each advertisement, the most-emphasized claim in each ad was identified based on claim iteration, mode of communication, duration and placement. This claim was then compared to evidence by trained coders, and categorized as being objectively true, potentially misleading, or false. Potentially misleading claims omitted important information, exaggerated information, made lifestyle associations, or expressed opinions. False claims were factually false or unsubstantiated. Of the most emphasized claims in prescription (n = 84) and nonprescription (n = 84) drug advertisements, 33 % were objectively true, 57 % were potentially misleading and 10 % were false. In prescription drug ads, there were more objectively true claims (43 %) and fewer false claims (2 %) than in nonprescription drug ads (23 % objectively true, 7 % false). There were similar numbers of potentially misleading claims in prescription (55 %) and nonprescription (61 %) drug ads. Potentially misleading claims are prevalent throughout consumer-targeted prescription and nonprescription drug advertising on television. These results are in conflict with proponents who argue the social value of drug advertising is found in informing consumers about drugs.

Functionally engineered nanosized particles in pharmaceutics: improved oral delivery of poorly water-soluble drugs.

PubMed

Ozeki, Tetsuya; Tagami, Tatsuaki

2013-01-01

The development of drug nanoparticles has attracted substantial attention because of their potential to improve the dissolution rate and oral availability of poorly water-soluble drugs. This review summarizes the recent articles that discussed nanoparticle-based oral drug delivery systems. The preparation methods were categorized as top-down and bottom-up methods, which are common methods for preparing drug nanoparticles. In addition, methods of handling drug nanoparticles (e.g., one-step preparation of nanocomposites which are microparticles containing drug nanoparticles) were introduced for the effective preservation of drug nanoparticles. The carrier-based preparation of drug nanoparticles was also introduced as a potentially promising oral drug delivery system.

Identifying novel drug indications through automated reasoning.

PubMed

Tari, Luis; Vo, Nguyen; Liang, Shanshan; Patel, Jagruti; Baral, Chitta; Cai, James

2012-01-01

With the large amount of pharmacological and biological knowledge available in literature, finding novel drug indications for existing drugs using in silico approaches has become increasingly feasible. Typical literature-based approaches generate new hypotheses in the form of protein-protein interactions networks by means of linking concepts based on their cooccurrences within abstracts. However, this kind of approaches tends to generate too many hypotheses, and identifying new drug indications from large networks can be a time-consuming process. In this work, we developed a method that acquires the necessary facts from literature and knowledge bases, and identifies new drug indications through automated reasoning. This is achieved by encoding the molecular effects caused by drug-target interactions and links to various diseases and drug mechanism as domain knowledge in AnsProlog, a declarative language that is useful for automated reasoning, including reasoning with incomplete information. Unlike other literature-based approaches, our approach is more fine-grained, especially in identifying indirect relationships for drug indications. To evaluate the capability of our approach in inferring novel drug indications, we applied our method to 943 drugs from DrugBank and asked if any of these drugs have potential anti-cancer activities based on information on their targets and molecular interaction types alone. A total of 507 drugs were found to have the potential to be used for cancer treatments. Among the potential anti-cancer drugs, 67 out of 81 drugs (a recall of 82.7%) are indeed known cancer drugs. In addition, 144 out of 289 drugs (a recall of 49.8%) are non-cancer drugs that are currently tested in clinical trials for cancer treatments. These results suggest that our method is able to infer drug indications (original or alternative) based on their molecular targets and interactions alone and has the potential to discover novel drug indications for existing drugs.

Recent Advancement and Technological Aspects of Pulsatile Drug Delivery System - A Laconic Review.

PubMed

Pandit, Vinay; Kumar, Ajay; Ashawat, Mahendra S; Verma, Chander P; Kumar, Pravin

2017-01-01

Pulsatile drug delivery system (PDDS) shows potential significance in the field of drug delivery to release the maximum amount of drug at a definite site and at specific time. PDDS are mainly time controlled delivery devices having a definite pause period for drug release, which is not affected by acidity, alkalinity, motility and enzymes present in the gastrointestinal tract. Pulsatile medication possess the potential to deliver the drugs in the therapy of diseases where drug dose is essential during sleep, drugs having greater first pass metabolism and absorption at precise location in digestive tract. The review article, discuss the general concepts, marketed formulations and patents or any other recent advancement in pulsatile release technology. It also highlights on diseases requiring therapy by pulsatile release, various researches on herbal pulsatile formulations and quality control aspects of PDDS. Pulsatile medication possess the potential to deliver the drugs in the therapy of diseases where drug dose is essential during sleep, drugs having greater first pass metabolism and absorption at precise location in digestive tract. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

75 FR 32952 - Draft Guidance for Industry and Food and Drug Administration Staff; “‘Harmful and Potentially...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-06-10

... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2010-D-0281] Draft Guidance for Industry and Food and Drug Administration Staff; ```Harmful and Potentially Harmful... Food, Drug, and Cosmetic Act.'' This draft guidance provides written guidance to industry and FDA staff...

The Influence of Drug Testing Attributes, Participation, and Personality on Potential Applicant's Attitudes and Job Pursuit Intentions.

ERIC Educational Resources Information Center

Stoffey, Ronald W.

Researchers are increasingly aware of the importance of job applicants' reactions to the personnel selection process. This study examines three variables in connection with drug testing policies: (1) the potential applicant's reactions to two different drug testing policies which varied in terms of drug policy characteristics and their impact on…

The Potential of Silk and Silk-Like Proteins as Natural Mucoadhesive Biopolymers for Controlled Drug Delivery.

PubMed

Brooks, Amanda E

2015-01-01

Drug delivery across mucus membranes is a particularly effective route of administration due to the large surface area. However, the unique environment present at the mucosa necessitates altered drug formulations designed to (1) deliver sensitive biologic molecules, (2) promote intimate contact between the mucosa and the drug, and (3) prolong the drug's local residence time. Thus, the pharmaceutical industry has an interest in drug delivery systems formulated around the use of mucoadhesive polymers. Mucoadhesive polymers, both synthetic and biological, have a history of use in local drug delivery. Prominently featured in the literature are chitosan, alginate, and cellulose derivatives. More recently, silk and silk-like derivatives have been explored for their potential as mucoadhesive polymers. Both silkworms and spiders produce sticky silk-like glue substances, sericin and aggregate silk respectively, that may prove an effective, natural matrix for drug delivery to the mucosa. This mini review will explore the potential of silk and silk-like derivatives as a biocompatible mucoadhesive polymer matrix for local controlled drug delivery.

Nanomedicine in pulmonary delivery

PubMed Central

Mansour, Heidi M; Rhee, Yun-Seok; Wu, Xiao

2009-01-01

The lung is an attractive target for drug delivery due to noninvasive administration via inhalation aerosols, avoidance of first-pass metabolism, direct delivery to the site of action for the treatment of respiratory diseases, and the availability of a huge surface area for local drug action and systemic absorption of drug. Colloidal carriers (ie, nanocarrier systems) in pulmonary drug delivery offer many advantages such as the potential to achieve relatively uniform distribution of drug dose among the alveoli, achievement of improved solubility of the drug from its own aqueous solubility, a sustained drug release which consequently reduces dosing frequency, improves patient compliance, decreases incidence of side effects, and the potential of drug internalization by cells. This review focuses on the current status and explores the potential of colloidal carriers (ie, nanocarrier systems) in pulmonary drug delivery with special attention to their pharmaceutical aspects. Manufacturing processes, in vitro/in vivo evaluation methods, and regulatory/toxicity issues of nanomedicines in pulmonary delivery are also discussed. PMID:20054434

The potential biomarkers of drug addiction: proteomic and metabolomics challenges.

PubMed

Wang, Lv; Wu, Ning; Zhao, Tai-Yun; Li, Jin

2016-07-28

Drug addiction places a significant burden on society and individuals. Proteomics and metabolomics approaches pave the road for searching potential biomarkers to assist the diagnosis and treatment. This review summarized putative drug addiction-related biomarkers in proteomics and metabolomics studies and discussed challenges and prospects in future studies. Alterations of several hundred proteins and metabolites were reported when exposure to abused drug, which enriched in energy metabolism, oxidative stress response, protein modification and degradation, synaptic function and neurotrasmission, etc. Hsp70, peroxiredoxin-6 and α- and β-synuclein, as well as n-methylserotonin and purine metabolites, were promising as potential biomarker for drug addiction.

Natural melanin: a potential pH-responsive drug release device.

PubMed

Araújo, Marco; Viveiros, Raquel; Correia, Tiago R; Correia, Ilídio J; Bonifácio, Vasco D B; Casimiro, Teresa; Aguiar-Ricardo, Ana

2014-07-20

This work proposes melanin as a new nanocarrier for pH-responsive drug release. Melanin is an abundant natural polymer that can be easily extracted from cuttlefish as nanoparticles with a suitable size range for drug delivery. However, despite its high potentiality, the application of this biopolymer in the pharmaceutical and biomedical fields is yet to be explored. Herein, melanin nanoparticles were impregnated with metronidazole, chosen as model antibiotic drug, using supercritical carbon dioxide. The drug release profile was investigated at acidic and physiologic pH, and the dominant mechanism was found to follow a non-Fickian transport. Drug release from melanin shows a strong pH dependency, which allied to its biocompatibility and lack of cytotoxicity envisages its potential application as nanocarrier in formulations for colon and intestine targeted drug delivery. Copyright © 2014 Elsevier B.V. All rights reserved.

National Institute on Drug Abuse symposium report: drugs of abuse, dopamine, and HIV-associated neurocognitive disorders/HIV-associated dementia.

PubMed

Purohit, Vishnudutt; Rapaka, Rao; Frankenheim, Jerry; Avila, Albert; Sorensen, Roger; Rutter, Joni

2013-04-01

The National Institute on Drug Abuse organized a symposium on drugs of abuse, dopamine, and HIV-associated neurocognitive disorders (HAND)/HIV-associated dementia (HAD) in Rockville, Maryland, October 4, 2011. The purpose of this symposium was to evaluate the potential role of dopamine in the potentiation of HAND/HAD by drugs of abuse. A summary of the symposium has been presented in this report.

SemaTyP: a knowledge graph based literature mining method for drug discovery.

PubMed

Sang, Shengtian; Yang, Zhihao; Wang, Lei; Liu, Xiaoxia; Lin, Hongfei; Wang, Jian

2018-05-30

Drug discovery is the process through which potential new medicines are identified. High-throughput screening and computer-aided drug discovery/design are the two main drug discovery methods for now, which have successfully discovered a series of drugs. However, development of new drugs is still an extremely time-consuming and expensive process. Biomedical literature contains important clues for the identification of potential treatments. It could support experts in biomedicine on their way towards new discoveries. Here, we propose a biomedical knowledge graph-based drug discovery method called SemaTyP, which discovers candidate drugs for diseases by mining published biomedical literature. We first construct a biomedical knowledge graph with the relations extracted from biomedical abstracts, then a logistic regression model is trained by learning the semantic types of paths of known drug therapies' existing in the biomedical knowledge graph, finally the learned model is used to discover drug therapies for new diseases. The experimental results show that our method could not only effectively discover new drug therapies for new diseases, but also could provide the potential mechanism of action of the candidate drugs. In this paper we propose a novel knowledge graph based literature mining method for drug discovery. It could be a supplementary method for current drug discovery methods.

Important drug-nutrient interactions.

PubMed

Mason, Pamela

2010-11-01

Drugs have the potential to interact with nutrients potentially leading to reduced therapeutic efficacy of the drug, nutritional risk or increased adverse effects of the drug. Despite significant interest in such interactions going back to over more than 40 years, the occurrence and clinical significance of many drug-nutrient interactions remains unclear. However, interactions involving drugs with a narrow therapeutic margin such as theophylline and digoxin and those that require careful blood monitoring such as warfarin are likely to be those of clinical significance. Drugs can affect nutrition as a result of changes in appetite and taste as well as having an influence on absorption or metabolism of nutrients. Moreover, foods and supplements can also interact with drugs, of which grapefruit juice and St John's wort are key examples. Significant numbers of people take both supplements and medication and are potentially at risk from interactions. Professionals, such as pharmacists, dietitians, nurses and doctors, responsible for the care of patients should therefore check whether supplements are being taken, while for researchers this is an area worthy of significant further study, particularly in the context of increasingly complex drug regimens and the plethora of new drugs.

Analysis of drug use in institutionalized individuals with intellectual disability and tube feeding.

PubMed

Joos, Elke; Mehuys, Els; Remon, Jean Paul; Van Winckel, Myriam; Boussery, Koen

2016-04-01

Little is known about the medication used by people with intellectual disabilities (ID) and enteral feeding tube (EFT). However, in light of the complexity associated with drug administration through EFT, data on medication use in this population may be helpful in the development of practical guidelines and staff training initiatives. A cross-sectional, observational study was conducted in six Belgian residential care facilities (RCFs) for individuals with ID. Anonymized medication records of all residents receiving chronic medication through EFT were collected (n = 156). All chronic drugs were categorized according to the ATC classification, and medication records were checked for potential major drug-drug interactions (DDI). The 156 residents used a total of 1029 chronic drugs via EFT, with a median of six drugs per resident (range 1-14). A total of 148 different drug molecules were identified, belonging to 38 main ATC therapeutic groups (ATC level 2). Antiepileptics, drugs for constipation and drugs for acid-related disorders were the most frequently used groups. Seventy-four of the 156 screened medication records (47%) contained at least one potential DDI; in total, 116 potential interactions were identified, which represent 38 different interacting drug pairs. This study describes medication use through EFT among people with ID in Belgian RCFs, with antiepileptics being the most frequently used group. Our study also demonstrated that a high number of drugs is administered through EFT, and that the number of potential DDIs is high. These observations warrant an increased attention for drug administration through the EFT in individuals with ID.

Potential savings from an evidence-based consumer-oriented public education campaign on prescription drugs.

PubMed

Donohue, Julie M; Fischer, Michael A; Huskamp, Haiden A; Weissman, Joel S

2008-10-01

To estimate potential savings associated with the Consumer Reports Best Buy Drugs program, a national educational program that provides consumers with price and effectiveness information on prescription drugs. National data on 2006 prescription sales and retail prices paid for angiotensin-converting enzyme inhibitors (ACEIs), β-blockers, calcium channel blockers, and 3-hydroxy-3-methylglutaryl coenzyme A (HMG-coA) reductase inhibitors (statins). We converted national data on aggregate unit sales of drugs in the four classes to defined daily doses (DDD) and estimated a range of potential savings from generic and therapeutic substitution. We estimated that $2.76 billion, or 7.83 percent of sales, could be saved if use of the drugs recommended by the educational program was increased. The recommended drugs' prices were 15-65 percent lower per DDD than their therapeutic alternatives. The majority (57.4 percent) of potential savings would be achieved through therapeutic substitution. Substantial savings can be achieved through greater use of comparatively effective and lower cost drugs recommended by a national consumer education program. However, barriers to dissemination of consumer-oriented drug information must be addressed before savings can be realized. © Health Research and Educational Trust.

[Prescription of Psychotropic Drugs with Potentially Restraining Effect: An Analysis of Care Need Assessment Data by MDK Bayern].

PubMed

Ezzat, Nadja; Müller-Barna, Peter; Krüger, Cornelia; Randzio, Ottilie

2018-06-12

Physical restraints in home care and residential care settings in the form of restraining devices have been reduced in the last years. Now psychotropic drugs with sedating and thus potentially restraining effect are of increasing interest. The objective of this study was to describe prescription of psychotropic drugs for insurants in need of care and factors influencing such prescription. On the "Annual Word Elder Abuse Awareness Day", the Medical Service of the Statutory Health Insurance undertook a reference day analysis. During the regular assessment of care needs, distribution of psychotropic drugs according to relevant aspects of care were analyzed. Additionally, prescribed drugs were rated with respect to inappropriateness for elder people according to the Priscus list. Data on 706 insured people were analyzed; 43% of them received at least one psychotropic drug as a regular medication, 22% of them at least one potentially sedating drug. According to the Priscus list, 16% of prescribed drugs were identified as potentially inappropriate for elder people. Significant correlation was shown between prescription of psychotropic drugs and location of assessment, care need, diagnosis and the degree of limitation in daily living skills. This paper supports results in literature and emphasizes the discrepancy between restraint in the prescription of psychotropic drugs as advised by experts and distribution of these drugs in reality. Further studies analyzing the quality of prescriptions taking into consideration the individual circumstances of patients are desirable. © Georg Thieme Verlag KG Stuttgart · New York.

Computerized pharmacy surveillance and alert system for drug-related problems.

PubMed

Ferrández, O; Urbina, O; Grau, S; Mateu-de-Antonio, J; Marin-Casino, M; Portabella, J; Mojal, S; Riu, M; Salas, E

2017-04-01

Because of the impact of drug-related problems (DRPs) on morbidity and mortality, there is a need for computerized strategies to increase drug safety. The detection and identification of the causes of potential DRPs can be facilitated by the incorporation of a pharmacy warning system (PWS) in the computerized prescriber order entry (CPOE) and its application in the routine validation of inpatient drug therapy. A limited number of studies have evaluated a clinical decision support system to monitor drug treatment. Most of these applications have utilized a small range of drugs with alerts and/or types of alert. The objective of this study was to describe the implementation of a PWS integrated in the electronic medical record (EMR). The PWS was developed in 2003-2004. Pharmacological information to generate drug alerts was entered on demographic data, drug dosage, laboratory tests related to the prescribed drug and drug combinations (interactions, duplications and necessary combinations). The PWS was applied in the prescription reviews conducted in patients admitted to the hospital in 2012. Information on 83% of the drugs included in the pharmacopeia was introduced into the PWS, allowing detection of 2808 potential DRPs, representing 79·1% of all potential DRPs detected during the study period. Twenty per cent of PWS DRPs were clinically relevant, requiring pharmacist intervention. The PWS detected most potential DRPs, thus increasing inpatient safety. The detection ability of the PWS was higher than that reported for other tools described in the literature. © 2017 John Wiley & Sons Ltd.

Blocking Plasmodium falciparum Malaria Transmission with Drugs: The Gametocytocidal and Sporontocidal Properties of Current and Prospective Antimalarials

PubMed Central

Kiszewski, Anthony E.

2011-01-01

Drugs that kill or inhibit the sexual stages of Plasmodium could potentially amplify or synergize the impact of other interventions by blocking transmission to mosquitoes. Primaquine and other 8-aminoquinolines have long offered such potential, but safety and other concerns have limited their use. Although transmission-blocking properties are not often a priority of drug discovery efforts, a number of interesting gametocytocidal and/or sporontocidal drug candidates have emerged in recent years. Some still bear significant technical and safety concerns, while others have passed clinical trials and are on the verge of entering the antimalarial armamentarium. Recent advances in our knowledge of gametocyte differentiation, gametogenesis and sporogony have also led to the identification of a large array of potential new targets for drugs that might interfere with malaria transmission. This review examines the properties of existing and prospective drugs, mechanisms of action, counter-indications and their potential role in regional malaria elimination efforts.

Predicting when biliary excretion of parent drug is a major route of elimination in humans.

PubMed

Hosey, Chelsea M; Broccatelli, Fabio; Benet, Leslie Z

2014-09-01

Biliary excretion is an important route of elimination for many drugs, yet measuring the extent of biliary elimination is difficult, invasive, and variable. Biliary elimination has been quantified for few drugs with a limited number of subjects, who are often diseased patients. An accurate prediction of which drugs or new molecular entities are significantly eliminated in the bile may predict potential drug-drug interactions, pharmacokinetics, and toxicities. The Biopharmaceutics Drug Disposition Classification System (BDDCS) characterizes significant routes of drug elimination, identifies potential transporter effects, and is useful in understanding drug-drug interactions. Class 1 and 2 drugs are primarily eliminated in humans via metabolism and will not exhibit significant biliary excretion of parent compound. In contrast, class 3 and 4 drugs are primarily excreted unchanged in the urine or bile. Here, we characterize the significant elimination route of 105 orally administered class 3 and 4 drugs. We introduce and validate a novel model, predicting significant biliary elimination using a simple classification scheme. The model is accurate for 83% of 30 drugs collected after model development. The model corroborates the observation that biliarily eliminated drugs have high molecular weights, while demonstrating the necessity of considering route of administration and extent of metabolism when predicting biliary excretion. Interestingly, a predictor of potential metabolism significantly improves predictions of major elimination routes of poorly metabolized drugs. This model successfully predicts the major elimination route for poorly permeable/poorly metabolized drugs and may be applied prior to human dosing.

Oral administration of drugs with hypersensitivity potential induces germinal center hyperplasia in secondary lymphoid organ/tissue in Brown Norway rats, and this histological lesion is a promising candidate as a predictive biomarker for drug hypersensitivity occurrence in humans

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tamura, Akitoshi, E-mail: akitoshi-tamura@ds-pharma.co.jp; Miyawaki, Izuru; Yamada, Toru

It is important to evaluate the potential of drug hypersensitivity as well as other adverse effects during the preclinical stage of the drug development process, but validated methods are not available yet. In the present study we examined whether it would be possible to develop a new predictive model of drug hypersensitivity using Brown Norway (BN) rats. As representative drugs with hypersensitivity potential in humans, phenytoin (PHT), carbamazepine (CBZ), amoxicillin (AMX), and sulfamethoxazole (SMX) were orally administered to BN rats for 28 days to investigate their effects on these animals by examinations including observation of clinical signs, hematology, determination ofmore » serum IgE levels, histology, and flow cytometric analysis. Skin rashes were not observed in any animals treated with these drugs. Increases in the number of circulating inflammatory cells and serum IgE level did not necessarily occur in the animals treated with these drugs. However, histological examination revealed that germinal center hyperplasia was commonly induced in secondary lymphoid organs/tissues in the animals treated with these drugs. In cytometric analysis, changes in proportions of lymphocyte subsets were noted in the spleen of the animals treated with PHT or CBZ during the early period of administration. The results indicated that the potential of drug hypersensitivity was identified in BN rat by performing histological examination of secondary lymphoid organs/tissues. Data obtained herein suggested that drugs with hypersensitivity potential in humans gained immune reactivity in BN rat, and the germinal center hyperplasia induced by administration of these drugs may serve as a predictive biomarker for drug hypersensitivity occurrence. - Highlights: • We tested Brown Norway rats as a candidate model for predicting drug hypersensitivity. • The allergic drugs did not induce skin rash, whereas D-penicillamine did so in the rats. • Some of allergic drugs increased inflammatory cells and IgE, but the others did not. • The allergic drugs commonly induced germinal center hyperplasia in lymphoid tissues. • Some of these allergic drugs transiently increased CD4{sup +}CD25{sup +} T cells in the spleen.« less

Drug sampling in dermatology.

PubMed

Reid, Erika E; Alikhan, Ali; Brodell, Robert T

2012-01-01

The use of drug samples in a dermatology clinic is controversial. Drug samples are associated with influencing physician prescribing patterns often toward costlier drugs, increasing health care costs, increasing waste, inducing potential conflicts of interest, and decreasing the quality of patient education. On the other hand, they have the potential to help those in financial need, to improve adherence and convenience, and to expose patients to better drugs. Although some academic centers have banned drug samples altogether, many academic and private practices continue to distribute drug samples. Given the controversy of the topic, physicians who wish to distribute drug samples must do so in an ethical manner. We believe, when handled properly, drug sampling can be used in an ethical manner. Copyright © 2012 Elsevier Inc. All rights reserved.

Adverse drug events and medication problems in "Hospital at Home" patients.

PubMed

Mann, Elizabeth; Zepeda, Orlando; Soones, Tacara; Federman, Alex; Leff, Bruce; Siu, Albert; Boockvar, Kenneth

2018-03-26

"Hospital at Home(HaH)" programs provide an alternative to traditional hospitalization. However, the incidence of adverse drug events in these programs is unknown. This study describes adverse drug events and potential adverse drug events in a new HaH program. We examined the charts of the first 50 patients admitted. We found 45 potential adverse drug events and 14 adverse drug events from admission to 30 days after HaH discharge. None of the adverse drug events were severe. Some events, like problems with medication administration, may be unique to the hospital at home setting. Monitoring for adverse drug events is feasible and important for hospital at home programs.

[Potential antimicrobial drug interactions in clinical practice: consequences of polypharmacy and multidrug resistance].

PubMed

Martínez-Múgica, Cristina

2015-12-01

Polypharmacy is a growing problem nowadays, which can increase the risk of potential drug interactions, and result in a loss of effectiveness. This is particularly relevant to the anti-infective therapy, especially when infection is produced by resistant bacteria, because therapeutic options are limited and interactions can cause treatment failure. All antimicrobial prescriptions were retrospectively reviewed during a week in the Pharmacy Department, in order to detect potential drug-interactions and analysing their clinical significance. A total of 314 antimicrobial prescriptions from 151 patients were checked. There was at least one potential interaction detected in 40% of patients, being more frequent and severe in those infected with multidrug-resistant microorganisms. Drugs most commonly involved were quinolones, azoles, linezolid and vancomycin. Potential drug interactions with antimicrobial agents are a frequent problem that can result in a loss of effectiveness. This is why they should be detected and avoided when possible, in order to optimize antimicrobial therapy, especially in case of multidrug resistant infections.

Exploring the Potential of Direct-To-Consumer Genomic Test Data for Predicting Adverse Drug Events.

PubMed

Zhang, Patrick M; Sarkar, Indra Neil

2018-01-01

Recent technological advancements in genetic testing and the growing accessibility of public genomic data provide researchers with a unique avenue to approach personalized medicine. This feasibility study examined the potential of direct-to-consumer (DTC) genomic tests (focusing on 23andMe) in research and clinical applications. In particular, we combined population genetics information from the Personal Genome Project with adverse event reports from AEOLUS and pharmacogenetic information from PharmGKB. Primarily, associations between drugs based on co-occurring genetic variations and associations between variants and adverse events were used to assess the potential for leveraging single nucleotide polymorphism information from 23andMe. The results of this study suggest potential clinical uses of DTC tests in light of potential drug interactions. Furthermore, the results suggest great potential for analyzing associations at a population level to facilitate knowledge discovery in the realm of predicting adverse drug events.

Potential drug-drug and drug-disease interactions in well-functioning community-dwelling older adults.

PubMed

Hanlon, J T; Perera, S; Newman, A B; Thorpe, J M; Donohue, J M; Simonsick, E M; Shorr, R I; Bauer, D C; Marcum, Z A

2017-04-01

There are few studies examining both drug-drug and drug-disease interactions in older adults. Therefore, the objective of this study was to describe the prevalence of potential drug-drug and drug-disease interactions and associated factors in community-dwelling older adults. This cross-sectional study included 3055 adults aged 70-79 without mobility limitations at their baseline visit in the Health Aging and Body Composition Study conducted in the communities of Pittsburgh PA and Memphis TN, USA. The outcome factors were potential drug-drug and drug-disease interactions as per the application of explicit criteria drawn from a number of sources to self-reported prescription and non-prescription medication use. Over one-third of participants had at least one type of interaction. Approximately one quarter (25·1%) had evidence of had one or more drug-drug interactions. Nearly 10·7% of the participants had a drug-drug interaction that involved a non-prescription medication. % The most common drug-drug interaction was non-steroidal anti-inflammatory drugs (NSAIDs) affecting antihypertensives. Additionally, 16·0% had a potential drug-disease interaction with 3·7% participants having one involving non-prescription medications. The most common drug-disease interaction was aspirin/NSAID use in those with history of peptic ulcer disease without gastroprotection. Over one-third (34·0%) had at least one type of drug interaction. Each prescription medication increased the odds of having at least one type of drug interaction by 35-40% [drug-drug interaction adjusted odds ratio (AOR) = 1·35, 95% confidence interval (CI) = 1·27-1·42; drug-disease interaction AOR = 1·30; CI = 1·21-1·40; and both AOR = 1·45; CI = 1·34-1·57]. A prior hospitalization increased the odds of having at least one type of drug interaction by 49-84% compared with those not hospitalized (drug-drug interaction AOR = 1·49, 95% CI = 1·11-2·01; drug-disease interaction AOR = 1·69, CI = 1·15-2·49; and both AOR = 1·84, CI = 1·20-2·84). Drug interactions are common among community-dwelling older adults and are associated with the number of medications and hospitalization in the previous year. Longitudinal studies are needed to evaluate the impact of drug interactions on health-related outcomes. © 2017 John Wiley & Sons Ltd.

A case study in generic drug use: should there be risk adjustment in incentive payments for the use of generic medications?

PubMed

Walton, Surrey M; Rash, Christine; Lambert, Bruce L; Galanter, William L

2014-11-01

Encouraging generic drug use has reduced health care costs for payers and consumers, but the availability of therapeutically interchangeable medications or generic medications of choice is not equal across disease states. The extent to which systems of care are able to substitute with generics is not well understood.  To (a) define and measure the maximum generic rate (MGR) of currently prescribed drugs within an academic medical group in and (b) illustrate differences across drugs associated with selected underlying diseases.   Prescription claims data were examined from an academic medical group in Chicago, Illinois. Based on pharmacologic and therapeutic criteria, drugs were classified into 2 categories-potentially substitutable and not potentially substitutable-based on whether the drugs are branded forms of the same chemical entities that are available as generics or are therapeutically interchangeable with other medications that have different chemical compositions but the same mechanisms of action and potential efficacy. A medication was considered potentially substitutable if it (a) did not have a narrow therapeutic index as defined by the FDA; (b) did not belong to 1 of 6 protected classes of drugs in the Medicare D provisions; (c) was substitutable with a generic medication containing the same chemical entity; or (d) was therapeutically interchangeable with a therapeutically equivalent medication. MGR was defined as the percentage of prescriptions that could potentially be prescribed in generic form. This rate was examined overall and across drugs known to be associated with illustrative diseases including hypertension, diabetes mellitus, and obstructive lung diseases.   The MGR ranged from 100% for drugs used in hypertension to 26.7% for drugs used in obstructive lung diseases. The MGR was 83.6%.  Payers wishing to promote generic substitution should incorporate the potential for substitution of clinically appropriate generic medications as part of incentives for generic utilization to avoid unintended consequences of using a fixed target rate. A practical methodology for determining an MGR is offered.

Information needs for making clinical recommendations about potential drug-drug interactions: a synthesis of literature review and interviews.

PubMed

Romagnoli, Katrina M; Nelson, Scott D; Hines, Lisa; Empey, Philip; Boyce, Richard D; Hochheiser, Harry

2017-02-22

Drug information compendia and drug-drug interaction information databases are critical resources for clinicians and pharmacists working to avoid adverse events due to exposure to potential drug-drug interactions (PDDIs). Our goal is to develop information models, annotated data, and search tools that will facilitate the interpretation of PDDI information. To better understand the information needs and work practices of specialists who search and synthesize PDDI evidence for drug information resources, we conducted an inquiry that combined a thematic analysis of published literature with unstructured interviews. Starting from an initial set of relevant articles, we developed search terms and conducted a literature search. Two reviewers conducted a thematic analysis of included articles. Unstructured interviews with drug information experts were conducted and similarly coded. Information needs, work processes, and indicators of potential strengths and weaknesses of information systems were identified. Review of 92 papers and 10 interviews identified 56 categories of information needs related to the interpretation of PDDI information including drug and interaction information; study design; evidence including clinical details, quality and content of reports, and consequences; and potential recommendations. We also identified strengths/weaknesses of PDDI information systems. We identified the kinds of information that might be most effective for summarizing PDDIs. The drug information experts we interviewed had differing goals, suggesting a need for detailed information models and flexible presentations. Several information needs not discussed in previous work were identified, including temporal overlaps in drug administration, biological plausibility of interactions, and assessment of the quality and content of reports. Richly structured depictions of PDDI information may help drug information experts more effectively interpret data and develop recommendations. Effective information models and system designs will be needed to maximize the utility of this information.

Potential Targets for Antifungal Drug Discovery Based on Growth and Virulence in Candida albicans

PubMed Central

Li, Xiuyun; Hou, Yinglong; Yue, Longtao; Liu, Shuyuan; Du, Juan

2015-01-01

Fungal infections, especially infections caused by Candida albicans, remain a challenging problem in clinical settings. Despite the development of more-effective antifungal drugs, their application is limited for various reasons. Thus, alternative treatments with drugs aimed at novel targets in C. albicans are needed. Knowledge of growth and virulence in fungal cells is essential not only to understand their pathogenic mechanisms but also to identify potential antifungal targets. This article reviews the current knowledge of the mechanisms of growth and virulence in C. albicans and examines potential targets for the development of new antifungal drugs. PMID:26195510

Bacterial Magnetosome: A Novel Biogenetic Magnetic Targeted Drug Carrier with Potential Multifunctions

PubMed Central

Sun, Jianbo; Li, Ying; Liang, Xing-Jie; Wang, Paul C.

2012-01-01

Bacterial magnetosomes (BMs) synthesized by magnetotactic bacteria have recently drawn great interest due to their unique features. BMs are used experimentally as carriers for antibodies, enzymes, ligands, nucleic acids, and chemotherapeutic drugs. In addition to the common attractive properties of magnetic carriers, BMs also show superiority as targeting nanoscale drug carriers, which is hardly matched by artificial magnetic particles. We are presenting the potential applications of BMs as drug carriers by introducing the drug-loading methods and strategies and the recent research progress of BMs which has contributed to the application of BMs as drug carriers. PMID:22448162

National estimates of exposure to prescription drugs with addiction potential in community-dwelling elders.

PubMed

Simoni-Wastila, Linda; Zuckerman, Ilene H; Singhal, Puneet K; Briesacher, Becky; Hsu, Van Doren

2005-03-01

The use of prescription drugs with addiction potential is an overlooked and growing problem among today's elderly. This paper provides national prevalence estimates of exposure to prescription drugs with addiction potential among community-dwelling elders and explores risk factors for such exposure. Using the Medicare Current Beneficiary Survey, a nationally-representative database of Medicare eligibles, we calculated the prevalence of abusable prescription drug use, overall, by therapeutic class, and by drug. Nearly 22% (7.22 million) of all community-dwelling Medicare elders used at least one prescription medication with addiction potential. Opioid analgesics were used most frequently (14.9%; 95% CI 14.0, 15.8%); central nervous system (CNS) depressants were used by 10.4% of the nation's elders (95% CI 9.5, 10.8%). Using logistic regression analysis, we examined the association of explanatory variables with three outcome variables: any controlled substances use, any opioid analgesic use, and any CNS depressant use. We found that females, whites, those aged 65-79, and those with non-spousal others, were significantly more likely to use one or more prescription drugs with addiction potential, controlling for health status and severity-of-illness. The significance and magnitude of several explanatory variables, including age, race, ethnicity, living arrangement, and health status, varied by therapeutic category. This paper provides an important first step in acknowledging the widespread use of abusable prescription drugs in elders, and provides a foundation for future research and practical solutions to preventing subsequent problem use of prescription drugs.

Opportunities for Web-based Drug Repositioning: Searching for Potential Antihypertensive Agents with Hypotension Adverse Events.

PubMed

Wang, Kejian; Wan, Mei; Wang, Rui-Sheng; Weng, Zuquan

2016-04-01

Drug repositioning refers to the process of developing new indications for existing drugs. As a phenotypic indicator of drug response in humans, clinical side effects may provide straightforward signals and unique opportunities for drug repositioning. We aimed to identify drugs frequently associated with hypotension adverse reactions (ie, the opposite condition of hypertension), which could be potential candidates as antihypertensive agents. We systematically searched the electronic records of the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) through the openFDA platform to assess the association between hypotension incidence and antihypertensive therapeutic effect regarding a list of 683 drugs. Statistical analysis of FAERS data demonstrated that those drugs frequently co-occurring with hypotension events were more likely to have antihypertensive activity. Ranked by the statistical significance of frequent hypotension reporting, the well-known antihypertensive drugs were effectively distinguished from others (with an area under the receiver operating characteristic curve > 0.80 and a normalized discounted cumulative gain of 0.77). In addition, we found a series of antihypertensive agents (particularly drugs originally developed for treating nervous system diseases) among the drugs with top significant reporting, suggesting the good potential of Web-based and data-driven drug repositioning. We found several candidate agents among the hypotension-related drugs on our list that may be redirected for lowering blood pressure. More important, we showed that a pharmacovigilance system could alternatively be used to identify antihypertensive agents and sustainably create opportunities for drug repositioning.

Multifunctional magnetic nanostructured hardystonite scaffold for hyperthermia, drug delivery and tissue engineering applications.

PubMed

Farzin, Ali; Fathi, Mohammadhossein; Emadi, Rahmatollah

2017-01-01

Hyperthermia and local drug delivery have been proposed as potential therapeutic approaches for killing cancer cells. The development of bioactive materials such as Hardystonite (HT) with magnetic and drug delivery properties can potentially meet this target. This new class of magnetic bioceramic can replace the widely used magnetic iron oxide nanoparticles, whose long-term biocompatibility is not clear. Magnetic HT can be potentially employed to develop new ceramic scaffolds for bone surgery and anticancer therapies. With this in mind, a synthesis procedure was developed to prepare multifunctional bioactive scaffold for tissue engineering, hyperthermia and drug delivery applications. To this end, iron (Fe 3+ )-containing HT scaffolds were prepared. The effect of Fe on biological, magnetic and drug delivery properties of HT scaffolds were investigated. The results showed that obtained Fe-HT is bioactive and magnetic with no magnetite or maghemite as secondary phases. The Fe-HT scaffolds obtained also possessed high specific surface areas and demonstrated sustained drug delivery. These results potentially open new aspects for biomaterials aimed at regeneration of large-bone defects caused by malignant bone tumors through a combination of hyperthermia, local drug delivery and osteoconductivity. Copyright © 2016 Elsevier B.V. All rights reserved.

Potential Savings from an Evidence-Based Consumer-Oriented Public Education Campaign on Prescription Drugs

PubMed Central

Donohue, Julie M; Fischer, Michael A; Huskamp, Haiden A; Weissman, Joel S

2008-01-01

Objective To estimate potential savings associated with the Consumer Reports Best Buy Drugs program, a national educational program that provides consumers with price and effectiveness information on prescription drugs. Data Sources National data on 2006 prescription sales and retail prices paid for angiotensin-converting enzyme inhibitors (ACEIs), β-blockers, calcium channel blockers, and 3-hydroxy-3-methylglutaryl coenzyme A (HMG-coA) reductase inhibitors (statins). Study Design We converted national data on aggregate unit sales of drugs in the four classes to defined daily doses (DDD) and estimated a range of potential savings from generic and therapeutic substitution. Principal Findings We estimated that $2.76 billion, or 7.83 percent of sales, could be saved if use of the drugs recommended by the educational program was increased. The recommended drugs’ prices were 15–65 percent lower per DDD than their therapeutic alternatives. The majority (57.4 percent) of potential savings would be achieved through therapeutic substitution. Conclusions Substantial savings can be achieved through greater use of comparatively effective and lower cost drugs recommended by a national consumer education program. However, barriers to dissemination of consumer-oriented drug information must be addressed before savings can be realized. PMID:18479406

Drug interactions between common illicit drugs and prescription therapies.

PubMed

Lindsey, Wesley T; Stewart, David; Childress, Darrell

2012-07-01

The aim was to summarize the clinical literature on interactions between common illicit drugs and prescription therapies. Medline, Iowa Drug Information Service, International Pharmaceutical Abstracts, EBSCO Academic Search Premier, and Google Scholar were searched from date of origin of database to March 2011. Search terms were cocaine, marijuana, cannabis, methamphetamine, amphetamine, ecstasy, N-methyl-3,4-methylenedioxymethamphetamine, methylenedioxymethamphetamine, heroin, gamma-hydroxybutyrate, sodium oxybate, and combined with interactions, drug interactions, and drug-drug interactions. This review focuses on established clinical evidence. All applicable full-text English language articles and abstracts found were evaluated and included in the review as appropriate. The interactions of illicit drugs with prescription therapies have the ability to potentiate or attenuate the effects of both the illicit agent and/or the prescription therapeutic agent, which can lead to toxic effects or a reduction in the prescription agent's therapeutic activity. Most texts and databases focus on theoretical or probable interactions due to the kinetic properties of the drugs and do not fully explore the pharmacodynamic and clinical implications of these interactions. Clinical trials with coadministration of illicit drugs and prescription drugs are discussed along with case reports that demonstrate a potential interaction between agents. The illicit drugs discussed are cocaine, marijuana, amphetamines, methylenedioxymethamphetamine, heroin, and sodium oxybate. Although the use of illicit drugs is widespread, there are little experimental or clinical data regarding the effects of these agents on common prescription therapies. Potential drug interactions between illicit drugs and prescription drugs are described and evaluated on the Drug Interaction Probability Scale by Horn and Hansten.

Discovery and Delivery of Synergistic Chemotherapy Drug Combinations to Tumors

NASA Astrophysics Data System (ADS)

Camacho, Kathryn Militar

Chemotherapy combinations for cancer treatments harbor immense therapeutic potentials which have largely been untapped. Of all diseases, clinical studies of drug combinations are the most prevalent in oncology, yet their effectiveness is disputable, as complete tumor regressions are rare. Our research has been devoted towards developing delivery vehicles for combinations of chemotherapy drugs which elicit significant tumor reduction yet limit toxicity in healthy tissue. Current administration methods assume that chemotherapy combinations at maximum tolerable doses will provide the greatest therapeutic effect -- a presumption which often leads to unprecedented side effects. Contrary to traditional administration, we have found that drug ratios rather than total cumulative doses govern combination therapeutic efficacy. In this thesis, we have developed nanoparticles to incorporate synergistic ratios of chemotherapy combinations which significantly inhibit cancer cell growth at lower doses than would be required for their single drug counterparts. The advantages of multi-drug incorporation in nano-vehicles are many: improved accumulation in tumor tissue via the enhanced permeation and retention effect, limited uptake in healthy tissue, and controlled exposure of tumor tissue to optimal synergistic drug ratios. To exploit these advantages for polychemotherapy delivery, two prominent nanoparticles were investigated: liposomes and polymer-drug conjugates. Liposomes represent the oldest class of nanoparticles, with high drug loading capacities and excellent biocompatibility. Polymer-drug conjugates offer controlled drug incorporations through reaction stoichiometry, and potentially allow for delivery of precise ratios. Here, we show that both vehicles, when armed with synergistic ratios of chemotherapy drugs, significantly inhibit tumor growth in an aggressive mouse breast carcinoma model. Furthermore, versatile drug incorporation methods investigated here can be broadly applied to various agents. Findings from our research can potentially widen the therapeutic window of chemotherapy combinations by emphasizing investigations of optimal drug ratios rather than maximum drug doses and by identifying appropriate nanoparticles for their delivery. Application of these concepts can ultimately help capture the full therapeutic potential of combination regimens.

Availability of human induced pluripotent stem cell-derived cardiomyocytes in assessment of drug potential for QT prolongation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nozaki, Yumiko, E-mail: yumiko-nozaki@ds-pharma.co.jp; Honda, Yayoi, E-mail: yayoi-honda@ds-pharma.co.jp; Tsujimoto, Shinji, E-mail: shinji-tsujimoto@ds-pharma.co.jp

2014-07-01

Field potential duration (FPD) in human-induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs), which can express QT interval in an electrocardiogram, is reported to be a useful tool to predict K{sup +} channel and Ca{sup 2+} channel blocker effects on QT interval. However, there is no report showing that this technique can be used to predict multichannel blocker potential for QT prolongation. The aim of this study is to show that FPD from MEA (Multielectrode array) of hiPS-CMs can detect QT prolongation induced by multichannel blockers. hiPS-CMs were seeded onto MEA and FPD was measured for 2 min every 10 min formore » 30 min after drug exposure for the vehicle and each drug concentration. I{sub Kr} and I{sub Ks} blockers concentration-dependently prolonged corrected FPD (FPDc), whereas Ca{sup 2+} channel blockers concentration-dependently shortened FPDc. Also, the multichannel blockers Amiodarone, Paroxetine, Terfenadine and Citalopram prolonged FPDc in a concentration dependent manner. Finally, the I{sub Kr} blockers, Terfenadine and Citalopram, which are reported to cause Torsade de Pointes (TdP) in clinical practice, produced early afterdepolarization (EAD). hiPS-CMs using MEA system and FPDc can predict the effects of drug candidates on QT interval. This study also shows that this assay can help detect EAD for drugs with TdP potential. - Highlights: • We focused on hiPS-CMs to replace in vitro assays in preclinical screening studies. • hiPS-CMs FPD is useful as an indicator to predict drug potential for QT prolongation. • MEA assay can help detect EAD for drugs with TdP potentials. • MEA assay in hiPS-CMs is useful for accurately predicting drug TdP risk in humans.« less

Conductive polymer nanotube patch for fast and controlled in vivo transdermal drug delivery

NASA Astrophysics Data System (ADS)

Nguyen, Thao M.

Transdermal drug delivery has created new applications for existing therapies and offered an alternative to the traditional oral route where drugs can prematurely metabolize in the liver causing adverse side effects. Opening the transdermal delivery route to large hydrophilic drugs is one of the greatest challenges due to the hydrophobicity of the skin. However, the ability to deliver hydrophilic drugs using a transdermal patch would provide a solution to problems of other delivery methods for hydrophilic drugs. The switching of conductive polymers (CP) between redox states cause simultaneous changes in the polymer charge, conductivity, and volume—properties that can all be exploited in the biomedical field of controlled drug delivery. Using the template synthesis method, poly(3,4-ethylenedioxythiophene (PEDOT) nanotubes were synthesized electrochemically and a transdermal drug delivery patch was successfully designed and developed. In vitro and in vivo uptake and release of hydrophilic drugs were investigated. The relationship between the strength of the applied potential and rate of drug release were also investigated. Results revealed that the strength of the applied potential is proportional to the rate of drug release; therefore one can control the rate of drug release by controlling the applied potential. The in vitro studies focused on the kinetics of the drug delivery system. It was determined that the drug released mainly followed zero-order kinetics. In addition, it was determined that applying a releasing potential to the transdermal drug delivery system lead to a higher release rate constant (up to 7 times greater) over an extended period of time (˜24h). In addition, over 24 hours, an average of 80% more model drug molecules were released with an applied potential than without. The in vivo study showed that the drug delivery system was capable of delivering model hydrophilic drugs molecules through the dermis layer of the skin within 30 minutes, while the control showed no visible drugs at the same depth. Most importantly, it was determined that the delivery of drugs into the blood stream was stable within 20 minutes. The functionalization of CP was also studied in order to enhance the properties and drug loading capabilities of the polymers. The co-polymerization of poly(3,4-(2-methylene)propylenedioxythiophene) (PMProDot) with polystyrene (PS) and polyvinylcarbazole (PVK) through the highly reactive methylene group was achieved. The modified PMProDot nanotubes demonstrated response times that were two times faster than without modification. The modification of PEDOT nanotubes with polydopamine, a biocompatible polymer, was also investigated and achieved. In depth characterization of functionalized CP demonstrate the ability to fine tune the properties of the polymer in order to achieve the required therapeutic drug release profile.

Pilot Certification, Age of Pilot, and Drug Use in Fatal Civil Aviation Accidents.

PubMed

Akparibo, Issaka Y; Stolfi, Adrienne

2017-10-01

This study examined the association between mean age of pilot, pilot license, pilot medical certificate and drug use trends in pilots fatally injured in aircraft accidents. The prevalence of prescription drugs, OTC drugs, controlled drugs and drugs that may be potentially impairing was also examined. This study was a descriptive observational study in which the NTSB Aviation Accident Database was searched from the period beginning January 1, 2012 to December 31, 2014. During the study period a total of 706 accidents involving 711 fatalities were investigated by the NTSB. This study included 633 of these accidents, involving 646 fatalities. Of these pilots, 42.1% had drugs in their biological samples. The prevalence of prescription drugs, controlled drugs, OTC drugs, opioids, and potentially impairing drugs in the fatally injured pilot population over the study period was 28.9%, 15.0%, 20.1%, 5.1%, and 25.5%, respectively. Pilots with any drugs in their samples were significantly older than those without drugs. Medical certificate held was associated with drug use; pilots who held third class certificates had the highest prevalence at 54.1%. Pilot license was not associated with drug use. In 3.8% of the accidents, drugs were a contributing factor in the cause. Despite current FAA medical regulations, potentially impairing drugs are frequently found in biological samples of fatally injured pilots in the U.S. More education of airmen by aviation medical examiners is needed on the safety of drug use.Akparibo IY, Stolfi A. Pilot certification, age of pilot, and drug use in fatal civil aviation accidents. Aerosp Med Hum Perform. 2017; 88(10):931-936.

Potential therapeutic targets and the role of technology in developing novel cannabinoid drugs from cyanobacteria.

PubMed

Vijayakumar, S; Manogar, P; Prabhu, S

2016-10-01

Cyanobacteria find several applications in pharmacology as potential candidates for drug design. The need for new compounds that can be used as drugs has always been on the rise in therapeutics. Cyanobacteria have been identified as promising targets of research in the quest for new pharmaceutical compounds as they can produce secondary metabolites with novel chemical structures. Cyanobacteria is now recognized as a vital source of bioactive molecules like Curacin A, Largazole and Apratoxin which have succeeded in reaching Phase II and Phase III into clinical trials. The discovery of several new clinical cannabinoid drugs in the past decade from diverse marine life should translate into a number of new drugs for cannabinoid in the years to come. Conventional cannabinoid drugs have high toxicity and as a result, they affect the efficacy of chemotherapy and patients' life very much. The present review focuses on how potential, safe and affordable drugs used for cannabinoid treatment could be developed from cyanobacteria. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Interaction of triblock co-polymer micelles with phospholipid-bilayer: a spectroscopic investigation using a potential chloride channel blocker.

PubMed

Ganguly, Aniruddha; Ghosh, Soumen; Guchhait, Nikhil

2015-03-07

Interaction of a potential chloride channel blocker, 9-methyl anthroate (9-MA), has been studied with zwitterionic l-α-phosphatidylcholine (egg-PC) lipid vesicles, which ascertains the utility of the drug as an efficient molecular reporter for probing the microheterogeneous environment of lipid-bilayers. The effect of a non-ionic triblock co-polymer P123 on the stability of these drug-bound lipid-bilayers has also been investigated by means of steady state and time-resolved spectroscopic techniques exploiting the fluorescence properties of the drug. Experimental results reveal that the addition of P123 to the drug-bound lipid results in a preferential complexation of the drug with the Pluronic leaving the lipid vesicles aside, which has been attributed to a substantially stronger binding interaction of the drug with P123 than that with egg-PC. The result is of potential interest from a medical perspective owing to the context of excess drug desorption from bio-membranes.

Potential drug-drug interactions with antiepileptic drugs in Medicaid recipients.

PubMed

Dickson, Michael; Bramley, Thomas J; Kozma, Chris; Doshi, Dilesh; Rupnow, Marcia F T

2008-09-15

The frequency of potential drug-drug interactions (DDIs) between antiepileptic drugs (AEDs) and other (non-AED) medications in Medicaid patients taking newer AED monotherapy, older AED monotherapy, and combinations of AED treatment was studied. A retrospective, observational study was conducted using administrative claims obtained from South Carolina Medicaid. Patients were included in the analysis if they (1) had at least one prescription for an AED between January 1, 2004, and December 31, 2004, (2) were taking a specific AED for at least 60 days, (3) had at least one epilepsy diagnosis during the 6 months before or during the enrollment period, and (4) were enrolled in Medicaid for at least 11 of the 12 months of the follow-up period. Possible DDI exposure was defined as 10 days of overlap between an AED and a non-AED known to have the potential to cause a clinically relevant interaction. A total of 4955 patients met the inclusion criteria. Approximately 45% of patients receiving monotherapy with an older AED had a potential DDI, compared with 3.9% receiving a newer AED. An average of 0.08 potential DDI per year of exposure occurred in the newer AED monotherapy cohort compared with 1.18 in the older AED monotherapy cohort. The most common potential interaction category was a decreased concentration of the non-AED. Older AEDs were associated with a greater likelihood of a potential DDI than were newer AEDs. Further research is needed to elucidate the relationship between the occurrence of potential DDIs and actual clinically relevant consequences.

The Contribution of Fetal Drug Exposure to Temperament: Potential Teratogenic Effects on Neuropsychiatric Risk

ERIC Educational Resources Information Center

Weiss, Sandra J.; St. Jonn-Seed, Mary; Harris-Muchell, Carolyn

2007-01-01

Background: Preliminary evidence indicates that fetal drug exposure may be associated with alterations in temperament. However, studies often do not dissociate the potential effects of drug exposure from other perinatal or environmental factors that could influence temperament phenotypes. Methods: High risk children (n = 120) were followed from…

78 FR 20327 - Joint Meeting of the Advisory Committee for Reproductive Health Drugs and the Drug Safety and...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-04-04

... Management Advisory Committee; Amendment of Notice AGENCY: Food and Drug Administration, HHS. ACTION: Notice... focus on postmarketing reports of oil microembolism in the lungs and potential anaphylactic reactions... in regard to oil microembolism and potential anaphylactic reactions reported for those products. This...

Addictive drugs and brain stimulation reward.

PubMed

Wise, R A

1996-01-01

Direct electrical or chemical stimulation of specific brain regions can establish response habits similar to those established by natural rewards such as food or sexual contact. Cocaine, mu and delta opiates, nicotine, phencyclidine, and cannabis each have actions that summate with rewarding electrical stimulation of the medial forebrain bundle (MFB). The reward-potentiating effects of amphetamine and opiates are associated with central sites of action where these drugs also have their direct rewarding effects, suggesting common mechanisms for drug reward per se and for drug potentiation of brain stimulation reward. The central sites at which these and perhaps other drugs of abuse potentiate brain stimulation reward and are rewarding in their own right are consistent with the hypothesis that the laboratory reward of brain stimulation and the pharmacological rewards of addictive drugs are habit forming because they act in the brain circuits that subserve more natural and biologically significant rewards.

Impact of direct drug delivery via gastric access devices.

PubMed

Kurien, Matthew; Penny, Hugo; Sanders, David S

2015-03-01

Gastric access devices such as nasogastric tubes and gastrostomy tubes are increasingly being used in clinical practice to provide both short- and long-term nutrition support therapy. Increasingly these devices are being utilized to help deliver oral medications, where swallowing is impaired. This concomitant administration of medications and enteral formulas could derive potential benefits in regard to time and cost; however, uncertainty exists regarding potential drug and nutrient interactions and the influence this may have on both safety and efficacy. This article provides an overview of the differing gastric access devices used in clinical practice and evaluates the evidence base for using oral medications via these routes. Alternative methods of drug administration are discussed, alongside common drug nutrient interactions and potential complications. Delivering medications via gastric access devices can be performed safely; however, careful consideration needs to be made regarding tube and patient influences, alongside drug-nutrient interactions. Improving practice in this area in the future necessitates enhancement of an evidence base to substantiate the safety of drug delivery via gastric access devices and improvement in education among healthcare professionals about the potential problems.

Biowaiver extension potential and IVIVC for BCS Class II drugs by formulation design: Case study for cyclosporine self-microemulsifying formulation.

PubMed

Yang, Su-Geun

2010-11-01

The objective of this work was to suggest the biowaiver potential of biopharmaceutical classification system (BCS) Class II drugs in self-microemulsifying drug delivery systems (SMEDDS) which are known to increase the solubility, dissolution and oral absorption of water-insoluble drugs. Cyclosporine was selected as a representative BCS Class II drug. New generic candidate of cyclosporine SMEDDS (test) was applied for the study with brand SMEDDS (reference I) and cyclosporine self-emulsifying drug delivery systems (SEDDS, reference II). Solubility and dissolution of cyclosporine from SMEDDS were critically enhanced, which were the similar behaviors with BCS class I drug. The test showed the identical dissolution rate and the equivalent bioavailability (0.34, 0.42 and 0.68 of p values for AUC₀(→)₂₄(h), C(max) and T(max), respectively) with the reference I. Based on the results, level A in vitro-in vivo correlation (IVIVC) was established from these two SMEDDS formulations. This study serves as a good example for speculating the biowaiver extension potential of BCS Class II drugs specifically in solubilizing formulation such as SMEDDS.

The potential of silk and silk-like proteins as natural mucoadhesive biopolymers for controlled drug delivery

NASA Astrophysics Data System (ADS)

Brooks, Amanda

2015-11-01

Drug delivery across mucus membranes is a particularly effective route of administration due to the large surface area. However, the unique environment present at the mucosa necessitates altered drug formulations designed to (1) deliver sensitive biologic molecules, (2) promote intimate contact between the mucosa and the drug, and (3) prolong the drug’s local residence time. Thus, the pharmaceutical industry has an interest in drug delivery systems formulated around the use of mucoadhesive polymers. Mucoadhesive polymers, both synthetic and biological, have a history of use in local drug delivery. Prominently featured in the literature are chitosan, alginate, and cellulose derivatives. More recently, silk and silk-like derivatives have been explored for their potential as mucoadhesive polymers. Both silkworms and spiders produce sticky silk-like glue substances, sericin and aggregate silk respectively, that may prove an effective, natural matrix for drug delivery to the mucosa. This mini review will explore the potential of silk and silk-like derivatives as a biocompatible mucoadhesive polymer matrix for local controlled drug delivery.

Calcium carbonate nanoparticles as cancer drug delivery system.

PubMed

Maleki Dizaj, Solmaz; Barzegar-Jalali, Mohammad; Zarrintan, Mohammad Hossein; Adibkia, Khosro; Lotfipour, Farzaneh

2015-01-01

Calcium carbonate (CaCO3) has broad biomedical utilizations owing to its availability, low cost, safety, biocompatibility, pH-sensitivity and slow biodegradability. Recently, there has been widespread interest in their application as drug delivery systems for different groups of drugs. Among them, CaCO3 nanoparticles have exhibited promising potential as drug carriers targeting cancer tissues and cells. The pH-dependent properties, alongside the potential to be functionalized with targeting agents give them the unique property that can be used in targeted delivery systems for anticancer drugs. Also, due to the slow degradation of CaCO3 matrices, these nanoparticles can be used as sustained release systems to retain drugs in cancer tissues for longer times after administration. Development of drug delivery carriers using CaCO3 nanoparticles has been reviewed. The current state of CaCO3 nanoparticles as cancer drug delivery systems with focus on their special properties like pH-sensitivity and biodegradability has also been evaluated. According to our review, CaCO3 nanoparticles, owing to their special characteristics, will have a potential role in safe and efficient cancer treatment in future.

Computational Approaches to Drug Repurposing and Pharmacology

PubMed Central

Hodos, Rachel A; Kidd, Brian A; Khader, Shameer; Readhead, Ben P; Dudley, Joel T

2016-01-01

Data in the biological, chemical, and clinical domains are accumulating at ever-increasing rates and have the potential to accelerate and inform drug development in new ways. Challenges and opportunities now lie in developing analytic tools to transform these often complex and heterogeneous data into testable hypotheses and actionable insights. This is the aim of computational pharmacology, which uses in silico techniques to better understand and predict how drugs affect biological systems, which can in turn improve clinical use, avoid unwanted side effects, and guide selection and development of better treatments. One exciting application of computational pharmacology is drug repurposing- finding new uses for existing drugs. Already yielding many promising candidates, this strategy has the potential to improve the efficiency of the drug development process and reach patient populations with previously unmet needs such as those with rare diseases. While current techniques in computational pharmacology and drug repurposing often focus on just a single data modality such as gene expression or drug-target interactions, we rationalize that methods such as matrix factorization that can integrate data within and across diverse data types have the potential to improve predictive performance and provide a fuller picture of a drug's pharmacological action. PMID:27080087

A toxicity assessment of 30 pharmaceuticals using Aliivibrio fischeri: a comparison of the acute effects of different formulations.

PubMed

Jacob, Raquel Sampaio; Santos, Lucilaine Valéria de Souza; de Souza, Ana Flávia Rodrigues; Lange, Liséte Celina

2016-11-01

Considerable quantities of different classes of drugs are consumed annually worldwide. These drugs, once disposed, often remain stable, even after conventional or advanced treatments. Although there have been a number of studies on the potential harm caused by drugs when released into the environment, few studies have investigated the toxicity of pharmaceutical excipients. In the present study, the acute toxicity of 30 drugs was tested to Aliivibrio fischeri. Ten different active ingredients were investigated, each in three distinct formulations: generic, similar and reference (brand drug). The aim of the study was to evaluate the harmful potential of drugs frequently sold in drugstores and to assess the contribution of excipients towards the observed acute toxicity. Within the 10 drugs evaluated, only one, dexchlorpheniramine maleate, was not toxic in any formulation. The toxicities of the three formulations were often different, even though the active ingredient has been the same. For some drugs, such as diazepam, glibenclamide, metformin, nimesulide, hydrochlorothiazide and simvastatin, only one or two of the three formulations tested were toxic to A. fischeri. These results highlight the toxicological potential of drug excipients, but not exclusively the toxicity of the active ingredients.

Drug prescribing before and during pregnancy in south west France: a retrolective study.

PubMed

Crespin, Sophie; Bourrel, Robert; Hurault-Delarue, Caroline; Lapeyre-Mestre, Maryse; Montastruc, Jean-Louis; Damase-Michel, Christine

2011-07-01

Several drugs that are known to exhibit teratogenic or fetotoxic risks when used during pregnancy should not be prescribed to pregnant women. However, most women of childbearing age use medications, and drug use cannot always be avoided during pregnancy, especially for women with chronic diseases for whom the benefit of treatment outweighs the potential risk of the drug for the fetus. Nevertheless, it is often possible to replace a drug with another one that has been better evaluated. The aim of the present study was to describe the prescribing of drugs to pregnant women before and during pregnancy in order to examine whether the occurrence of pregnancy modifies drug prescribing and dispensing to women. In particular, drugs that are contraindicated or must be avoided during pregnancy, such as retinoids, ACE inhibitors, angiotensin II receptor blockers, NSAIDs and valproic acid, will be analysed. This retrolective study used data already prospectively recorded in the database of the French Health Insurance Service. It analysed pharmacy records of women who gave birth between 1 January 2007 and 31 December 2007 in Midi-Pyrenees. Pharmacy data were analysed from 9 months before pregnancy until delivery. Drugs were classified according to the Anatomical Therapeutic Chemical code. The study included 23 898 women. Approximately 77% and 96% of the women received at least one prescription before and during pregnancy, respectively. The number of women who were prescribed contraindicated drugs significantly decreased with pregnancy (p < 0.0001). Most of the drugs were stopped during the 3 months before pregnancy without alternative treatment, even for chronic diseases. However, for some women, potentially dangerous prescriptions were maintained during pregnancy, and for others these drugs were dispensed for the first time during critical periods of pregnancy. Despite recommendations, some teratogenic and/or fetotoxic drugs are still prescribed and dispensed to pregnant women in France. There is a need to repeat information to sensitize health professionals and women to the harmful potential of drugs. Moreover, discontinuation of a needed treatment must be avoided. Therefore, attention must be given to ensuring that younger females and women of childbearing potential who are likely to need continued treatment in adolescence and adulthood are aware of the potential risks that some drugs may pose during pregnancy.

A network-based drug repositioning infrastructure for precision cancer medicine through targeting significantly mutated genes in the human cancer genomes.

PubMed

Cheng, Feixiong; Zhao, Junfei; Fooksa, Michaela; Zhao, Zhongming

2016-07-01

Development of computational approaches and tools to effectively integrate multidomain data is urgently needed for the development of newly targeted cancer therapeutics. We proposed an integrative network-based infrastructure to identify new druggable targets and anticancer indications for existing drugs through targeting significantly mutated genes (SMGs) discovered in the human cancer genomes. The underlying assumption is that a drug would have a high potential for anticancer indication if its up-/down-regulated genes from the Connectivity Map tended to be SMGs or their neighbors in the human protein interaction network. We assembled and curated 693 SMGs in 29 cancer types and found 121 proteins currently targeted by known anticancer or noncancer (repurposed) drugs. We found that the approved or experimental cancer drugs could potentially target these SMGs in 33.3% of the mutated cancer samples, and this number increased to 68.0% by drug repositioning through surveying exome-sequencing data in approximately 5000 normal-tumor pairs from The Cancer Genome Atlas. Furthermore, we identified 284 potential new indications connecting 28 cancer types and 48 existing drugs (adjusted P < .05), with a 66.7% success rate validated by literature data. Several existing drugs (e.g., niclosamide, valproic acid, captopril, and resveratrol) were predicted to have potential indications for multiple cancer types. Finally, we used integrative analysis to showcase a potential mechanism-of-action for resveratrol in breast and lung cancer treatment whereby it targets several SMGs (ARNTL, ASPM, CTTN, EIF4G1, FOXP1, and STIP1). In summary, we demonstrated that our integrative network-based infrastructure is a promising strategy to identify potential druggable targets and uncover new indications for existing drugs to speed up molecularly targeted cancer therapeutics. © The Author 2016. Published by Oxford University Press on behalf of the American Medical Informatics Association. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Allosteric cross-talk in chromatin can mediate drug-drug synergy

NASA Astrophysics Data System (ADS)

Adhireksan, Zenita; Palermo, Giulia; Riedel, Tina; Ma, Zhujun; Muhammad, Reyhan; Rothlisberger, Ursula; Dyson, Paul J.; Davey, Curt A.

2017-03-01

Exploitation of drug-drug synergism and allostery could yield superior therapies by capitalizing on the immensely diverse, but highly specific, potential associated with the biological macromolecular landscape. Here we describe a drug-drug synergy mediated by allosteric cross-talk in chromatin, whereby the binding of one drug alters the activity of the second. We found two unrelated drugs, RAPTA-T and auranofin, that yield a synergistic activity in killing cancer cells, which coincides with a substantially greater number of chromatin adducts formed by one of the compounds when adducts from the other agent are also present. We show that this occurs through an allosteric mechanism within the nucleosome, whereby defined histone adducts of one drug promote reaction of the other drug at a distant, specific histone site. This opens up possibilities for epigenetic targeting and suggests that allosteric modulation in nucleosomes may have biological relevance and potential for therapeutic interventions.

Multimodal assessment of spatial distribution of drug-tracer uptake by brain tissue after intra-arterial injections

NASA Astrophysics Data System (ADS)

Singh-Moon, Rajinder; Chaudhuri, Durba; Wang, Mei; Straubinger, Robert; Bigio, Irving J.; Joshi, Shailendra

2014-02-01

It is challenging to track the rapid changes in drug concentrations after intra-arterial (IA) administration to elucidate the pharmacokinetics of this method of drug delivery. Traditional pharmacokinetic parameters (such as protein binding) that are highly relevant to intravenous (IV) administration do not seem to apply to IA injections. Regional drug delivery is affected by the biomechanics of drug injection, resting blood flow, and local tissue extraction. In-vivo and ex-vivo, optical methods for spatial mapping of drug deposition can assist in visualizing drug distributions and aid in the screening of potential drugs and carrier candidates. We present a multimodal approach for the assessment of drug distribution in postmortem tissue specimens using diffuse reflectance spectroscopy, multispectral imaging, and confocal microscopy and demonstrate feasibility of distinguishing route of administration advantages of liposome-dye conjugate delivery. The results of this study suggest that insight on drug dynamics gained by this aggregated approach can be used to help screen and/or optimize potential drug candidates and drug delivery protocols.

Open-source chemogenomic data-driven algorithms for predicting drug-target interactions.

PubMed

Hao, Ming; Bryant, Stephen H; Wang, Yanli

2018-02-06

While novel technologies such as high-throughput screening have advanced together with significant investment by pharmaceutical companies during the past decades, the success rate for drug development has not yet been improved prompting researchers looking for new strategies of drug discovery. Drug repositioning is a potential approach to solve this dilemma. However, experimental identification and validation of potential drug targets encoded by the human genome is both costly and time-consuming. Therefore, effective computational approaches have been proposed to facilitate drug repositioning, which have proved to be successful in drug discovery. Doubtlessly, the availability of open-accessible data from basic chemical biology research and the success of human genome sequencing are crucial to develop effective in silico drug repositioning methods allowing the identification of potential targets for existing drugs. In this work, we review several chemogenomic data-driven computational algorithms with source codes publicly accessible for predicting drug-target interactions (DTIs). We organize these algorithms by model properties and model evolutionary relationships. We re-implemented five representative algorithms in R programming language, and compared these algorithms by means of mean percentile ranking, a new recall-based evaluation metric in the DTI prediction research field. We anticipate that this review will be objective and helpful to researchers who would like to further improve existing algorithms or need to choose appropriate algorithms to infer potential DTIs in the projects. The source codes for DTI predictions are available at: https://github.com/minghao2016/chemogenomicAlg4DTIpred. Published by Oxford University Press 2018. This work is written by US Government employees and is in the public domain in the US.

Differential impact of pavlovian drug conditioned stimuli on in vivo dopamine transmission in the rat accumbens shell and core and in the prefrontal cortex.

PubMed

Bassareo, Valentina; De Luca, Maria Antonietta; Di Chiara, Gaetano

2007-04-01

Conditioned stimuli (CSs) by pavlovian association with reinforcing drugs (US) are thought to play an important role in the acquisition, maintenance and relapse of drug dependence. The aim of this study was to investigate by microdialysis the impact of pavlovian drug CSs on behaviour and on basal and drug-stimulated dopamine (DA) in three terminal DA areas: nucleus accumbens shell, core and prefrontal cortex (PFCX). Conditioned rats were trained once a day for 3 days by presentation of Fonzies filled box (FFB, CS) for 10 min followed by administration of morphine (1 mg/kg), nicotine (0.4 mg/kg) or saline, respectively. Pseudo-conditioned rats were presented with the FFB 10 h after drug or saline administration. Rats were implanted with microdialysis probes in the shell, core and PFCX. The effect of stimuli conditioned with morphine and nicotine on DA and on DA response to drugs was studied. Drug CSs elicited incentive reactions and released DA in the shell and PFCX but not in the core. Pre-exposure to morphine CS potentiated DA release to morphine challenge in the shell but not in the core and PFCX. This effect was related to the challenge dose of morphine and was stimulus-specific since a food CS did not potentiate the shell DA response to morphine. Pre-exposure to nicotine CS potentiated DA release in the shell and PFCX. The results show that drug CSs stimulate DA release in the shell and medial PFCX and specifically potentiate the primary stimulant drug effects on DA transmission.

Financial Impact of Cancer Drug Wastage and Potential Cost Savings From Mitigation Strategies.

PubMed

Leung, Caitlyn Y W; Cheung, Matthew C; Charbonneau, Lauren F; Prica, Anca; Ng, Pamela; Chan, Kelvin K W

2017-07-01

Cancer drug wastage occurs when a parenteral drug within a fixed vial is not administered fully to a patient. This study investigated the extent of drug wastage, the financial impact on the hospital budget, and the cost savings associated with current mitigation strategies. We conducted a cross-sectional study in three University of Toronto-affiliated hospitals of various sizes. We recorded the actual amount of drug wasted over a 2-week period while using current mitigation strategies. Single-dose vial cancer drugs with the highest wastage potentials were identified (14 drugs). To calculate the hypothetical drug wastage with no mitigation strategies, we determined how many vials of drugs would be needed to fill a single prescription. The total drug costs over the 2 weeks ranged from $50,257 to $716,983 in the three institutions. With existing mitigation strategies, the actual drug wastage over the 2 weeks ranged from $928 to $5,472, which was approximately 1% to 2% of the total drug costs. In the hypothetical model with no mitigation strategies implemented, the projected drug cost wastage would have been $11,232 to $149,131, which accounted for 16% to 18% of the total drug costs. As a result, the potential annual savings while using current mitigation strategies range from 15% to 17%. The financial impact of drug wastage is substantial. Mitigation strategies lead to substantial cost savings, with the opportunity to reinvest those savings. More research is needed to determine the appropriate methods to minimize risk to patients while using the cost-saving mitigation strategies.

Current trends in the use of vitamin E-based micellar nanocarriers for anticancer drug delivery.

PubMed

Muddineti, Omkara Swami; Ghosh, Balaram; Biswas, Swati

2017-06-01

Owing to the complexity of cancer pathogenesis, conventional chemotherapy can be an inadequate method of killing cancer cells effectively. Nanoparticle-based drug delivery systems have been widely exploited pre-clinically in recent years. Areas covered: Incorporation of vitamin-E in nanocarriers have the advantage of (1) improving the hydrophobicity of the drug delivery system, thereby improving the solubility of the loaded poorly soluble anticancer drugs, (2) enhancing the biocompatibility of the polymeric drug carriers, and (3) improving the anticancer potential of the chemotherapeutic agents by reversing the cellular drug resistance via simultaneous administration. In addition to being a powerful antioxidant, vitamin E demonstrated its anticancer potential by inducing apoptosis in various cancer cell lines. Various vitamin E analogs have proven their ability to cause marked inhibition of drug efflux transporters. Expert opinion: The review discusses the potential of incorporating vitamin E in the polymeric micelles which are designed to carry poorly water-soluble anticancer drugs. Current applications of various vitamin E-based polymeric micelles with emphasis on the use of α-tocopherol, D-α-tocopheryl succinate (α-TOS) and its conjugates such as D-α-tocopheryl polyethylene glycol-succinate (TPGS) in micellar system is delineated. Advantages of utilizing polymeric micelles for drug delivery and the challenges to treat cancer, including multiple drug resistance have been discussed.

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

PubMed

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

2016-05-01

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

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

NASA Astrophysics Data System (ADS)

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

2016-05-01

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

Using Social Media Data to Identify Potential Candidates for Drug Repurposing: A Feasibility Study.

PubMed

Rastegar-Mojarad, Majid; Liu, Hongfang; Nambisan, Priya

2016-06-16

Drug repurposing (defined as discovering new indications for existing drugs) could play a significant role in drug development, especially considering the declining success rates of developing novel drugs. Typically, new indications for existing medications are identified by accident. However, new technologies and a large number of available resources enable the development of systematic approaches to identify and validate drug-repurposing candidates. Patients today report their experiences with medications on social media and reveal side effects as well as beneficial effects of those medications. Our aim was to assess the feasibility of using patient reviews from social media to identify potential candidates for drug repurposing. We retrieved patient reviews of 180 medications from an online forum, WebMD. Using dictionary-based and machine learning approaches, we identified disease names in the reviews. Several publicly available resources were used to exclude comments containing known indications and adverse drug effects. After manually reviewing some of the remaining comments, we implemented a rule-based system to identify beneficial effects. The dictionary-based system and machine learning system identified 2178 and 6171 disease names respectively in 64,616 patient comments. We provided a list of 10 common patterns that patients used to report any beneficial effects or uses of medication. After manually reviewing the comments tagged by our rule-based system, we identified five potential drug repurposing candidates. To our knowledge, this is the first study to consider using social media data to identify drug-repurposing candidates. We found that even a rule-based system, with a limited number of rules, could identify beneficial effect mentions in patient comments. Our preliminary study shows that social media has the potential to be used in drug repurposing.

Vincristine-sulphate-loaded liposome-templated calcium phosphate nanoshell as potential tumor-targeting delivery system.

PubMed

Thakkar, Hetal Paresh; Baser, Amit Kumar; Parmar, Mayur Prakashbhai; Patel, Ketul Harshadbhai; Ramachandra Murthy, Rayasa

2012-06-01

Vincristine-sulfate-loaded liposomes were prepared with an aim to improve stability, reduce drug leakage during systemic circulation, and increase intracellular uptake. Liposomes were prepared by the thin-film hydration method, followed by coating with calcium phosphate, using the sequential addition approach. Prepared formulations were characterized for size, zeta potential, drug-entrapment efficiency, morphology by transmission electron microscopy (TEM), in vitro drug-release profile, and in vitro cell cytotoxicity study. Effect of formulation variables, such as drug:lipid ratio as well as nature and volume of hydration media, were found to affect drug entrapment, and the concentration of calcium chloride in coating was found to affect size and coating efficiency. Size, zeta potential, and TEM images confirmed that the liposomes were effectively coated with calcium phosphate. The calcium phosphate nanoshell exhibited pH-dependent drug release, showing significantly lower release at pH 7.4, compared to the release at pH 4.5, which is the pH of the tumor interstitium. The in vitro cytotoxicity study done on the lung cancer cell line indicated that coated liposomes are more cytotoxic than plain liposomes and drug solution, indicating their potential for intracellular drug delivery. The cell-uptake study done on the lung cancer cell line indicated that calcium-phosphate-coated liposomes show higher cell uptake than uncoated liposomes.

Single chemical entity legal highs: assessing the risk for long term harm.

PubMed

McNabb, Carolyn B; Russell, Bruce R; Caprioli, Daniele; Nutt, David J; Gibbons, Simon; Dalley, Jeffrey W

2012-12-01

A recent and dramatic increase in the emergence of novel psychoactive substances ('legal highs') has left many governments unable to provide a timely response to an increasing number of potentially harmful drugs now available to the public. In response to this rapid increase in lawful drug use, the UK government intends to implement temporary class drug orders, whereby substances with a potential for misuse and harm can be regulated for a 12 month period. During this period an investigation of the potential for harms induced by these drugs will take place. However, the short time-frame in which information must be gathered, and the paucity of data available on novel psychoactive substances, means that robust pharmacological and toxicological analyses may be replaced by extrapolating data from illegal drugs with similar chemical structures. This review explores the potential pharmacology and toxicology of past and present 'legal highs' and discusses the risks of failing to carry out in-depth scientific research on individual substances.

NLLSS: Predicting Synergistic Drug Combinations Based on Semi-supervised Learning

PubMed Central

Chen, Ming; Wang, Quanxin; Zhang, Lixin; Yan, Guiying

2016-01-01

Fungal infection has become one of the leading causes of hospital-acquired infections with high mortality rates. Furthermore, drug resistance is common for fungus-causing diseases. Synergistic drug combinations could provide an effective strategy to overcome drug resistance. Meanwhile, synergistic drug combinations can increase treatment efficacy and decrease drug dosage to avoid toxicity. Therefore, computational prediction of synergistic drug combinations for fungus-causing diseases becomes attractive. In this study, we proposed similar nature of drug combinations: principal drugs which obtain synergistic effect with similar adjuvant drugs are often similar and vice versa. Furthermore, we developed a novel algorithm termed Network-based Laplacian regularized Least Square Synergistic drug combination prediction (NLLSS) to predict potential synergistic drug combinations by integrating different kinds of information such as known synergistic drug combinations, drug-target interactions, and drug chemical structures. We applied NLLSS to predict antifungal synergistic drug combinations and showed that it achieved excellent performance both in terms of cross validation and independent prediction. Finally, we performed biological experiments for fungal pathogen Candida albicans to confirm 7 out of 13 predicted antifungal synergistic drug combinations. NLLSS provides an efficient strategy to identify potential synergistic antifungal combinations. PMID:27415801

Drug-drug interactions involving lysosomes: mechanisms and potential clinical implications.

PubMed

Logan, Randall; Funk, Ryan S; Axcell, Erick; Krise, Jeffrey P

2012-08-01

Many commercially available, weakly basic drugs have been shown to be lysosomotropic, meaning they are subject to extensive sequestration in lysosomes through an ion trapping-type mechanism. The extent of lysosomal trapping of a drug is an important therapeutic consideration because it can influence both activity and pharmacokinetic disposition. The administration of certain drugs can alter lysosomes such that their accumulation capacity for co-administered and/or secondarily administered drugs is altered. In this review the authors explore what is known regarding the mechanistic basis for drug-drug interactions involving lysosomes. Specifically, the authors address the influence of drugs on lysosomal pH, volume and lipid processing. Many drugs are known to extensively accumulate in lysosomes and significantly alter their structure and function; however, the therapeutic and toxicological implications of this remain controversial. The authors propose that drug-drug interactions involving lysosomes represent an important potential source of variability in drug activity and pharmacokinetics. Most evaluations of drug-drug interactions involving lysosomes have been performed in cultured cells and isolated tissues. More comprehensive in vivo evaluations are needed to fully explore the impact of this drug-drug interaction pathway on therapeutic outcomes.

Exploring drug-target interaction networks of illicit drugs.

PubMed

Atreya, Ravi V; Sun, Jingchun; Zhao, Zhongming

2013-01-01

Drug addiction is a complex and chronic mental disease, which places a large burden on the American healthcare system due to its negative effects on patients and their families. Recently, network pharmacology is emerging as a promising approach to drug discovery by integrating network biology and polypharmacology, allowing for a deeper understanding of molecular mechanisms of drug actions at the systems level. This study seeks to apply this approach for investigation of illicit drugs and their targets in order to elucidate their interaction patterns and potential secondary drugs that can aid future research and clinical care. In this study, we extracted 188 illicit substances and their related information from the DrugBank database. The data process revealed 86 illicit drugs targeting a total of 73 unique human genes, which forms an illicit drug-target network. Compared to the full drug-target network from DrugBank, illicit drugs and their target genes tend to cluster together and form four subnetworks, corresponding to four major medication categories: depressants, stimulants, analgesics, and steroids. External analysis of Anatomical Therapeutic Chemical (ATC) second sublevel classifications confirmed that the illicit drugs have neurological functions or act via mechanisms of stimulants, opioids, and steroids. To further explore other drugs potentially having associations with illicit drugs, we constructed an illicit-extended drug-target network by adding the drugs that have the same target(s) as illicit drugs to the illicit drug-target network. After analyzing the degree and betweenness of the network, we identified hubs and bridge nodes, which might play important roles in the development and treatment of drug addiction. Among them, 49 non-illicit drugs might have potential to be used to treat addiction or have addictive effects, including some results that are supported by previous studies. This study presents the first systematic review of the network characteristics of illicit drugs, their targets, and other drugs that share the targets of these illicit drugs. The results, though preliminary, provide some novel insights into the molecular mechanisms of drug addiction. The observation of illicit-related drugs, with partial verification from previous studies, demonstrated that the network-assisted approach is promising for the identification of drug repositioning.

Exploring drug-target interaction networks of illicit drugs

PubMed Central

2013-01-01

Background Drug addiction is a complex and chronic mental disease, which places a large burden on the American healthcare system due to its negative effects on patients and their families. Recently, network pharmacology is emerging as a promising approach to drug discovery by integrating network biology and polypharmacology, allowing for a deeper understanding of molecular mechanisms of drug actions at the systems level. This study seeks to apply this approach for investigation of illicit drugs and their targets in order to elucidate their interaction patterns and potential secondary drugs that can aid future research and clinical care. Results In this study, we extracted 188 illicit substances and their related information from the DrugBank database. The data process revealed 86 illicit drugs targeting a total of 73 unique human genes, which forms an illicit drug-target network. Compared to the full drug-target network from DrugBank, illicit drugs and their target genes tend to cluster together and form four subnetworks, corresponding to four major medication categories: depressants, stimulants, analgesics, and steroids. External analysis of Anatomical Therapeutic Chemical (ATC) second sublevel classifications confirmed that the illicit drugs have neurological functions or act via mechanisms of stimulants, opioids, and steroids. To further explore other drugs potentially having associations with illicit drugs, we constructed an illicit-extended drug-target network by adding the drugs that have the same target(s) as illicit drugs to the illicit drug-target network. After analyzing the degree and betweenness of the network, we identified hubs and bridge nodes, which might play important roles in the development and treatment of drug addiction. Among them, 49 non-illicit drugs might have potential to be used to treat addiction or have addictive effects, including some results that are supported by previous studies. Conclusions This study presents the first systematic review of the network characteristics of illicit drugs, their targets, and other drugs that share the targets of these illicit drugs. The results, though preliminary, provide some novel insights into the molecular mechanisms of drug addiction. The observation of illicit-related drugs, with partial verification from previous studies, demonstrated that the network-assisted approach is promising for the identification of drug repositioning. PMID:24268016

Antimicrobial Resistance Risks of Cholera Prophylaxis for United Nations Peacekeepers

PubMed Central

Lewnard, Joseph A.; Pitzer, Virginia E.; Cohen, Ted

2017-01-01

ABSTRACT More than 5 years after a United Nations peacekeeping battalion introduced cholera to Haiti, over 150,000 peacekeepers continue to be deployed annually from countries where cholera is endemic. The United Nations has thus far declined to provide antimicrobial chemoprophylaxis to peacekeepers, a policy based largely on concerns that the risks of drug resistance generation and spread would outweigh the potential benefits of preventing future cholera importations. In this study, we sought to better understand the relative benefits and risks of cholera chemoprophylaxis for peacekeepers in terms of antibiotic resistance. Using a stochastic model to quantify the potential impact of chemoprophylaxis on importation and transmission of drug-resistant and drug-sensitive Vibrio cholerae, we found that chemoprophylaxis would decrease the probability of cholera importation but would increase the expected number of drug-resistant infections if an importation event were to occur. Despite this potential increase, we found that at least 10 drug-sensitive infections would likely be averted per excess drug-resistant infection under a wide range of assumptions about the underlying prevalence of drug resistance and risk of acquired resistance. Given these findings, policymakers should reconsider whether the potential resistance risks of providing antimicrobial chemoprophylaxis to peacekeepers are sufficient to outweigh the anticipated benefits. PMID:28533237

Antimicrobial Resistance Risks of Cholera Prophylaxis for United Nations Peacekeepers.

PubMed

Kunkel, Amber; Lewnard, Joseph A; Pitzer, Virginia E; Cohen, Ted

2017-08-01

More than 5 years after a United Nations peacekeeping battalion introduced cholera to Haiti, over 150,000 peacekeepers continue to be deployed annually from countries where cholera is endemic. The United Nations has thus far declined to provide antimicrobial chemoprophylaxis to peacekeepers, a policy based largely on concerns that the risks of drug resistance generation and spread would outweigh the potential benefits of preventing future cholera importations. In this study, we sought to better understand the relative benefits and risks of cholera chemoprophylaxis for peacekeepers in terms of antibiotic resistance. Using a stochastic model to quantify the potential impact of chemoprophylaxis on importation and transmission of drug-resistant and drug-sensitive Vibrio cholerae , we found that chemoprophylaxis would decrease the probability of cholera importation but would increase the expected number of drug-resistant infections if an importation event were to occur. Despite this potential increase, we found that at least 10 drug-sensitive infections would likely be averted per excess drug-resistant infection under a wide range of assumptions about the underlying prevalence of drug resistance and risk of acquired resistance. Given these findings, policymakers should reconsider whether the potential resistance risks of providing antimicrobial chemoprophylaxis to peacekeepers are sufficient to outweigh the anticipated benefits. Copyright © 2017 American Society for Microbiology.

Childhood Trauma and Illicit Drug Use in Adolescence: A Population-Based National Comorbidity Survey Replication–Adolescent Supplement Study

PubMed Central

Carliner, Hannah; Keyes, Katherine M.; McLaughlin, Katie A.; Meyers, Jacquelyn L.; Dunn, Erin C.; Martins, Silvia S.

2016-01-01

Objective Although potentially traumatic events (PTEs) are established risk factors for substance use disorders among adults, little is known about associations with drug use during adolescence, an important developmental stage for drug use prevention. We examined whether childhood PTEs were associated with illicit drug use among a representative sample of US adolescents. Method Data were drawn from the National Comorbidity Survey Replication–Adolescent Supplement (NCS-A), which included adolescents aged 13-18 years (N=9,956). Weighted logistic regression models estimated risk ratios for lifetime use of marijuana, cocaine, nonmedical prescription drugs, other drugs, and multiple drugs. Results Exposure to any PTE prior to age 11 was reported by 36% of the sample and was associated with higher risk for use of marijuana (risk ratio [RR] = 1.50), cocaine (RR = 2.78), prescription drugs (RR=1.80), other drugs (RR=1.90), and multiple drugs (RR=1.74). A positive monotonic relationship was observed between number of PTEs and marijuana, other drug, and multiple drug use. Interpersonal violence was associated with all drug use outcomes. Accidents and unspecified events were associated with higher risk for marijuana, cocaine, and prescription drug use. Conclusion Potentially traumatic events in childhood are associated with risk for illicit drug use among US adolescents. These findings add to the literature by illustrating a potentially modifiable health behavior that may be a target for intervention; and that adolescents with a trauma history are a high-risk group for illicit drug use and may benefit from trauma-focused prevention efforts that specifically address traumatic memories and coping strategies for dealing with stressful life events. PMID:27453084

Childhood Trauma and Illicit Drug Use in Adolescence: A Population-Based National Comorbidity Survey Replication-Adolescent Supplement Study.

PubMed

Carliner, Hannah; Keyes, Katherine M; McLaughlin, Katie A; Meyers, Jacquelyn L; Dunn, Erin C; Martins, Silvia S

2016-08-01

Although potentially traumatic events (PTEs) are established risk factors for substance use disorders among adults, little is known about associations with drug use during adolescence, an important developmental stage for drug use prevention. We examined whether childhood PTEs were associated with illicit drug use among a representative sample of US adolescents. Data were drawn from the National Comorbidity Survey Replication-Adolescent Supplement (NCS-A), which included adolescents aged 13 to 18 years (N = 9,956). Weighted logistic regression models estimated risk ratios for lifetime use of marijuana, cocaine, nonmedical prescription drugs, other drugs, and multiple drugs. Exposure to any PTE before age 11 years was reported by 36% of the sample and was associated with higher risk for use of marijuana (risk ratio [RR] = 1.50), cocaine (RR = 2.78), prescription drugs (RR = 1.80), other drugs (RR = 1.90), and multiple drugs (RR = 1.74). A positive monotonic relationship was observed between number of PTEs and marijuana, other drug, and multiple drug use. Interpersonal violence was associated with all drug use outcomes. Accidents and unspecified events were associated with higher risk for marijuana, cocaine, and prescription drug use. Potentially traumatic events in childhood are associated with risk for illicit drug use among US adolescents. These findings add to the literature by illustrating a potentially modifiable health behavior that may be a target for intervention. The results also highlight that adolescents with a trauma history are a high-risk group for illicit drug use and may benefit from trauma-focused prevention efforts that specifically address traumatic memories and coping strategies for dealing with stressful life events. Copyright © 2016 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.

Adverse drug reactions and off-label drug use in paediatric outpatients

PubMed Central

Horen, Benjamin; Montastruc, Jean-Louis; Lapeyre-mestre, Maryse

2002-01-01

Aims To investigate the potential relationship between off-label drug use and increased risk of adverse drug reactions in paediatric outpatients. Methods A prospective pharmacovigilance survey of drug prescribing in office based paediatricians was carried out in Haute-Garonne County (south west of France). Results The study involved a sample of 1419 children under 16 years old. Forty-two percent of patients were exposed to at least one off-label prescription. The incidence of adverse drug reactions was 1.41% (95% CI 0.79, 2.11). Off-label drug use was significantly associated with adverse drug reactions (relative risk 3.44; 95% CI 1.26, 9.38), particularly when it was due to an indication different than that defined in the Summary Product Characteristics (relative risk 4.42; 95% CI 1.60, 12.25). Conclusions Our data suggest an increasing risk of adverse drug reactions related to off-label drug use. This risk would be acceptable if further studies prove the potential benefit of such a drug use. PMID:12492616

4-methylamphetamine (4-MA): chemistry, pharmacology and toxicology of a new potential recreational drug.

PubMed

Coppola, M; Mondola, R

2013-12-01

From 2005 to 2012, 236 new substances have been officially notified in European Union via the Early Warning System with an increasing trend from year by year. In October 2009, 4-methylamphetamine (4-MA), an amphetamine derivative, was detected in Belgium and on 14 December 2009 this stimulant was notified to the European Monitoring Centre for Drugs and Drug Addiction. Since its appearance within the recreational drug market, some cases of severe intoxication and deaths have been signaled across Europe. In this paper we summarized the chemical, pharmacological and toxicological information about this new potential recreational drug.

Managing psychotropic drug costs: will formularies work?

PubMed

Huskamp, Haiden A

2003-01-01

Payers of pharmaceutical benefits are increasingly turning to drug formularies in an attempt to control rising pharmacy costs, including those for psychotropic drugs. In this paper I examine several issues that policymakers should consider when addressing formulary design for psychotropic drugs: heterogeneity within mental health disorders and limited information about treatment effectiveness for individual patients; the potential for plans to try to use formularies to avoid adverse selection and implications for psychotropic coverage; the interaction of Medicaid formulary policy and manufacturers' incentives for psychotropic innovation; and incentives created by mental health institutions that decrease formularies' potential effectiveness in controlling psychotropic drug costs.

Potential risks resulting from fruit/vegetable-drug interactions: effects on drug-metabolizing enzymes and drug transporters.

PubMed

Rodríguez-Fragoso, Lourdes; Martínez-Arismendi, José Luis; Orozco-Bustos, Danae; Reyes-Esparza, Jorge; Torres, Eliseo; Burchiel, Scott W

2011-05-01

It has been well established that complex mixtures of phytochemicals in fruits and vegetables can be beneficial for human health. Moreover, it is becoming increasingly apparent that phytochemicals can influence the pharmacological activity of drugs by modifying their absorption characteristics through interactions with drug transporters as well as drug-metabolizing enzyme systems. Such effects are more likely to occur in the intestine and liver, where high concentrations of phytochemicals may occur. Alterations in cytochrome P450 and other enzyme activities may influence the fate of drugs subject to extensive first-pass metabolism. Although numerous studies of nutrient-drug interactions have been published and systematic reviews and meta-analyses of these studies are available, no generalizations on the effect of nutrient-drug interactions on drug bioavailability are currently available. Several publications have highlighted the unintended consequences of the combined use of nutrients and drugs. Many phytochemicals have been shown to have pharmacokinetic interactions with drugs. The present review is limited to commonly consumed fruits and vegetables with significant beneficial effects as nutrients and components in folk medicine. Here, we discuss the phytochemistry and pharmacokinetic interactions of the following fruit and vegetables: grapefruit, orange, tangerine, grapes, cranberry, pomegranate, mango, guava, black raspberry, black mulberry, apple, broccoli, cauliflower, watercress, spinach, tomato, carrot, and avocado. We conclude that our knowledge of the potential risk of nutrient-drug interactions is still limited. Therefore, efforts to elucidate potential risks resulting from food-drug interactions should be intensified in order to prevent undesired and harmful clinical consequences. © 2011 Institute of Food Technologists®

Prescribing quality for older people in Norwegian nursing homes and home nursing services using multidose dispensed drugs.

PubMed

Halvorsen, Kjell H; Granas, Anne Gerd; Engeland, Anders; Ruths, Sabine

2012-09-01

To examine and compare the quality of drug prescribing for older patients in nursing homes and home nursing services. Cross-sectional study comprising 11,254 patients aged ≥ 65 years in nursing homes (n = 2986) and home nursing services (n = 8268). Potentially inappropriate medications were identified by using the Norwegian General Practice criteria and drug-drug interactions through a Norwegian Web-based tool. The impact of care setting on exposure to selected drug groups, potentially inappropriate medications, and drug interactions was calculated, adjusting for patients' age, gender, and number of drugs used. Patients in nursing homes and home nursing services used on average 5.7 (SD = 2.6) multidose dispensed regular drugs. Twenty-six percent used at least one potentially inappropriate medication, 31% in nursing homes and 25% in home nursing services, p < .001. Concomitant use of three or more psychotropic and/or opioid drugs was the criterion most commonly identified in nursing homes (18%) and home nursing services (9%), p < .001. Compared with nursing homes, more patients in home nursing services used cardiovascular drugs and fewer patients used psychotropic drugs. Altogether, 8615 drug-drug interactions were identified in 55% of patients, 48% in nursing homes and 57% in home nursing services, p < .001. There are significant differences in the quality of drug prescribing in nursing homes compared with home nursing services. Explanations as to why these differences exist need to be further explored. Copyright © 2011 John Wiley & Sons, Ltd.

Emerging potential of stimulus-responsive nanosized anticancer drug delivery systems for systemic applications.

PubMed

Ruttala, Hima Bindu; Ramasamy, Thiruganesh; Madeshwaran, Thiagarajan; Hiep, Tran Tuan; Kandasamy, Umadevi; Oh, Kyung Taek; Choi, Han-Gon; Yong, Chul Soon; Kim, Jong Oh

2018-02-01

The development of novel drug delivery systems based on well-defined polymer therapeutics has led to significant improvements in the treatment of multiple disorders. Advances in material chemistry, nanotechnology, and nanomedicine have revolutionized the practices of drug delivery. Stimulus-responsive material-based nanosized drug delivery systems have remarkable properties that allow them to circumvent biological barriers and achieve targeted intracellular drug delivery. Specifically, the development of novel nanocarrier-based therapeutics is the need of the hour in managing complex diseases. In this review, we have briefly described the fundamentals of drug targeting to diseased tissues, physiological barriers in the human body, and the mechanisms/modes of drug-loaded carrier systems. To that end, this review serves as a comprehensive overview of the recent developments in stimulus-responsive drug delivery systems, with focus on their potential applications and impact on the future of drug delivery.

Prime-, Stress- and Cue-Induced Reinstatement of Extinguished Drug-Reinforced Responding in Rats: Cocaine as the Prototypical Drug of Abuse

PubMed Central

Beardsley, Patrick M.; Shelton, Keith L.

2012-01-01

This unit describes the testing of rats in prime-, footshock- and cue-induced reinstatement procedures. Evaluating rats in these procedures enables the assessment of treatments on behavior thought to model drug relapse precipitated by re-contact with an abused drug (prime-induced), induced by stress (footshock-induced), or by stimuli previously associated with drug administration (cue-induced). For instance, levels of reinstatement under the effects of test compound administration could be compared to levels under vehicle administration to help identify potential treatments for drug relapse, or reinstatement levels of different rat strains could be compared to identify potential genetic determinants of perseverative drug-seeking behavior. Cocaine is used as a prototypical drug of abuse, and relapse to its use serves as the model in this unit, but other self-administered drugs could readily be substituted with little modification to the procedures. PMID:23093352

Self-assembled lipid--polymer hybrid nanoparticles: a robust drug delivery platform.

PubMed

Zhang, Liangfang; Chan, Juliana M; Gu, Frank X; Rhee, June-Wha; Wang, Andrew Z; Radovic-Moreno, Aleksandar F; Alexis, Frank; Langer, Robert; Farokhzad, Omid C

2008-08-01

We report the engineering of a novel lipid-polymer hybrid nanoparticle (NP) as a robust drug delivery platform, with high drug encapsulation yield, tunable and sustained drug release profile, excellent serum stability, and potential for differential targeting of cells or tissues. The NP comprises three distinct functional components: (i) a hydrophobic polymeric core where poorly water-soluble drugs can be encapsulated; (ii) a hydrophilic polymeric shell with antibiofouling properties to enhance NP stability and systemic circulation half-life; and (iii) a lipid monolayer at the interface of the core and the shell that acts as a molecular fence to promote drug retention inside the polymeric core, thereby enhancing drug encapsulation efficiency, increasing drug loading yield, and controlling drug release. The NP is prepared by self-assembly through a single-step nanoprecipitation method in a reproducible and predictable manner, making it potentially suitable for scale-up.

Self-Assembled Lipid-Polymer Hybrid Nanoparticles: A Robust Drug Delivery Platform

PubMed Central

Zhang, Liangfang; Chan, Juliana M; Gu, Frank X; Rhee, June-Wha; Wang, Andrew Z; Radovic-Moreno, Aleksandar F; Alexis, Frank; Langer, Robert; Farokhzad, Omid C

2014-01-01

We report the engineering of a novel lipid-polymer hybrid nanoparticle (NP) as a robust drug delivery platform, with high drug encapsulation yield, tunable and sustained drug release profile, excellent serum stability, and potential for differential targeting of cells or tissues. The NP is comprised of three distinct functional components: i) a hydrophobic polymeric core where poorly water-soluble drugs can be encapsulated; ii) a hydrophilic polymeric shell with anti-biofouling properties to enhance NP stability and systemic circulation half-life; and iii) a lipid monolayer at the interface of the core and the shell that acts as a molecular fence to promote drug retention inside the polymeric core, thereby enhancing drug encapsulation efficiency, increasing drug loading yield, and controlling drug release. The NP is prepared by self-assembly through a single-step nanoprecipitation method in a reproducible and predictable manner, making it potentially suitable for scale-up PMID:19206374

Systematic drug repositioning through mining adverse event data in ClinicalTrials.gov.

PubMed

Su, Eric Wen; Sanger, Todd M

2017-01-01

Drug repositioning (i.e., drug repurposing) is the process of discovering new uses for marketed drugs. Historically, such discoveries were serendipitous. However, the rapid growth in electronic clinical data and text mining tools makes it feasible to systematically identify drugs with the potential to be repurposed. Described here is a novel method of drug repositioning by mining ClinicalTrials.gov. The text mining tools I2E (Linguamatics) and PolyAnalyst (Megaputer) were utilized. An I2E query extracts "Serious Adverse Events" (SAE) data from randomized trials in ClinicalTrials.gov. Through a statistical algorithm, a PolyAnalyst workflow ranks the drugs where the treatment arm has fewer predefined SAEs than the control arm, indicating that potentially the drug is reducing the level of SAE. Hypotheses could then be generated for the new use of these drugs based on the predefined SAE that is indicative of disease (for example, cancer).

Pharmacokinetic drug interactions of morphine, codeine, and their derivatives: theory and clinical reality, Part II.

PubMed

Armstrong, Scott C; Cozza, Kelly L

2003-01-01

Pharmacokinetic drug-drug interactions with codeine, dihydrocodeine, hydrocodone, oxycodone, and buprenorphine are reviewed in this column. These compounds have a very similar chemical structure to morphine. Unlike morphine, which is metabolized chiefly through conjugation reactions with uridine diphosphate glucuronosyl transferase (UGT) enzymes, these five drugs are metabolized both through oxidative reactions by the cytochrome P450 (CYP450) enzyme and conjugation by UGT enzymes. There is controversy as to whether codeine, dihydrocodeine, and hydrocodone are actually prodrugs requiring activation by the CYP450 2D6 enzyme or UGT enzymes. Oxycodone and buprenorphine, however, are clearly not prodrugs and are metabolized by the CYP450 2D6 and 3A4 enzymes, respectively. Knowledge of this metabolism assists in the understanding for the potential of drug-drug interactions with these drugs. This understanding is important so that clinicians can choose the proper dosages for analgesia and anticipate potential drug-drug interactions.

Pharmacological Treatment of Mood Disturbances, Aggression, and Self-Injury in Persons with Pervasive Developmental Disorders.

ERIC Educational Resources Information Center

King, Bryan H.

2000-01-01

This article reviews the psychopharmacological treatment of aggression, mood disturbances, and self-injurious behavior in persons with autistic disorder. It highlights the use of dopaminergic drugs, serotonergic drugs, opioidergic drugs, adrenergic drugs, thymoleptic drugs, and glutamatergic drugs for their potential utility in treating…

Drug-nutrient interactions: a case and clinical guide.

PubMed

Plotnikoff, Gregory A

2011-10-01

Advances in pharmacokinetics and pharmacodynamics require new competencies related to pharmaceutical prescribing. First, both physicians and pharmacists need to recognize the potential negative impact of nutrients and dietary supplements on the absorption, metabolism, and utilization of prescription drugs. Second, physicians, even more than pharmacists, need to recognize the potential negative effects of pharmaceuticals on the absorption, metabolism, and utilization of nutrients. This article discusses common drug-nutrient interactions and presents a case that illustrates how unrecognized nutrient disruption may negatively affect a patient's health and potentially result in unnecessary prescribing of medications. In presenting the case, we also provide a conceptual framework for assessing and treating this patient and a summary of current knowledge regarding drug-nutrient interactions.

Conductive polymer nanotube patch for fast and controlled ex vivo transdermal drug delivery.

PubMed

Nguyen, Thao M; Lee, Sebin; Lee, Sang Bok

2014-10-01

To uptake and release hydrophilic model drugs and insulin in a novel conductive polymer (CP) nanotube transdermal patch. The externally controlled transdermal delivery of model drugs and insulin were tested ex vivo and results were compared with CP films. The unique intrinsic properties of CPs provide electrostatic interaction between the model drugs and polymer backbone. When a pulsed potential was applied, the drug delivery release profile mimics that of injection delivery. With a constant potential applied, the release rate constants of the patch system were up to three-times faster than the control (0 V) and released approximately 80% more drug molecules over 24 h. The CP nanotube transdermal patch represents a new and promising drug method, specifically for hydrophilic molecules, which have been a large obstacle for conventional transdermal drug delivery systems.

In vitro screening techniques for reactive metabolites for minimizing bioactivation potential in drug discovery.

PubMed

Prakash, Chandra; Sharma, Raman; Gleave, Michelle; Nedderman, Angus

2008-11-01

Drug induced toxicity remains one of the major reasons for failures of new pharmaceuticals, and for the withdrawal of approved drugs from the market. Efforts are being made to reduce attrition of drug candidates, and to minimize their bioactivation potential in the early stages of drug discovery in order to bring safer compounds to the market. Therefore, in addition to potency and selectivity; drug candidates are now selected on the basis of acceptable metabolism/toxicology profiles in preclinical species. To support this, new approaches have been developed, which include extensive in vitro methods using human and animal hepatic cellular and subcellular systems, recombinant human drug metabolizing enzymes, increased automation for higher-throughput screens, sensitive analytical technologies and in silico computational models to assess the metabolism aspects of the new chemical entities. By using these approaches many compounds that might have serious adverse reactions associated with them are effectively eliminated before reaching clinical trials, however some toxicities such as those caused by idiosyncratic responses, are not detected until a drug is in late stages of clinical trials or has become available to the market. One of the proposed mechanisms for the development of idiosyncratic drug toxicity is the bioactivation of drugs to form reactive metabolites by drug metabolizing enzymes. This review discusses the different approaches to, and benefits of using existing in vitro techniques, for the detection of reactive intermediates in order to minimize bioactivation potential in drug discovery.

The contribution of fetal drug exposure to temperament: potential teratogenic effects on neuropsychiatric risk.

PubMed

Weiss, Sandra J; St Jonn-Seed, Mary; Harris-Muchell, Carolyn

2007-08-01

Preliminary evidence indicates that fetal drug exposure may be associated with alterations in temperament. However, studies often do not dissociate the potential effects of drug exposure from other perinatal or environmental factors that could influence temperament phenotypes. High risk children (n = 120) were followed from birth to 6 months of age to determine the effects of fetal drug exposure on temperament, after controlling for the child's gender, gestational age, medical morbidity, ethnicity, and maltreatment as well as the mother's stress, income adequacy, and quality of caregiving. Methods included medical chart review, questionnaires, and videotapes of mother-child interaction. Preliminary analyses indicated that fetal drug exposure was associated with both distractibility and intensity of children's responses to the environment at 6 months of age. After adjusting for potentially confounding variables, drug exposure accounted for 12% of the variance in distractibility but was not a significant predictor in the regression model for intensity. Findings suggest that drug-exposed children may experience difficulty sustaining their focus of attention and be more easily distracted by environmental stimuli than non-drug-exposed children. Results converge with previous research to implicate cortical hyperarousal, stemming from teratogenic effects on the dopaminergic system during fetal development.

The Impact of Peers and Social Disapproval on High-Risk Cannabis Use: Gender Differences and Implications for Drug Education

ERIC Educational Resources Information Center

Butters, Jennifer E.

2004-01-01

Drug education programs that rely on an abstinence based philosophy neglect, and may even contribute to, the potentially adverse consequences experienced by young people who already engage in this potentially health-compromising behaviour. A predominant focus of drug research during the initial wave of rising cannabis use by young people in the…

Freezing of Gait in Parkinsonism and its Potential Drug Treatment.

PubMed

Zhang, Li-Li; Canning, S Duff; Wang, Xiao-Ping

2016-01-01

Freezing of gait (FOG) is a heterogeneous symptom. Studies of treatment for FOG are scarce. Levodopa and monoamine oxidase inhibitors (rasagiline and selegiline) have shown effective improvement for FOG. Other drugs, such as L-threo-3, 4-dihydroxyphenylserine, amantadine, and botulinum toxin have exhibited some beneficial effects. The present review summarizes the potential drug treatment for FOG in Parkinsonism.

Freezing of Gait in Parkinsonism and its Potential Drug Treatment

PubMed Central

Zhang, Li-Li; Canning, S. Duff; Wang, Xiao-Ping

2016-01-01

Freezing of gait (FOG) is a heterogeneous symptom. Studies of treatment for FOG are scarce. Levodopa and monoamine oxidase inhibitors (rasagiline and selegiline) have shown effective improvement for FOG. Other drugs, such as L-threo-3, 4-dihydroxyphenylserine, amantadine, and botulinum toxin have exhibited some beneficial effects. The present review summarizes the potential drug treatment for FOG in Parkinsonism. PMID:26635194

Overlooked and underestimated? Problematic alcohol use in clients recovering from drug dependence.

PubMed

Staiger, Petra K; Richardson, Ben; Long, Caroline M; Carr, Victoria; Marlatt, G Alan

2013-07-01

Despite recognition of the harms related to alcohol misuse and its potential to interfere substantially with sustained recovery from drug dependency, research evaluating drug treatment outcomes has not addressed the issue comprehensively. It has been overlooked possibly because treatment research has been framed according to the primary drug of choice, rather than investigating the interactions between different combinations of drugs and/or alcohol use. This paper reports on a systematic review investigating whether concurrent alcohol use could impede recovery from illicit drug use in two potential ways: first, alcohol could become a substitute addiction and/or secondly, alcohol misuse post-treatment may place an individual at risk for relapse to their primary drug problem. A systematic search of four relevant databases was undertaken to identify peer-reviewed, quantitative drug treatment outcome studies that reported alcohol use pre-, post-treatment and follow-up. The search revealed 567 papers, of which 13 were assessed as fulfilling the key inclusion criteria.The review indicated inconsistent and therefore inconclusive support for the substitution hypothesis. However, the data revealed consistent support for the hypothesis that alcohol use increases relapse to drug use. (i) The potential negative impact of alcohol misuse on drug treatment outcomes remains under-researched and overlooked; (ii) alcohol consumption post-drug treatment may increase the likelihood that an individual will relapse to their primary drug; (ii) existing evidence regarding the substitution hypothesis is inconclusive, although there was an indication that a subgroup of participants will be vulnerable to alcohol becoming the primary addiction instead of drugs. We argue that future drug treatment outcome studies need to include detailed analysis of the influence of alcohol use pre- and post-drug treatment. © 2012 The Authors, Addiction © 2012 Society for the Study of Addiction.

A side-effect free method for identifying cancer drug targets.

PubMed

Ashraf, Md Izhar; Ong, Seng-Kai; Mujawar, Shama; Pawar, Shrikant; More, Pallavi; Paul, Somnath; Lahiri, Chandrajit

2018-04-27

Identifying effective drug targets, with little or no side effects, remains an ever challenging task. A potential pitfall of failing to uncover the correct drug targets, due to side effect of pleiotropic genes, might lead the potential drugs to be illicit and withdrawn. Simplifying disease complexity, for the investigation of the mechanistic aspects and identification of effective drug targets, have been done through several approaches of protein interactome analysis. Of these, centrality measures have always gained importance in identifying candidate drug targets. Here, we put forward an integrated method of analysing a complex network of cancer and depict the importance of k-core, functional connectivity and centrality (KFC) for identifying effective drug targets. Essentially, we have extracted the proteins involved in the pathways leading to cancer from the pathway databases which enlist real experimental datasets. The interactions between these proteins were mapped to build an interactome. Integrative analyses of the interactome enabled us to unearth plausible reasons for drugs being rendered withdrawn, thereby giving future scope to pharmaceutical industries to potentially avoid them (e.g. ESR1, HDAC2, F2, PLG, PPARA, RXRA, etc). Based upon our KFC criteria, we have shortlisted ten proteins (GRB2, FYN, PIK3R1, CBL, JAK2, LCK, LYN, SYK, JAK1 and SOCS3) as effective candidates for drug development.

The maximum potential market for dengue drugs V 1.0.

PubMed

Dow, Geoffrey; Mora, Eric

2012-11-01

Drugs offer a complementary approach to vaccines for preventing the progression of symptoms and onset of the severe manifestations of dengue. Despite the rapid maturation of the research and development infrastructure for dengue drugs and the increasing frequency of dengue inhibitors reported in the scientific literature, the potential size of the market for dengue drugs has not been articulated. In the present work, extrapolating from publicly available information, we explored the economic burden attributable to dengue, the impact of dengue vaccines on clinical case loads, a possible alternative to tiered pricing for products for neglected diseases, and defined the maximum potential market for a dengue drug. Our projections suggest that in 2006, the annual global burden of dengue was US $1.7billion. Our proposed alternative to existing tiered pricing structures is that during a temporary period of market exclusivity, individual countries would pay 50% of the per-case equivalent of economic costs saved through the use of a dengue drug. This would yield prices per case of US $13-$239 depending on drug effectiveness and cost of medical and indirect costs and lost productivity in different countries. Assuming that such a pricing scheme was embraced, the maximum potential market for a dengue drug or drugs that on average reduced 40% of economic costs might be as high as US $338million annually. Our simulations suggest that dengue vaccines will begin to reduce the clinical case load of dengue in 2022, but that the number of cases will not decrease below 2006 levels and the proportion vaccinated will remain well below that required for the onset of herd immunity during the period of market exclusivity after the licensure of the first wave of dengue drugs. Copyright © 2012 Elsevier B.V. All rights reserved.

Parenting beliefs and practices of opiate-addicted parents: concealment and taboo.

PubMed

Hogan, Diane M

2003-07-01

The lifestyle associated with opiate dependence, including drug taking, the buying and selling of drugs, and contact with other drug users, carries potential risks for the safety and well-being of children of drug-using parents. Based on a qualitative interview study conducted with 50 opiate-dependent parents in Dublin, Ireland, the parenting beliefs and practices in relation to children's exposure to drugs and the associated lifestyle are described. Parents saw their lifestyle as potentially risky for their children and their families. The most common strategy adopted by parents was to conceal their drug-related activities and maintain a strict family taboo about these activities. Intervention programmes should be offered to support effective family communication about parental drug dependence. Copyright 2003 S. Karger AG, Basel

An update on applications of nanostructured drug delivery systems in cancer therapy: a review.

PubMed

Aberoumandi, Seyed Mohsen; Mohammadhosseini, Majid; Abasi, Elham; Saghati, Sepideh; Nikzamir, Nasrin; Akbarzadeh, Abolfazl; Panahi, Yunes; Davaran, Soodabeh

2017-09-01

Cancer is a main public health problem that is known as a malignant tumor and out-of-control cell growth, with the potential to assault or spread to other parts of the body. Recently, remarkable efforts have been devoted to develop nanotechnology to improve the delivery of anticancer drug to tumor tissue as minimizing its distribution and toxicity in healthy tissue. Nanotechnology has been extensively used in the advance of new strategies for drug delivery and cancer therapy. Compared to customary drug delivery systems, nano-based drug delivery method has greater potential in different areas, like multiple targeting functionalization, in vivo imaging, extended circulation time, systemic control release, and combined drug delivery. Nanofibers are used for different medical applications such as drug delivery systems.

Introduction of low dose transdermal buprenorphine -- did it influence use of potentially addictive drugs in chronic non-malignant pain patients?

PubMed

Skurtveit, Svetlana; Furu, Kari; Kaasa, Stein; Borchgrevink, Petter C

2009-10-01

The aim was to study the introduction of the new low dose transdermal buprenorphine (LD-TD-BUP) in Norway, particularly with regard to former use and co-medication with other potentially addictive drugs. The nationwide Norwegian Prescription Database contains information on all prescription drugs dispensed to individual non-institutionalised patients, and we may follow all individuals who received LD-TD-BUP (Norspan) after marketing on the Norwegian market on 15/11/05. We studied all prescriptions of opioids and other potentially addictive drugs to patients receiving at least two LD-TD-BUP prescriptions during 2004-2006. Poisson regressions were run with concomitant use of addictive drugs (yes, no) as the endpoint. Overall, 1884, non cancer individuals received at least two prescription of LD-TD-BUP. Of these 91.7% received prescriptions of other opioids and 58.6% of them had also been prescribed benzodiazepines/carisoprodol before the prescription of LD-TD-BUP. Of the LD-TD-BUP users who received more than one prescription, 60% co-medicated with at least one other potentially addictive drug, and 24% with at least two. In the multivariate analysis, the variables associated with a higher likelihood of using co-medicated drugs were: previous use of benzodiazepines/carisoprodol relative risk RR=16.7 (95% CI 10.4-26.9), previous use of opioids RR=4.0 (1.9-8.7) and younger age 20-40 years RR=1.9 (1.6-2.3). So far, it is questionable whether the introduction of LD-TD-BUP actually has stabilised opioids consumption or whether it has complicated and increased the consumption of potentially addictive drugs.

Improving the Clinical Pharmacologic Assessment of Abuse Potential: Part 1: Regulatory Context and Risk Management.

PubMed

Sellers, Edward M

2018-02-01

This article brings to the attention of drug developers the Food and Drug Administration's (FDA's) recent final Guidance to Industry on Assessment of Abuse Potential and provides practical suggestions about compliance with the Guidance. The Guidance areas are reviewed, analyzed, and placed in the context of current scientific knowledge and best practices to mitigate regulatory risk. The Guidance provides substantial new detail on what needs to be done at all stages of drug development for central nervous system-active drugs. However, because many psychopharmacologic agents have unique preclinical and clinical features, the plan for each agent needs to be not only carefully prepared but also reviewed and approved by the FDA. Examples are provided where assumptions about interpretation of the Guidance can delay development. If the expertise and experience needed for assessing abuse potential during drug development do not exist within a company, external preclinical and clinical expert should be involved. Consultation with the FDA is encouraged and important because the specific requirements for each drug will vary.

Medicated chewing gum--a potential drug delivery system.

PubMed

Chaudhary, Shivang A; Shahiwala, Aliasgar F

2010-07-01

Over the years, patient convenience and patient compliance-orientated research in the field of drug delivery has resulted in bringing out potential innovative drug delivery options. Out of which, medicated chewing gum (MCG) offers a highly convenient patient-compliant way of dosing medications, not only for special population groups with swallowing difficulties such as children and the elderly, but also for the general population, including the young generation. In this review, various formulation ingredients, different manufacturing processes, and assessment of in vivo and in vitro drug release from MCG are thoroughly discussed along with the therapeutic potential and limitations of MCG. Readers will gain knowledge about the rationale and prominent formulation and performance evaluation strategies behind chewing gum as a drug delivery system. The availability of directly compressible co-processed gum material enables rapid, safe and low-cost development of MCG as a drug delivery option. By MCG formulation, revitalization of old products and reformulation of new patented products is possible, to differentiate them from upcoming generics competition in the market.

78 FR 32669 - New Approaches to Antibacterial Drug Development; Request for Comments

Federal Register 2010, 2011, 2012, 2013, 2014

2013-05-31

...] New Approaches to Antibacterial Drug Development; Request for Comments AGENCY: Food and Drug... related to antibacterial drug development: Potential new study designs, proposed priorities for CDER guidances, and strategies intended to slow the rate of emerging resistance to antibacterial drugs. The...

42 CFR 484.55 - Condition of participation: Comprehensive assessment of patients.

Code of Federal Regulations, 2014 CFR

2014-10-01

...) Standard: Drug regimen review. The comprehensive assessment must include a review of all medications the patient is currently using in order to identify any potential adverse effects and drug reactions, including ineffective drug therapy, significant side effects, significant drug interactions, duplicate drug...

From the Cover: Potentiation of Drug-Induced Phospholipidosis In Vitro through PEGlyated Graphene Oxide as the Nanocarrier.

PubMed

Yang, Liecheng; Zhong, Xiaoyan; Li, Qian; Zhang, Xihui; Wang, Yangyun; Yang, Kai; Zhang, Leshuai W

2017-03-01

Cationic amphiphilic drugs (CADs) are small molecules that can induce phospholipidosis (PLD), causing the intracellular accumulation of phospholipid in the lamellar bodies. Nanotechnology based drug delivery systems have been used widely, while it is unknown if drug-induced PLD (DIP) can be potentiated through drug retention by indigestible nanocarriers. Due to the high drug loading capacity of graphene, we investigated if PEGylated graphene oxide (PEG-GO) loaded with CAD could potentiate DIP. Tamoxifen induced the accumulation of NBD-PE, a fluorescence labeled phospholipid in human hepatoma HepG2 cells, while PEG-GO loaded with tamoxifen (PEG-GO/tamoxifen) further potentiated PLD. PEG-GO/tamoxifen induced more gene expression of PLD marker than tamoxifen alone. PEG-GO enhanced DIP was also observed for other CAD, indicating that nanocarrier potentiated DIP could be universal. More lamellar bodies were observed in PEG-GO/tamoxifen treated cells than tamoxifen alone by transmission electron microscopy. When compared with tamoxifen alone, PEG-GO/tamoxifen showed a delayed but potent PLD. In addition, the retarded PLD recovery by PEG-GO/tamoxifen indicated that the reversibility of DIP was interfered. Confocal microscopy revealed the increased number of lysosomes, greater expression of lysosomal associated membrane protein 2 (LAMP2) (a PLD marker), and an increase in the co-localization between lysosome/LAMP2 and NBD-PE by PEG-GO/tamoxifen rather than tamoxifen alone. Finally, we found that PEG-GO or/and tamoxifen-induced PLD seemed to have no correlation with autophagy. This research suggests pharmaceutical companies and regulatory agencies that if nanoparticles are used as the vectors for drug delivery, the adverse drug effects may be further potentiated probably through the long-term accumulation of nanocarriers. © The Author 2016. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Development and characterization of pilocarpine loaded Eudragit nanosuspensions for ocular drug delivery.

PubMed

Khan, Mohammed S; Vishakante, Gowda D; Bathool, Afifa

2013-01-01

With aim of improving the availability of drug at intraocular level and to reduce the frequency of drug administration, pilocarpine nitrate nanosuspensions were made from inert polymer resin (Eudragit RL 100) with varying drug to polymer ratios using Lutrol F68 solution in various concentration. Nanosuspensions were successfully prepared by solvent displacement method. Size of nanoparticles varied between 121.5 +/- 2.28 to 291.5 +/- 1.28 nm, a polydispersity index ranging from 0.218 +/- 0.003 to 0.658 +/- 0.035 with zeta potential ranging +14.1 +/- 0.7 to +19.8 +/- 2.3 mV. Differential scanning calorimetry (DSC) and Fourier transform infrared spectroscopy (FTIR) studies clearly suggest the compatibility of the drug with the polymer used. Scanning electron microscopy (SEM) and Transmission electron microscopy (TEM) studies completely revealed that the drug loaded nanoparticles were found to be distinct, spherical in shape having a smooth surface and the drug is molecularly dispersed uniformly throughout the whole polymer matrix. PRL4 was successfully able to sustain the drug release for 24 hr as compared to other batches of formulated nanosuspensions. No significant change in average particle size and zeta potential were observed after conducting stability studies. Results of the studies clearly suggest the suitability of Eudragit RL 100 as a promising potential drug delivery adjuvant for ocular drug administration.

DNA Adducts from Anticancer Drugs as Candidate Predictive Markers for Precision Medicine

PubMed Central

2016-01-01

Biomarker-driven drug selection plays a central role in cancer drug discovery and development, and in diagnostic strategies to improve the use of traditional chemotherapeutic drugs. DNA-modifying anticancer drugs are still used as first line medication, but drawbacks such as resistance and side effects remain an issue. Monitoring the formation and level of DNA modifications induced by anticancer drugs is a potential strategy for stratifying patients and predicting drug efficacy. In this perspective, preclinical and clinical data concerning the relationship between drug-induced DNA adducts and biological response for platinum drugs and combination therapies, nitrogen mustards and half-mustards, hypoxia-activated drugs, reductase-activated drugs, and minor groove binding agents are presented and discussed. Aspects including measurement strategies, identification of adducts, and biological factors that influence the predictive relationship between DNA modification and biological response are addressed. A positive correlation between DNA adduct levels and response was observed for the majority of the studies, demonstrating the high potential of using DNA adducts from anticancer drugs as mechanism-based biomarkers of susceptibility, especially as bioanalysis approaches with higher sensitivity and throughput emerge. PMID:27936622

Effects of anti-malarial drugs on the electrocardiographic QT interval modelled in the isolated perfused guinea pig heart system

PubMed Central

2010-01-01

Background Concern over the potential cardiotoxicity of anti-malarial drugs inducing a prolonged electrocardiographic QT interval has resulted in the almost complete withdrawal from the market of one anti-malarial drug - halofantrine. The effects on the QT interval of four anti-malarial drugs were examined, using the guinea pig heart. Methods The guinea pig heart was isolated, mounted on a Langendorff apparatus, and was then perfused with pyruvate-added Klebs-Henseleit solutions containing graded concentrations of the four agents such as quinidine (0.15 - 1.2 μM), quinine (0.3 - 2.4 μM), halofantrine (0.1 - 2.0 μM) and mefloquine (0.1 - 2.0 μM). The heart rate-corrected QaTc intervals were measured to evaluate drug-induced QT prolongation effects. Results Quinidine, quinine, and halofantrine prolonged the QaTc interval in a dose-dependent manner, whereas no such effect was found with mefloquine. The EC50 values for the QaTc prolongation effects, the concentration that gives a half-maximum effect, were quinidine < quinine ≈ halofantrine. Conclusions In this study, an isolated, perfused guinea pig heart system was constructed to assess the cardiotoxic potential of anti-malarial drugs. This isolated perfused guinea pig heart system could be used to test newly developed anti-malarial drugs for their inherent QT lengthening potential. More information is required on the potential variation in unbound drug concentrations in humans, and their role in cardiotoxicity. PMID:21067575

Boston Collaborative Drug Surveillance Program

Cancer.gov

The Boston Collaborative Drug Surveillance Program started in 1966 and conducted epidemiologic research to quantify the potential adverse effects of prescription drugs, utilizing in-hospital monitoring.

Gene expression-based chemical genomics identifies potential therapeutic drugs in hepatocellular carcinoma.

PubMed

Chen, Ming-Huang; Yang, Wu-Lung R; Lin, Kuan-Ting; Liu, Chia-Hung; Liu, Yu-Wen; Huang, Kai-Wen; Chang, Peter Mu-Hsin; Lai, Jin-Mei; Hsu, Chun-Nan; Chao, Kun-Mao; Kao, Cheng-Yan; Huang, Chi-Ying F

2011-01-01

Hepatocellular carcinoma (HCC) is an aggressive tumor with a poor prognosis. Currently, only sorafenib is approved by the FDA for advanced HCC treatment; therefore, there is an urgent need to discover candidate therapeutic drugs for HCC. We hypothesized that if a drug signature could reverse, at least in part, the gene expression signature of HCC, it might have the potential to inhibit HCC-related pathways and thereby treat HCC. To test this hypothesis, we first built an integrative platform, the "Encyclopedia of Hepatocellular Carcinoma genes Online 2", dubbed EHCO2, to systematically collect, organize and compare the publicly available data from HCC studies. The resulting collection includes a total of 4,020 genes. To systematically query the Connectivity Map (CMap), which includes 6,100 drug-mediated expression profiles, we further designed various gene signature selection and enrichment methods, including a randomization technique, majority vote, and clique analysis. Subsequently, 28 out of 50 prioritized drugs, including tanespimycin, trichostatin A, thioguanosine, and several anti-psychotic drugs with anti-tumor activities, were validated via MTT cell viability assays and clonogenic assays in HCC cell lines. To accelerate their future clinical use, possibly through drug-repurposing, we selected two well-established drugs to test in mice, chlorpromazine and trifluoperazine. Both drugs inhibited orthotopic liver tumor growth. In conclusion, we successfully discovered and validated existing drugs for potential HCC therapeutic use with the pipeline of Connectivity Map analysis and lab verification, thereby suggesting the usefulness of this procedure to accelerate drug repurposing for HCC treatment.

Psychophysiological responses to drug-associated stimuli in chronic heavy cannabis use.

PubMed

Wölfling, Klaus; Flor, Herta; Grüsser, Sabine M

2008-02-01

Due to learning processes originally neutral stimuli become drug-associated and can activate an implicit drug memory, which leads to a conditioned arousing 'drug-seeking' state. This condition is accompanied by specific psychophysiological responses. The goal of the present study was the analysis of changes in cortical and peripheral reactivity to cannabis as well as alcohol-associated pictures compared with emotionally significant drug-unrelated and neutral pictures in long-term heavy cannabis users. Participants were 15 chronic heavy cannabis users and 15 healthy controls. Verbal reports as well as event-related potentials of the electroencephalogram and skin conductance responses were assessed in a cue-reactivity paradigm to determine the psychophysiological effects caused by drug-related visual stimulus material. The evaluation of self-reported craving and emotional processing showed that cannabis stimuli were perceived as more arousing and pleasant and elicited significantly more cannabis craving in cannabis users than in healthy controls. Cannabis users also demonstrated higher cannabis stimulus-induced arousal, as indicated by significantly increased skin conductance and a larger late positivity of the visual event-related brain potential. These findings support the assumption that drug-associated stimuli acquire increased incentive salience in addiction history and induce conditioned physiological patterns, which lead to craving and potentially to drug intake. The potency of visual drug-associated cues to capture attention and to activate drug-specific memory traces and accompanying physiological symptoms embedded in a cycle of abstinence and relapse--even in a 'so-called' soft drug--was assessed for the first time.

Potential geographic "hotspots" for drug-injection related transmission of HIV and HCV and for initiation into injecting drug use in New York City, 2011-2015, with implications for the current opioid epidemic in the US.

PubMed

Des Jarlais, D C; Cooper, H L F; Arasteh, K; Feelemyer, J; McKnight, C; Ross, Z

2018-01-01

We identified potential geographic "hotspots" for drug-injecting transmission of HIV and hepatitis C virus (HCV) among persons who inject drugs (PWID) in New York City. The HIV epidemic among PWID is currently in an "end of the epidemic" stage, while HCV is in a continuing, high prevalence (> 50%) stage. We recruited 910 PWID entering Mount Sinai Beth Israel substance use treatment programs from 2011-2015. Structured interviews and HIV/ HCV testing were conducted. Residential ZIP codes were used as geographic units of analysis. Potential "hotspots" for HIV and HCV transmission were defined as 1) having relatively large numbers of PWID 2) having 2 or more HIV (or HCV) seropositive PWID reporting transmission risk-passing on used syringes to others, and 3) having 2 or more HIV (or HCV) seronegative PWID reporting acquisition risk-injecting with previously used needles/syringes. Hotspots for injecting drug use initiation were defined as ZIP codes with 5 or more persons who began injecting within the previous 6 years. Among PWID, 96% injected heroin, 81% male, 34% White, 15% African-American, 47% Latinx, mean age 40 (SD = 10), 7% HIV seropositive, 62% HCV seropositive. Participants resided in 234 ZIP codes. No ZIP codes were identified as potential hotspots due to small numbers of HIV seropositive PWID reporting transmission risk. Four ZIP codes were identified as potential hotspots for HCV transmission. 12 ZIP codes identified as hotspots for injecting drug use initiation. For HIV, the lack of potential hotspots is further validation of widespread effectiveness of efforts to reduce injecting-related HIV transmission. Injecting-related HIV transmission is likely to be a rare, random event. HCV prevention efforts should include focus on potential hotspots for transmission and on hotspots for initiation into injecting drug use. We consider application of methods for the current opioid epidemic in the US.

Maternal drug use: evaluation of risks to breast-fed infants.

PubMed

Kirksey, A; Groziak, S M

1984-01-01

This paper, based on a review of the literature, evaluates the risks to infants of maternal drug use during lactation. The potential harm of a particular drug to the breastfed infant is related both to the complex mechanism of milk synthesis and secretion and the mode of passage of the drug from plasma into milk. The 1st part of the paper discusses mammary cell and milk synthesis, milk secretion and composition, the mode of passage of drugs into milk, and factors influencing drug concentrations in milk. Drug concentrations in milk are dependent on 6 major factors: drug dosage, proportion bound in plasma, molecular weight, lipid solubility, degree of ionization, and pH difference between plasma and milk. Drugs that are weak acids are ionized to a greater extent and are more protein-bound than weak alkaline drugs. The 2nd part of the paper evaluates the risks to breastfed infants of selected pharmacons. Some categories of drugs that contain pharmacons that should be limited or avoided by nursing mothers are alkylating agents, analgesics and anti-inflammatory agents, anticoagulants, anticonvulsants, anti-infective agents, central nervous system stimulants, hormones, laxatives, minerals, provitamins, psychotherapeutic agents, thyroid affecting agents, and vitamins. The following precautions are suggested to minimize the risks of potentially harmful pharmacons: 1) all unnecessary medications should be avoided by nrusing mothers; 2) if medication is necessary during lactation, drug dosage should be controlled and the infant should be monitored for adverse symptoms; 3) drugs should be administered shortly after breastfeeding and the interval prolonged before the next feeding; and 4) if the infant must be fed soon after a potentially harmful drug has been taken by the mother, bottle feeding is recommended.

Cancer stem cells and drug resistance: the potential of nanomedicine

PubMed Central

Vinogradov, Serguei; Wei, Xin

2012-01-01

Properties of the small group of cancer cells called tumor-initiating or cancer stem cells (CSCs) involved in drug resistance, metastasis and relapse of cancers can significantly affect tumor therapy. Importantly, tumor drug resistance seems to be closely related to many intrinsic or acquired properties of CSCs, such as quiescence, specific morphology, DNA repair ability and overexpression of antiapoptotic proteins, drug efflux transporters and detoxifying enzymes. The specific microenvironment (niche) and hypoxic stability provide additional protection against anticancer therapy for CSCs. Thus, CSC-focused therapy is destined to form the core of any effective anticancer strategy. Nanomedicine has great potential in the development of CSC-targeting drugs, controlled drug delivery and release, and the design of novel gene-specific drugs and diagnostic modalities. This review is focused on tumor drug resistance-related properties of CSCs and describes current nanomedicine approaches, which could form the basis of novel combination therapies for eliminating metastatic and CSCs. PMID:22471722

Investigation of Carrageenan Aerogel Microparticles as a Potential Drug Carrier.

PubMed

Obaidat, Rana M; Alnaief, Mohammad; Mashaqbeh, Hadeia

2018-05-07

Carrageenan is an anionic polysaccharide offering many advantages to be used in drug delivery applications. These include availability, thermo-stability, low toxicity, and encapsulating properties. Combination of these properties with aerogel properties like large surface area and porosity make them an ideal candidate for drug adsorption and delivery applications. Emulsion-gelation technique was used to prepare carrageenan gel microparticles with supercritical CO 2 for drying and loading purposes. Ibuprofen has been selected as a model drug for drug loading inside. The prepared microparticles were characterized using particle size analysis, X-ray diffraction, differential scanning calorimetry, Fourier transform infrared spectroscopy, density measurements, surface area, and porosity measurements. Finally, dissolution was applied to the loaded preparations to test in vitro drug release. Ibuprofen was successfully loaded in the amorphous form inside the prepared microparticles with a significant enhancement in the drug release profile. In conclusion, prepared carrageenan aerogel microparticles showed an excellent potential for use as a drug carrier.

Enteral feeding: drug/nutrient interaction.

PubMed

Lourenço, R

2001-04-01

Enteral nutrition support via a feeding tube is the first choice for artificial nutrition. Most patients also require simultaneous drug therapy, with the potential risk for drug-nutrient interactions which may become relevant in clinical practice. During enteral nutrition, drug-nutrient interactions are more likely to occur than in patients fed orally. However, there is a lack of awareness about its clinical significance, which should be recognised and prevented in order to optimise nutritional and pharmacological therapeutic goals of safety and efficacy. To raise the awareness of potential drug-nutrient interactions and influence on clinical outcomes. To identify factors that can promote drug-nutrient interactions and contribute to nutrition and/or therapeutic failure. To be aware of different types of drug-nutrient interactions. To understand complex underlying mechanisms responsible for drug-nutrient interactions. To learn basic rules for the administration of medications during tube-feeding. Copyright 2001 Harcourt Publishers Ltd.

Thiolated polymers as mucoadhesive drug delivery systems.

PubMed

Duggan, Sarah; Cummins, Wayne; O' Donovan, Orla; Hughes, Helen; Owens, Eleanor

2017-03-30

Mucoadhesion is the process of binding a material to the mucosal layer of the body. Utilising both natural and synthetic polymers, mucoadhesive drug delivery is a method of controlled drug release which allows for intimate contact between the polymer and a target tissue. It has the potential to increase bioavailability, decrease potential side effects and offer protection to more sensitive drugs such as proteins and peptide based drugs. The thiolation of polymers has, in the last number of years, come to the fore of mucoadhesive drug delivery, markedly improving mucoadhesion due to the introduction of free thiol groups onto the polymer backbone while also offering a more cohesive polymeric matrix for the slower and more controlled release of drug. This review explores the concept of mucoadhesion and the recent advances in both the polymers and the methods of thiolation used in the synthesis of mucoadhesive drug delivery devices. Copyright © 2017 Elsevier B.V. All rights reserved.

Glucose-6-phosphate dehydrogenase deficiency and antimalarial drug development.

PubMed

Beutler, Ernest; Duparc, Stephan

2007-10-01

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is relatively common in populations exposed to malaria. This deficiency appears to provide some protection from this infection, but it can also cause hemolysis after administration of some antimalarial drugs, especially primaquine. The risk of drug-induced G6PD deficiency-related hemolysis depends on a number of factors including the G6PD variant, the drug and drug dosage schedule, patient status, and disease factors. Although a great deal is known about the molecular biology of G6PD, determining the potential for drug-induced hemolysis in the clinical setting is still challenging. This report discusses the potential strategies for assessing drug-induced G6PD deficiency-related hemolytic risk preclinically and in early clinical trials. Additionally, the issues important for conducting larger clinical trials in populations in which G6PD deficiency is prevalent are examined, with a particular focus on antimalarial drug development.

Drug Interactions and Antiretroviral Drug Monitoring

PubMed Central

Foy, Matthew; Sperati, C. John; Lucas, Gregory M.

2014-01-01

Due to the improved longevity afforded by combination antiretroviral therapy (cART), HIV-infected individuals are developing several non-AIDS related comorbid conditions. Consequently, medical management of the HIV-infected population is increasingly complex, with a growing list of potential drug-drug interactions (DDIs). This article reviews some of the most relevant and emerging potential interactions between antiretroviral medications and other agents. The most common DDIs are those involving protease inhibitors or non-nucleoside reverse transcriptase inhibitors which alter the cytochrome P450 enzyme system and/or drug transporters such as p-glycoprotein. Of note are the new agents for the treatment of chronic hepatitis C virus infection. These new classes of drugs and others drugs which are increasingly used in this patient population represent a significant challenge with regard to achieving the goals of effective HIV suppression and minimization of drug-related toxicities. Awareness of DDIs and a multidisciplinary approach are imperative in reaching these goals. PMID:24950731

Discovery of novel drugs for promising targets.

PubMed

Martell, Robert E; Brooks, David G; Wang, Yan; Wilcoxen, Keith

2013-09-01

Once a promising drug target is identified, the steps to actually discover and optimize a drug are diverse and challenging. The goal of this study was to provide a road map to navigate drug discovery. Review general steps for drug discovery and provide illustrating references. A number of approaches are available to enhance and accelerate target identification and validation. Consideration of a variety of potential mechanisms of action of potential drugs can guide discovery efforts. The hit to lead stage may involve techniques such as high-throughput screening, fragment-based screening, and structure-based design, with informatics playing an ever-increasing role. Biologically relevant screening models are discussed, including cell lines, 3-dimensional culture, and in vivo screening. The process of enabling human studies for an investigational drug is also discussed. Drug discovery is a complex process that has significantly evolved in recent years. © 2013 Elsevier HS Journals, Inc. All rights reserved.

Nanobiotechnology and its applications in drug delivery system: a review.

PubMed

Khan, Imran; Khan, Momin; Umar, Muhammad Naveed; Oh, Deog-Hwan

2015-12-01

Nanobiotechnology holds great potential in various regimes of life sciences. In this review, the potential applications of nanobiotechnology in various sectors of nanotechnologies, including nanomedicine and nanobiopharmaceuticals, are highlighted. To overcome the problems associated with drug delivery, nanotechnology has gained increasing interest in recent years. Nanosystems with different biological properties and compositions have been extensively investigated for drug delivery applications. Nanoparticles fabricated through various techniques have elevated therapeutic efficacy, provided stability to the drugs and proved capable of targeting the cells and controlled release inside the cell. Polymeric nanoparticles have shown increased development and usage in drug delivery as well as in diagnostics in recent decades.

Sample preservation for the analysis of antibiotics in water.

PubMed

Llorca, Marta; Gros, Meritxell; Rodríguez-Mozaz, Sara; Barceló, Damià

2014-11-21

This paper describes a stability study performed for 56 antibiotics belonging to 9 different groups--macrolides, tetracyclines, fluoroquinolones, quinolones, penicillins, cephalosporines, lincosamides, sulfonamides and nitroimidazole antibiotics--in purified water samples fortified with the selected compounds at 10 ng/ml. For this purpose, three different sample preservation modes were tested with the aim of avoiding biotic and abiotic degradation: (i) storage at -20°C, (ii) storage at -20°C with 0.1% of EDTA and (iii) pre-concentration in a solid phase extraction cartridge (SPE), which was afterwards stored at -20°C. Concentrations of antibiotics in the samples preserved using the different protocols were monitored after 0, 1, 2 and 12 weeks. The results showed that, for the accurate determination of all compounds they should be analyzed right after sampling. However, if this is not possible, most of the antibiotics can be analyzed within the 1st week after sampling and preservation at -20°C (with or without EDTA) or in a SPE cartridges at -20°C. Nonetheless, some antibiotics found extensively in the environment, such as sulfamethoxazole, ciprofloxacin, ofloxacin, erythromycin, azithromycin and clarithromycin exhibited low stability after 1 week preservation and, therefore, they should be analyzed within this time. Copyright © 2014 Elsevier B.V. All rights reserved.

PET radiopharmaceuticals for imaging of tumor hypoxia: a review of the evidence

PubMed Central

Lopci, Egesta; Grassi, Ilaria; Chiti, Arturo; Nanni, Cristina; Cicoria, Gianfranco; Toschi, Luca; Fonti, Cristina; Lodi, Filippo; Mattioli, Sandro; Fanti, Stefano

2014-01-01

Hypoxia is a pathological condition arising in living tissues when oxygen supply does not adequately cover the cellular metabolic demand. Detection of this phenomenon in tumors is of the utmost clinical relevance because tumor aggressiveness, metastatic spread, failure to achieve tumor control, increased rate of recurrence, and ultimate poor outcome are all associated with hypoxia. Consequently, in recent decades there has been increasing interest in developing methods for measurement of oxygen levels in tumors. Among the image-based modalities for hypoxia assessment, positron emission tomography (PET) is one of the most extensively investigated based on the various advantages it offers, i.e., broad range of radiopharmaceuticals, good intrinsic resolution, three-dimensional tumor representation, possibility of semiquantification/quantification of the amount of hypoxic tumor burden, overall patient friendliness, and ease of repetition. Compared with the other non-invasive techniques, the biggest advantage of PET imaging is that it offers the highest specificity for detection of hypoxic tissue. Starting with the 2-nitroimidazole family of compounds in the early 1980s, a great number of PET tracers have been developed for the identification of hypoxia in living tissue and solid tumors. This paper provides an overview of the principal PET tracers applied in cancer imaging of hypoxia and discusses in detail their advantages and pitfalls. PMID:24982822

Hypoxia-activated prodrug enhances therapeutic effect of sunitinib in melanoma

PubMed Central

Liu, Shujing; Tetzlaff, Michael T.; Wang, Tao; Chen, Xiang; Yang, Ruifeng; Kumar, Suresh M.; Vultur, Adina; Li, Pengxiang; Martin, James S.; Herlyn, Meenhard; Amaravadi, Ravi

2017-01-01

Angiogenesis is a critical step during tumor progression. Anti-angiogenic therapy has only provided modest benefits in delaying tumor progression despite its early promise in cancer treatment. It has been postulated that anti-angiogenic therapy may promote the emergence of a more aggressive cancer cell phenotype by generating increased tumor hypoxia—a well-recognized promoter of tumor progression. TH-302 is a 2-nitroimidazole triggered hypoxia-activated prodrug (HAP) which has been shown to selectively target the hypoxic tumor compartment and reduce tumor volume. Here, we show that melanoma cells grown under hypoxic conditions exhibit increased resistance to a wide variety of therapeutic agents in vitro and generate larger and more aggressive tumors in vivo than melanoma cells grown under normoxic conditions. However, hypoxic melanoma cells exhibit a pronounced sensitivity to TH-302 which is further enhanced by the addition of sunitinib. Short term sunitinib treatment fails to prolong the survival of melanoma bearing genetically engineered mice (Tyr::CreER; BRafCA;Ptenlox/lox) but increases tumor hypoxia. Long term TH-302 alone modestly prolongs the overall survival of melanoma bearing mice. Combination therapy of TH-302 with sunitinib further increases the survival of treated mice. These studies provide a translational rationale for combining hypoxic tumor cell targeted therapies with anti-angiogenics for treatment of melanoma. PMID:29383148

Use of Ronidazole and Limited Culling To Eliminate Tritrichomonas muris from Laboratory Mice.

PubMed

Steiner, Jörg M; Schwamberger, Sabine; Pantchev, Nikola; Balzer, Hans-Jörg; Vrhovec, Majda Globokar; Lesina, Marina; Algül, Hana

2016-01-01

Tritrichomonas muris is occasionally identified during routine fecal screening of laboratory mice. Frequently, entire racks are affected, and because no effective treatment is available, culling of affected mice and rederivation by embryo transfer have been suggested. The current study evaluated whether treatment with ronidazole, a nitroimidazole efficacious against T. fetus infections in cats, combined with limited culling was effective against T. muris in laboratory mice (Mus musculus). A subset (n = 39) of mice were treated with ronidazole (400 mg/L in drinking water) for 15 d, after which 6 of the mice still shed T. muris. Consequently all mice in the affected rack received ronidazole (500 mg /L in drinking water) for 25 d. All mice were retested by using pooled samples, and those positive for T. muris (except for a valuable breeding pair) were culled. The remaining mice continued to receive ronidazole for another 17 d. At the end of the treatment period, all mice were tested (days 60 and 81) and were shown to be negative for T. muris. Over the following year, sentinel mice from the rack were tested every 3 mo and remained negative for tritrichomonads by fecal smear. Thus, a combination of limited culling and treatment with ronidazole in the drinking water successfully cleared research mice of infection with T. muris.

Evaluation of hypoxic tissue dynamics with 18F-FMISO PET in a rat model of permanent cerebral ischemia.

PubMed

Rojas, Santiago; Herance, José Raul; Abad, Sergio; Jiménez, Xavier; Pareto, Deborah; Ruiz, Alba; Torrent, Èlia; Figueiras, Francisca P; Popota, Foteini; Fernández-Soriano, Francisco J; Planas, Anna M; Gispert, Juan D

2011-06-01

[¹⁸F]Fluoromisonidazole (¹⁸F-FMISO) is a nitroimidazole derivative that has been proposed as a positron emission tomography (PET) radiotracer to detect hypoxic tissue in vivo. This compound accumulates in hypoxic but viable tissue and may be a good candidate for evaluating the ischemic penumbra. We evaluated the time course of ¹⁸F-FMISO uptake using PET in a rat model of permanent cerebral ischemia and the correlation with histological changes. Rats (n = 14) were subjected to permanent ischemia by intraluminal occlusion of the middle cerebral artery in order to assess by PET the uptake of ¹⁸F-FMISO at various times over 24 h following ischemia. The PET results were compared to histological changes with Nissl and 2,3,5 triphenyltetrazolium chloride staining. Elevated uptake of ¹⁸F-FMISO was detected in the infarcted area up to 8 h after occlusion but was no longer detected at 24 h, a time point coincident with pan necrosis of the tissue. Our findings suggest that salvageable tissue persists for up to 8 h in this rat model of brain ischemia. We propose ¹⁸F-FMISO PET as a tool for evaluating the ischemic penumbra after cerebral ischemia.

Teratogenic Potential of Antiepileptic Drugs in the Zebrafish Model

PubMed Central

Lee, Sung Hak; Kang, Jung Won; Lin, Tao; Lee, Jae Eun; Jin, Dong Il

2013-01-01

The zebrafish model is an attractive candidate for screening of developmental toxicity during early drug development. Antiepileptic drugs (AEDs) arouse concern for the risk of teratogenicity, but the data are limited. In this study, we evaluated the teratogenic potential of seven AEDs (carbamazepine (CBZ), ethosuximide (ETX), valproic acid (VPN), lamotrigine (LMT), lacosamide (LCM), levetiracetam (LVT), and topiramate (TPM)) in the zebrafish model. Zebrafish embryos were exposed to AEDs from initiation of gastrula (5.25 hours post-fertilization (hpf)) to termination of hatching (72 hpf) which mimic the mammalian teratogenic experimental design. The lethality and teratogenic index (TI) of AEDs were determined and the TI values of each drug were compared with the US FDA human pregnancy categories. Zebrafish model was useful screening model for teratogenic potential of antiepilepsy drugs and was in concordance with in vivo mammalian data and human clinical data. PMID:24324971

Teratogenic potential of antiepileptic drugs in the zebrafish model.

PubMed

Lee, Sung Hak; Kang, Jung Won; Lin, Tao; Lee, Jae Eun; Jin, Dong Il

2013-01-01

The zebrafish model is an attractive candidate for screening of developmental toxicity during early drug development. Antiepileptic drugs (AEDs) arouse concern for the risk of teratogenicity, but the data are limited. In this study, we evaluated the teratogenic potential of seven AEDs (carbamazepine (CBZ), ethosuximide (ETX), valproic acid (VPN), lamotrigine (LMT), lacosamide (LCM), levetiracetam (LVT), and topiramate (TPM)) in the zebrafish model. Zebrafish embryos were exposed to AEDs from initiation of gastrula (5.25 hours post-fertilization (hpf)) to termination of hatching (72 hpf) which mimic the mammalian teratogenic experimental design. The lethality and teratogenic index (TI) of AEDs were determined and the TI values of each drug were compared with the US FDA human pregnancy categories. Zebrafish model was useful screening model for teratogenic potential of antiepilepsy drugs and was in concordance with in vivo mammalian data and human clinical data.

Therapeutic Potential of Foldamers: From Chemical Biology Tools To Drug Candidates?

PubMed

Gopalakrishnan, Ranganath; Frolov, Andrey I; Knerr, Laurent; Drury, William J; Valeur, Eric

2016-11-10

Over the past decade, foldamers have progressively emerged as useful architectures to mimic secondary structures of proteins. Peptidic foldamers, consisting of various amino acid based backbones, have been the most studied from a therapeutic perspective, while polyaromatic foldamers have barely evolved from their nascency and remain perplexing for medicinal chemists due to their poor drug-like nature. Despite these limitations, this compound class may still offer opportunities to study challenging targets or provide chemical biology tools. The potential of foldamer drug candidates reaching the clinic is still a stretch. Nevertheless, advances in the field have demonstrated their potential for the discovery of next generation therapeutics. In this perspective, the current knowledge of foldamers is reviewed in a drug discovery context. Recent advances in the early phases of drug discovery including hit finding, target validation, and optimization and molecular modeling are discussed. In addition, challenges and focus areas are debated and gaps highlighted.

Gemcitabine-based polymer-drug conjugate for enhanced anticancer effect in colon cancer.

PubMed

Liang, Tie-Jun; Zhou, Zhong-Mei; Cao, Ying-Qing; Ma, Ming-Ze; Wang, Xiao-Jun; Jing, Kai

2016-11-20

In this study, we have demonstrated gemcitabine (GEM)-conjugated amphiphilic biodegradable polymeric drug carriers. Our aim was to increase the chemotherapeutic potential of GEM in colon cancer by forming a unique polymer-drug conjugates. The polymer-drug conjugate micelles were nanosized with a typical spherical shape. The GEM-conjugated methoxy poly(ethylene glycol)-poly(lactic acid) (GEM-PL) exhibited a controlled release of drug in both the pH conditions. The developed GEM-PL efficiently killed the HT29 cancers cells in a typical time dependent manner. The clonogenic assay further confirmed the superior anticancer effect of GEM-PL which showed least number of colonies. GEM-PL formulation exhibited a significantly higher apoptosis of cancer cells (∼25%) when stained using Annexin-V/PI kit. Conjugation of GEM to the mPEG-PLA significantly enhanced the blood circulation potential in animal model compared to that of free GEM. GEM-PL could prevent quick elimination of the drug and can provide sufficient time for the greater accumulation of GEM at the tumor sites. GEM-PL showed a remarkable tumor regression effect as evident from the lowest tumor volume in HT-29 containing tumor model. Overall, mPEG-PLA/GEM conjugates showed the potential of polymer-based drug targeting and might hold significant clinical potential in the treatment of colon cancers. Copyright © 2016 Elsevier B.V. All rights reserved.

Intimate partner violence and prescription of potentially addictive drugs: prospective cohort study of women in the Oslo Health Study.

PubMed

Stene, Lise Eilin; Dyb, Grete; Tverdal, Aage; Jacobsen, Geir Wenberg; Schei, Berit

2012-01-01

To investigate the prescription of potentially addictive drugs, including analgesics and central nervous system depressants, to women who had experienced intimate partner violence (IPV). Prospective population-based cohort study. Information about IPV from the Oslo Health Study 2000/2001 was linked with prescription data from the Norwegian Prescription Database from 1 January 2004 through 31 December 2009. The study included 6081 women aged 30-60 years. Prescription rate ratios (RRs) for potentially addictive drugs derived from negative binomial models, adjusted for age, education, paid employment, marital status, chronic musculoskeletal pain, mental distress and sleep problems. Altogether 819 (13.5%) of 6081 women reported ever experiencing IPV: 454 (7.5%) comprised physical and/or sexual IPV and 365 (6.0%) psychological IPV alone. Prescription rates for potentially addictive drugs were clearly higher among women who had experienced IPV: crude RRs were 3.57 (95% CI 2.89 to 4.40) for physical/sexual IPV and 2.13 (95% CI 1.69 to 2.69) for psychological IPV alone. After full adjustment RRs were 1.83 (1.50 to 2.22) for physical/sexual IPV, and 1.97 (1.59 to 2.45) for psychological IPV alone. Prescription rates were increased both for potentially addictive analgesics and central nervous system depressants. Furthermore, women who reported IPV were more likely to receive potentially addictive drugs from multiple physicians. Women who had experienced IPV, including psychological violence alone, more often received prescriptions for potentially addictive drugs. Researchers and clinicians should address the possible adverse health and psychosocial impact of such prescription and focus on developing evidence-based healthcare for women who have experienced IPV.

[Use of urine drug screening in the emergency department of a paediatric hospital].

PubMed

Ferrer Bosch, Núria; Martínez Sánchez, Lidia; Trenchs Sainz de la Maza, Victoria; Velasco Rodríguez, Jesús; García González, Elsa; Luaces Cubells, Carles

2018-01-01

To describe the situations in which urine drug screening is used in a Paediatric Emergency Department (ED). An analysis is also made on its potential usefulness on whether it changes the patient management, and if the results are confirmed by using specific techniques. A retrospective study was conducted on patients under the age of 18 attended in the ED during 2014 and in whom urine drug screening was requested. Depending on the potential capacity of the screening result to change patient management, two groups were defined (potentially useful and not potentially useful). Urine drug screening was performed on a total of 161 patients. The screening was considered not to be potentially useful in 87 (54.0%). This was because the clinical history already explained the symptoms the patient had in 55 (34.1%) patients, in 29 (18.0%) because the patient was asymptomatic, and in 3 (1.9%) because the suspected drug was not detectable in the screening. The drug screening results changed the patient management in 5 (3.1%) cases. A toxic substance was detected in 44 (27.3%). Two out of the 44 that were positive (2.1%) were re-tested by specific techniques, and presence of the toxic substance was ruled out in both of them (false positives). Most of the drug screening tests are not justified, and it is very infrequent that they change patient management. It is very rare that the results are confirmed using more specific methods. Urine drug screening tests should be restricted to particular cases and if the result has legal implications, or if the patient denies using the drug, it should be followed by a specific toxicological study to provide a conclusive result. Copyright © 2016 Asociación Española de Pediatría. Publicado por Elsevier España, S.L.U. All rights reserved.

Evolving regulatory paradigm for proarrhythmic risk assessment for new drugs.

PubMed

Vicente, Jose; Stockbridge, Norman; Strauss, David G

Fourteen drugs were removed from the market worldwide because their potential to cause torsade de pointes (torsade), a potentially fatal ventricular arrhythmia. The observation that most drugs that cause torsade block the potassium channel encoded by the human ether-à-go-go related gene (hERG) and prolong the heart rate corrected QT interval (QTc) on the ECG, led to a focus on screening new drugs for their potential to block the hERG potassium channel and prolong QTc. This has been a successful strategy keeping torsadogenic drugs off the market, but has resulted in drugs being dropped from development, sometimes inappropriately. This is because not all drugs that block the hERG potassium channel and prolong QTc cause torsade, sometimes because they block other channels. The regulatory paradigm is evolving to improve proarrhythmic risk prediction. ECG studies can now use exposure-response modeling for assessing the effect of a drug on the QTc in small sample size first-in-human studies. Furthermore, the Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative is developing and validating a new in vitro paradigm for cardiac safety evaluation of new drugs that provides a more accurate and comprehensive mechanistic-based assessment of proarrhythmic potential. Under CiPA, the prediction of proarrhythmic potential will come from in vitro ion channel assessments coupled with an in silico model of the human ventricular myocyte. The preclinical assessment will be checked with an assessment of human phase 1 ECG data to determine if there are unexpected ion channel effects in humans compared to preclinical ion channel data. While there is ongoing validation work, the heart rate corrected J-T peak interval is likely to be assessed under CiPA to detect inward current block in presence of hERG potassium channel block. Copyright © 2016 Elsevier Inc. All rights reserved.

A Review of the Toxicity of HIV Medications II: Interactions with Drugs and Complementary and Alternative Medicine Products.

PubMed

Stolbach, Andrew; Paziana, Karolina; Heverling, Harry; Pham, Paul

2015-09-01

For many patients today, HIV has become a chronic disease. For those patients who have access to and adhere to lifelong antiretroviral (ARV) therapy, the potential for drug-drug interactions has become a real and life-threatening concern. It is known that most ARV drug interactions occur through the cytochrome P450 (CYP) pathway. Medications for comorbid medical conditions, holistic supplements, and illicit drugs can be affected by CYP inhibitors and inducers and have the potential to cause harm and toxicity. Protease inhibitors (PIs) tend to inhibit CYP3A4, while most non-nucleoside reverse transcriptase inhibitors (NNRTIs) tend to induce the enzyme. As such, failure to adjust the dose of co-administered medications, such as statins and steroids, may lead to serious complications including rhabdomyolysis and hypercortisolism, respectively. Similarly, gastric acid blockers can decrease several ARV absorption, and warfarin doses may need to be adjusted to maintain therapeutic concentrations. Illicit drugs such as methylenedioxymethamphetamine (MDMA, "ecstasy") in combination with PIs lead to increased toxicity, while the concomitant administration of sedative drugs such as midazolam and alprazolam in patients taking PIs can result in prolonged sedation, delayed recovery, and increased length of stay. Even supplements like St. John's Wort can alter PI concentrations. In theory, any drug that is metabolized by CYP has potential for a pharmacokinetic drug-drug interaction with all PIs, cobicistat, and most NNRTIs. When adding a new medication to an ARV regimen, use of a drug-drug interaction software and/or consultation with a clinical pharmacist/pharmacologist or HIV specialist is recommended.

Basophil Reactivity as Biomarker in Immediate Drug Hypersensitivity Reactions—Potential and Limitations

PubMed Central

Steiner, Markus; Harrer, Andrea; Himly, Martin

2016-01-01

Immediate drug hypersensitivity reactions (DHRs) resemble typical immunoglobulin E (IgE)-mediated symptoms. Clinical manifestations range from local skin reactions, gastrointestinal and/or respiratory symptoms to severe systemic involvement with potential fatal outcome. Depending on the substance group of the eliciting drug the correct diagnosis is a major challenge. Skin testing and in vitro diagnostics are often unreliable and not reproducible. The involvement of drug-specific IgE is questionable in many cases. The culprit substance (parent drug or metabolite) and potential cross-reacting compounds are difficult to identify, patient history and drug provocation testing often remain the only means for diagnosis. Hence, several groups proposed basophil activation test (BAT) for the diagnosis of immediate DHRs as basophils are well-known effector cells in allergic reactions. However, the usefulness of BAT in immediate DHRs is highly variable and dependent on the drug itself plus its capacity to spontaneously conjugate to serum proteins. Stimulation with pure solutions of the parent drug or metabolites thereof vs. drug-protein conjugates may influence sensitivity and specificity of the test. We thus, reviewed the available literature about the use of BAT for diagnosing immediate DHRs against drug classes such as antibiotics, radio contrast media, neuromuscular blocking agents, non-steroidal anti-inflammatory drugs, and biologicals. Influencing factors like the selection of stimulants or of the identification and activation markers, the stimulation protocol, gating strategies, and cut-off definition are addressed in this overview on BAT performance. The overall aim is to evaluate the suitability of BAT as biomarker for the diagnosis of immediate drug-induced hypersensitivity reactions. PMID:27378928

Emergence of cytotoxic resistance in cancer cell populations: Single-cell mechanisms and population-level consequences

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lorenzi, Tommaso; Chisholm, Rebecca H.; Lorz, Alexander

We formulate an individual-based model and a population model of phenotypic evolution, under cytotoxic drugs, in a cancer cell population structured by the expression levels of survival-potential and proliferation-potential. We apply these models to a recently studied experimental system. Our results suggest that mechanisms based on fundamental laws of biology can reversibly push an actively-proliferating, and drug-sensitive, cell population to transition into a weakly-proliferative and drug-tolerant state, which will eventually facilitate the emergence of more potent, proliferating and drug-tolerant cells.

Epigenetic drug discovery for Alzheimer's disease.

PubMed

Cacabelos, Ramón; Torrellas, Clara

2014-09-01

It is assumed that epigenetic modifications are reversible and could potentially be targeted by pharmacological and dietary interventions. Epigenetic drugs are gaining particular interest as potential candidates for the treatment of Alzheimer's disease (AD). This article covers relevant information from over 50 different epigenetic drugs including: DNA methyltransferase inhibitors; histone deacetylase inhibitors; histone acetyltransferase modulators; histone methyltransferase inhibitors; histone demethylase inhibitors; non-coding RNAs (microRNAs) and dietary regimes. The authors also review the pharmacoepigenomics and the pharmacogenomics of epigenetic drugs. The readers will gain insight into i) the classification of epigenetic drugs; ii) the mechanisms by which these drugs might be useful in AD; iii) the pharmacological properties of selected epigenetic drugs; iv) pharmacoepigenomics and the influence of epigenetic drugs on genes encoding CYP enzymes, transporters and nuclear receptors; and v) the genes associated with the pharmacogenomics of anti-dementia drugs. Epigenetic drugs reverse epigenetic changes in gene expression and might open future avenues in AD therapeutics. Unfortunately, clinical trials with this category of drugs are lacking in AD. The authors highlight the need for pharmacogenetic and pharmacoepigenetic studies to properly evaluate any efficacy and safety issues.

Drugs in hair. Part I. Metabolisms of major drug classes.

PubMed

White, R M

2017-01-01

Currently, hair can be reliably tested for the presence of drugs. However, one major drawback to the use of parent drugs is the question of potential external or environmental contamination. The analysis of metabolites to confirm the use of the parent drugs was proposed in this short review. The development of hair as a test matrix and the incorporation of xenobiotics, in general, into the hair matrix were discussed. What constitutes an appropriate metabolite for drug testing to mirror the use of a parent drug was proposed and discussed. The use of metabolites rather than parent drugs to indicate unequivocal use rather than external exposure was also discussed for amphetamines, cannabinoids, cocaine, opiates (codeine, morphine, 6-acetylmorphine, hydrocodone, hydromorphone, oxycodone, oxymorphone), phencyclidine, fentanyl, benzodiazepines, and ethanol. This, however, was discussed in terms of class and/or individual drug. In addition, selection or potential selection of appropriate metabolites was reviewed. The actual incorporation of drug metabolites into hair versus the metabolism of drugs which was incorporated into hair were also considered. Copyright © 2017 Central Police University.

75 FR 23782 - Drug Safety and Risk Management Advisory Committee; Notice of Meeting

Federal Register 2010, 2011, 2012, 2013, 2014

2010-05-04

...] Drug Safety and Risk Management Advisory Committee; Notice of Meeting AGENCY: Food and Drug...: Drug Safety and Risk Management Advisory Committee. General Function of the Committee: To provide... potential of the drug dextromethorphan and the public health benefits and risks of dextromethorphan use as a...

An Application of Fractional Factorial Designs to Study Drug Combinations

PubMed Central

Jaynes, Jessica; Ding, Xianting; Xu, Hongquan; Wong, Weng Kee; Ho, Chih-Ming

2013-01-01

Herpes simplex virus type 1 (HSV-1) is known to cause diseases of various severities. There is increasing interest to find drug combinations to treat HSV-1 by reducing drug resistance and cytotoxicity. Drug combinations offer potentially higher efficacy and lower individual drug dosage. In this paper, we report a new application of fractional factorial designs to investigate a biological system with HSV-1 and six antiviral drugs, namely, Interferon-alpha, Interferon-beta, Interferon-gamma, Ribavirin, Acyclovir, and TNF-alpha. We show how the sequential use of two- and three-level fractional factorial designs can screen for important drugs and drug interactions, as well as determine potential optimal drug dosages through the use of contour plots. Our initial experiment using a two-level fractional factorial design suggests that there is model inadequacy and drug dosages should be reduced. A follow-up experiment using a blocked three-level fractional factorial design indicates that TNF-alpha has little effect and HSV-1 infection can be suppressed effectively by using a right combination of the other five antiviral drugs. These observations have practical implications in the understanding of antiviral drug mechanism that can result in better design of antiviral drug therapy. PMID:22859316

Drug-drug interactions between anti-retroviral therapies and drugs of abuse in HIV systems.

PubMed

Kumar, Santosh; Rao, P S S; Earla, Ravindra; Kumar, Anil

2015-03-01

Substance abuse is a common problem among HIV-infected individuals. Importantly, addictions as well as moderate use of alcohol, smoking, or other illicit drugs have been identified as major reasons for non-adherence to antiretroviral therapy (ART) among HIV patients. The literature also suggests a decrease in the response to ART among HIV patients who use these substances, leading to failure to achieve optimal virological response and increased disease progression. This review discusses the challenges with adherence to ART as well as observed drug interactions and known toxicities with major drugs of abuse, such as alcohol, smoking, methamphetamine, cocaine, marijuana, and opioids. The lack of adherence and drug interactions potentially lead to decreased efficacy of ART drugs and increased ART, and drugs of abuse-mediated toxicity. As CYP is the common pathway in metabolizing both ART and drugs of abuse, we discuss the possible involvement of CYP pathways in such drug interactions. We acknowledge that further studies focusing on common metabolic pathways involving CYP and advance research in this area would help to potentially develop novel/alternate interventions and drug dose/regimen adjustments to improve medication outcomes in HIV patients who consume drugs of abuse.

In vitro screening of 50 highly prescribed drugs for thiol adduct formation--comparison of potential for drug-induced toxicity and extent of adduct formation.

PubMed

Gan, Jinping; Ruan, Qian; He, Bing; Zhu, Mingshe; Shyu, Wen C; Humphreys, W Griffith

2009-04-01

Reactive metabolite formation has been associated with drug-induced liver, skin, and hematopoietic toxicity of many drugs that has resulted in serious clinical toxicity, leading to clinical development failure, black box warnings, or, in some cases, withdrawal from the market. In vitro and in vivo screening for reactive metabolite formation has been proposed and widely adopted in the pharmaceutical industry with the aim of minimizing the property and thus the risk of drug-induced toxicity (DIT). One of the most common screening methods is in vitro thiol trapping of reactive metabolites. Although it is well-documented that many hepatotoxins form thiol adducts, there is no literature describing the adduct formation potential of safer drugs that are widely used. The objective of this study was to quantitatively assess the thiol adduct formation potential of 50 drugs (10 associated with DIT and 40 not associated) and document apparent differences in adduct formation between toxic and safer drugs. Dansyl glutathione was used as a trapping agent to aid the quantitation of adducts following in vitro incubation of drugs with human liver microsomes in the presence and absence of NADPH. Metabolic turnover of these drugs was also monitored by LC/UV. Overall, 15 out of the 50 drugs screened formed detectable levels of thiol adducts. There were general trends toward more positive findings in the DIT group vs the non-DIT group. These trends became more marked when the relative amount of thiol adducts was taken into account and improved further when dose and total daily reactive metabolite burdens were considered. In conclusion, there appears to be a general trend between the extent of thiol adduct formation and the potential for DIT, which would support the preclinical measurement and minimization of the property through screening of thiol adduct formation as part of an overall discovery optimization paradigm.

Identifying Cytochrome P450 Functional Networks and Their Allosteric Regulatory Elements

DTIC Science & Technology

2013-12-03

drug alters the metabolism of another drug, potentially altering the pharmacological properties of either drug and leading to adverse toxic effects ...Despite extensive efforts in past decades to understand the mechanism behind these effects , drug metabolism and drug-drug interactions remain...important isoforms that is responsible for >50% of all drug metabolism, exhibits atypical kinetics due to allosteric effects [6]. Recently, Woods et al

Clinical Confirmation that the Selective JAK1 Inhibitor Filgotinib (GLPG0634) has a Low Liability for Drug-drug Interactions.

PubMed

Namour, Florence; Desrivot, Julie; Van der Aa, Annegret; Harrison, Pille; Tasset, Chantal; van't Klooster, Gerben

2016-01-01

The selective Janus kinase 1 inhibitor filgotinib (GLPG0634), which is currently in clinical development for the treatment of rheumatoid arthritis (RA) and Crohn's disease, demonstrated encouraging safety and efficacy profiles in RA patients after 4 weeks of daily dosing. As RA patients might be treated with multiple medications simultaneously, possible drug-drug interactions of filgotinib with cytochrome P450 enzymes and with key drug transporters were evaluated in vitro and in clinical studies. The enzymes involved in filgotinib's metabolism and the potential interactions of the parent and its active major metabolite with drug-metabolizing enzymes and drug transporters, were identified using recombinant enzymes, human microsomes, and cell systems. Furthermore, filgotinib's interaction potential with CYP3A4 was examined in an open-label study in healthy volunteers, which evaluated the impact of filgotinib co-administration on the CYP3A4-sensitive substrate midazolam. The potential interaction with the common RA drug methotrexate was investigated in a clinical study in RA patients. In vitro, filgotinib and its active metabolite at clinically relevant concentrations did not interact with cytochrome P450 enzymes and uridine 5'-diphospho-glucuronosyltransferases, and did not inhibit key drug transporters. In the clinic, a lack of relevant pharmacokinetic drug interactions by filgotinib and its active metabolite with substrates of CYP3A4, as well as with organic anion transporters involved in methotrexate elimination were found. the collective in vivo and in vitro data on drug-metabolizing enzymes and on key drug transporters, support co-administration of filgotinib with commonly used RA drugs to patients without the need for dose adjustments.

Using clinical trial data and linked administrative health data to reduce the risk of adverse events associated with the uptake of newly released drugs by older Australians: a model process.

PubMed

Whitstock, Margaret T; Pearce, Christopher M; Ridout, Stephen C; Eckermann, Elizabeth J

2011-05-21

The study was undertaken to evaluate the contribution of a process which uses clinical trial data plus linked de-identified administrative health data to forecast potential risk of adverse events associated with the use of newly released drugs by older Australian patients. The study uses publicly available data from the clinical trials of a newly released drug to ascertain which patient age groups, gender, comorbidities and co-medications were excluded in the trials. It then uses linked de-identified hospital morbidity and medications dispensing data to investigate the comorbidities and co-medications of patients who suffer from the target morbidity of the new drug and who are the likely target population for the drug. The clinical trial information and the linked morbidity and medication data are compared to assess which patient groups could potentially be at risk of an adverse event associated with use of the new drug. Applying the model in a retrospective real-world scenario identified that the majority of the sample group of Australian patients aged 65 years and over with the target morbidity of the newly released COX-2-selective NSAID rofecoxib also suffered from a major morbidity excluded in the trials of that drug, indicating a substantial potential risk of adverse events amongst those patients. This risk was borne out in post-release morbidity and mortality associated with use of that drug. Clinical trial data and linked administrative health data can together support a prospective assessment of patient groups who could be at risk of an adverse event if they are prescribed a newly released drug in the context of their age, gender, comorbidities and/or co-medications. Communication of this independent risk information to prescribers has the potential to reduce adverse events in the period after the release of the new drug, which is when the risk is greatest.Note: The terms 'adverse drug reaction' and 'adverse drug event' have come to be used interchangeably in the current literature. For consistency, the authors have chosen to use the wider term 'adverse drug event' (ADE).

Homeless drug users' awareness and risk perception of peer "Take Home Naloxone" use – a qualitative study

PubMed Central

Wright, Nat; Oldham, Nicola; Francis, Katharine; Jones, Lesley

2006-01-01

Background Peer use of take home naloxone has the potential to reduce drug related deaths. There appears to be a paucity of research amongst homeless drug users on the topic. This study explores the acceptability and potential risk of peer use of naloxone amongst homeless drug users. From the findings the most feasible model for future treatment provision is suggested. Methods In depth face-to-face interviews conducted in one primary care centre and two voluntary organisation centres providing services to homeless drug users in a large UK cosmopolitan city. Interviews recorded, transcribed and analysed thematically by framework techniques. Results Homeless people recognise signs of a heroin overdose and many are prepared to take responsibility to give naloxone, providing prior training and support is provided. Previous reports of the theoretical potential for abuse and malicious use may have been overplayed. Conclusion There is insufficient evidence to recommend providing "over the counter" take home naloxone" to UK homeless injecting drug users. However a programme of peer use of take home naloxone amongst homeless drug users could be feasible providing prior training is provided. Peer education within a health promotion framework will optimise success as current professionally led health promotion initiatives are failing to have a positive impact amongst homeless drug users. PMID:17014725

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

PubMed

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

2017-11-01

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

Molecular mechanisms and theranostic potential of miRNAs in drug resistance of gastric cancer.

PubMed

Yang, Wanli; Ma, Jiaojiao; Zhou, Wei; Cao, Bo; Zhou, Xin; Yang, Zhiping; Zhang, Hongwei; Zhao, Qingchuan; Fan, Daiming; Hong, Liu

2017-11-01

Systemic chemotherapy is a curative approach to inhibit gastric cancer cells proliferation. Despite the great progress in anti-cancer treatment achieved during the last decades, drug resistance and treatment refractoriness still extensively persists. Recently, accumulating studies have highlighted the role of miRNAs in drug resistance of gastric cancers by modulating some drug resistance-related proteins and genes expression. Pre-clinical reports indicate that miRNAs might serve as ideal biomarkers and potential targets, thus holding great promise for developing targeted therapy and personalized treatment for the patients with gastric cancer. Areas covered: This review provide a comprehensive overview of the current advances of miRNAs and molecular mechanisms underlying miRNA-mediated drug resistance in gastric cancer. We particularly focus on the potential values of drug resistance-related miRNAs as biomarkers and novel targets in gastric cancer therapy and envisage the future research developments of these miRNAs and challenges in translating the new findings into clinical applications. Expert opinion: Although the concrete mechanisms of miRNAs in drug resistance of gastric cancer have not been fully clarified, miRNA may be a promising theranostic approach. Further studies are still needed to facilitate the clinical applications of miRNAs in drug resistant gastric cancer.

[Potentially addictive drugs on reimbursable prescription for chronic severe pain].

PubMed

Persheim, Marthe Sæther; Helland, Arne; Spigset, Olav; Slørdal, Lars

2013-01-22

Changes in the Norwegian drug reimbursement system in 2008 included the establishment of a new reimbursement code (-71) which authorises coverage of expenditures for potentially addictive drugs in patients with severe, predominantly non-malignant, chronic pain. This reform has hitherto not been evaluated. We assessed national data on drug reimbursements in accordance with code -71 for the period 2008-2011, and anonymised copies of all confirmation letters granting reimbursements according to code -71 in Central Norway (three counties) for 2010. Approximately 1300 individual applicants' gender and age, diagnosis, potentially addictive drug applied for, drug dose, and identity and specialty of the prescribing physician, were recorded. From the time of establishment, reimbursement code -71 has been utilised by an increasing number of individuals, encompassing close to 10,000 subjects in 3rd quarter 2011. Almost one-third of the approved applications were for pregabalin, and the rest were for various opioids. The diagnoses were most often derived from the musculoskeletal and nervous systems, and were often nonspecific. A considerable number of treatment regimens were not in accordance with current principles for the management of chronic non-malignant pain, and drug doses were at times remarkably high. Aspects of this drug reimbursement regulation should be closely monitored, and may be in need of changes.

Perspectives on NMR in drug discovery: a technique comes of age

PubMed Central

Pellecchia, Maurizio; Bertini, Ivano; Cowburn, David; Dalvit, Claudio; Giralt, Ernest; Jahnke, Wolfgang; James, Thomas L.; Homans, Steve W.; Kessler, Horst; Luchinat, Claudio; Meyer, Bernd; Oschkinat, Hartmut; Peng, Jeff; Schwalbe, Harald; Siegal, Gregg

2009-01-01

In the past decade, the potential of harnessing the ability of nuclear magnetic resonance (NMR) spectroscopy to monitor intermolecular interactions as a tool for drug discovery has been increasingly appreciated in academia and industry. In this Perspective, we highlight some of the major applications of NMR in drug discovery, focusing on hit and lead generation, and provide a critical analysis of its current and potential utility. PMID:19172689

The role of adverse events and related safety data in the pre-market evaluation of drug abuse potential.

PubMed

Mansbach, Robert S; Schoedel, Kerri A; Kittrelle, Jeffrey P; Sellers, Edward M

2010-12-01

The scientific and regulatory assessment of abuse and dependence potential of drugs involves a multi-layered evaluation of its properties related to chemistry, formulation, pharmacology, animal behavior and clinical response. In addition to the primary laboratory-based assessment in experienced drug users, data are also reviewed from studies in healthy volunteers and in the patient population. Much of the emphasis in these latter studies is placed on adverse events that are reported by the subject or observed by the investigator. Unlike other aspects of abuse potential assessment, the evaluation of abuse- and dependence-related events has not been the subject of scholarly research. The present commentary presents recommendations for several areas that would benefit from a consensus review to result in greater standardization for the analysis and presentation of abuse- and dependence-related data from clinical trials. These include special investigator training, a system of weighted primary and secondary terms, adjudication of individual events, case report management, organization of integrated safety data, and protocols for drug accountability. Such an effort would aid in implementing the evolving efforts of health authorities to guide drug developers in the collection and presentation of data needed for the regulation of drugs with the potential for abuse and dependence. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

Drug-nutrient interactions in three long-term-care facilities.

PubMed

Lewis, C W; Frongillo, E A; Roe, D A

1995-03-01

To assess the risk of drug-nutrient interactions (DNIs) in three long-term-care facilities. Retrospective audit of charts. Three long-term-care facilities in central New York State. Fifty-three patients selected randomly from each facility. Data were collected from the medical record of each patient for a period of 6 months. A computerized algorithm was used to assess the risk for DNIs. Mean drug use, most frequently consumed drugs, incidence of potential DNIs, and the most commonly observed potential DNIs are reported. In facilities A, B, and C, respectively, patients consumed a mean of 4.86, 4.04, and 5.27 drugs per patient per month and were at risk for a mean of 1.43, 2.69, and 1.43 potential DNIs per patient per month. The most commonly observed potential DNIs were gastrointestinal interactions affecting drug bioavailability and interactions affecting electrolyte status. Patients in long-term-care facilities, who are primarily elderly and chronically ill and who consume multiple medications, are at notable risk for certain DNIs. Efforts need to be made to ensure appropriate pharmacologic and nutrition therapies as well as adequate and timely monitoring of patients in these facilities. Dietitians can play an important role in training other health professionals and in designing policies to prevent DNIs.

Gene-set analysis based on the pharmacological profiles of drugs to identify repurposing opportunities in schizophrenia.

PubMed

de Jong, Simone; Vidler, Lewis R; Mokrab, Younes; Collier, David A; Breen, Gerome

2016-08-01

Genome-wide association studies (GWAS) have identified thousands of novel genetic associations for complex genetic disorders, leading to the identification of potential pharmacological targets for novel drug development. In schizophrenia, 108 conservatively defined loci that meet genome-wide significance have been identified and hundreds of additional sub-threshold associations harbour information on the genetic aetiology of the disorder. In the present study, we used gene-set analysis based on the known binding targets of chemical compounds to identify the 'drug pathways' most strongly associated with schizophrenia-associated genes, with the aim of identifying potential drug repositioning opportunities and clues for novel treatment paradigms, especially in multi-target drug development. We compiled 9389 gene sets (2496 with unique gene content) and interrogated gene-based p-values from the PGC2-SCZ analysis. Although no single drug exceeded experiment wide significance (corrected p<0.05), highly ranked gene-sets reaching suggestive significance including the dopamine receptor antagonists metoclopramide and trifluoperazine and the tyrosine kinase inhibitor neratinib. This is a proof of principle analysis showing the potential utility of GWAS data of schizophrenia for the direct identification of candidate drugs and molecules that show polypharmacy. © The Author(s) 2016.

Potential drug therapies for the treatment of fibromyalgia.

PubMed

Lawson, Kim

2016-09-01

Fibromyalgia (FM) is a common, complex chronic widespread pain condition is characterized by fatigue, sleep disturbance and cognitive dysfunction. Treatment of FM is difficult, requiring both pharmacological and non-pharmacological approaches, with an empiric approach to drug therapy focused toward individual symptoms, particularly pain. The effectiveness of current medications is limited with many patients discontinuing use. A systemic database search has identified 26 molecular entities as potential emerging drug therapies. Advances in the understanding of the pathophysiology of FM provides clues to targets for new medications. Investigation of bioamine modulation and α2δ ligands and novel targets such as dopamine receptors, NMDA receptors, cannabinoid receptors, melatonin receptors and potassium channels has identified potential drug therapies. Modest improvement of health status in patients with FM has been observed with drugs targeting a diverse range of molecular mechanisms. No single drug, however, offered substantial efficacy against all the symptoms characteristic of FM. Identification of new and improved therapies for FM needs to address the heterogeneity of the condition, which suggests existence of patient subgroups, the relationship of central and peripheral aspects of the pathophysiology and a requirement of combination therapy with drugs targeting multiple molecular mechanisms.

Teratogenic medications and concurrent contraceptive use in women of childbearing ability with epilepsy.

PubMed

Bhakta, Janki; Bainbridge, Jacquelyn; Borgelt, Laura

2015-11-01

Many antiepileptic drugs (AEDs) have the potential to cause teratogenicity. We evaluated eight antiepileptic drugs (AEDs) classified as Federal Drug Administration (FDA) pregnancy category D, X, or N designations and having documented teratogenic effects. These include carbamazepine, ethosuximide, fosphenytoin, phenobarbital, phenytoin, primidone, topiramate, and valproate. Women with epilepsy (WWE) may need one or more of these AEDs for seizure control but may be unaware of the potential teratogenicity associated with their use. In utero exposure to AEDs increases the risks for both congenital malformations and other teratogenic defects. Given that approximately 50% of pregnancies are unintended, it is likely that women with epilepsy taking these medications could unknowingly put a growing fetus at risk. For women using contraception while taking these medications, many choose combined hormonal contraceptives (CHCs). Drug-drug interactions exist between AEDs and CHCs that may decrease contraceptive efficacy. The aim of this study was to evaluate prescribing patterns for potentially teratogenic AEDs and contraceptive use in WWE of childbearing ability, including those with potential drug-drug interactions. This study also determined the number of WWE of childbearing ability prescribed potentially teratogenic AEDs and documentation of a pregnancy or contraception plan. This was a retrospective, observational study of WWE age 15-44 years, of childbearing ability, prescribed an AED from July 1, 2011 to June 30, 2012, and who had an appointment at the University of Colorado Hospital Outpatient Neurology Clinic (Anschutz Medical Campus). One hundred fifteen women with an average age of 30.7 years and various types of seizures were evaluated. The majority of patients were prescribed topiramate (34/115, 30%) or carbamazepine (27/115, 23%). Of the women, 30/115 (26%) had a documented contraception method when taking a potentially teratogenic AED. Of these women prescribed contraception, most (18/30, 60%) used an oral combined hormonal contraceptive or progestin-only pill, a majority of which had a potential for a drug-drug interaction with their AEDs (16/18, 89%). Less than 7% of women received counseling on a contraception plan, and 18% of subjects received counseling on a pregnancy plan. Most WWE of childbearing ability taking potentially teratogenic AEDs were not using contraception. Those using contraception frequently had a method that has a significant drug-drug interaction which reduces the effectiveness of contraception. Women with epilepsy of childbearing ability prescribed an AED should be using effective contraception or participating in active discussions about pregnancy planning to avoid unplanned pregnancies and possible teratogenic effects of these AEDs. Documentation about pregnancy planning or contraceptive use in WWE of childbearing ability is minimal and should be discussed at least annually. It is critical for providers to discuss with WWE of childbearing ability the benefits and risks of various AED treatments; the need to select appropriate, effective contraception when pregnancy is not desired; and the importance of counseling regarding contraceptive or pregnancy planning. Copyright © 2015 Elsevier Inc. All rights reserved.

Predicting A Drug'S Membrane Permeability: Evolution of a Computational Model Validated with in Vitro Permeability Assay Data

DOE PAGES

Carpenter, Timothy S.; McNerney, M. Windy; Be, Nicholas A.; ...

2016-02-16

Membrane permeability is a key property to consider in drug design, especially when the drugs in question need to cross the blood-brain barrier (BBB). A comprehensive in vivo assessment of the BBB permeability of a drug takes considerable time and financial resources. A current, simplified in vitro model to investigate drug permeability is a Parallel Artificial Membrane Permeability Assay (PAMPA) that generally provides higher throughput and initial quantification of a drug's passive permeability. Computational methods can also be used to predict drug permeability. Our methods are highly advantageous as they do not require the synthesis of the desired drug, andmore » can be implemented rapidly using high-performance computing. In this study, we have used umbrella sampling Molecular Dynamics (MD) methods to assess the passive permeability of a range of compounds through a lipid bilayer. Furthermore, the permeability of these compounds was comprehensively quantified using the PAMPA assay to calibrate and validate the MD methodology. And after demonstrating a firm correlation between the two approaches, we then implemented our MD method to quantitatively predict the most permeable potential drug from a series of potential scaffolds. This permeability was then confirmed by the in vitro PAMPA methodology. Therefore, in this work we have illustrated the potential that these computational methods hold as useful tools to help predict a drug's permeability in a faster and more cost-effective manner. Release number: LLNL-ABS-677757.« less

Mathematical modeling of drug release from lipid dosage forms.

PubMed

Siepmann, J; Siepmann, F

2011-10-10

Lipid dosage forms provide an interesting potential for controlled drug delivery. In contrast to frequently used poly(ester) based devices for parenteral administration, they do not lead to acidification upon degradation and potential drug inactivation, especially in the case of protein drugs and other acid-labile active agents. The aim of this article is to give an overview on the current state of the art of mathematical modeling of drug release from this type of advanced drug delivery systems. Empirical and semi-empirical models are described as well as mechanistic theories, considering diffusional mass transport, potentially limited drug solubility and the leaching of other, water-soluble excipients into the surrounding bulk fluid. Various practical examples are given, including lipid microparticles, beads and implants, which can successfully be used to control the release of an incorporated drug during periods ranging from a few hours up to several years. The great benefit of mechanistic mathematical theories is the possibility to quantitatively predict the effects of different formulation parameters and device dimensions on the resulting drug release kinetics. Thus, in silico simulations can significantly speed up product optimization. This is particularly useful if long release periods (e.g., several months) are targeted, since experimental trial-and-error studies are highly time-consuming in these cases. In the future it would be highly desirable to combine mechanistic theories with the quantitative description of the drug fate in vivo, ideally including the pharmacodynamic efficacy of the treatments. Copyright © 2011 Elsevier B.V. All rights reserved.

Significant differences in pediatric psychotropic side effects: Implications for school performance.

PubMed

Kubiszyn, Thomas; Mire, Sarah; Dutt, Sonia; Papathopoulos, Katina; Burridge, Andrea Backsheider

2012-03-01

Some side effects (SEs) of increasingly prescribed psychotropic medications can impact student performance in school. SE risk varies, even among drugs from the same class (e.g., antidepressants). Knowing which SEs occur significantly more often than others may enable school psychologists to enhance collaborative risk-benefit analysis, medication monitoring, data-based decision-making, and inform mitigation efforts. SE data from Full Prescribing Information (PI) on the FDA website for ADHD drugs, atypical antipsychotics, and antidepressants with pediatric indications were analyzed. Risk ratios (RR) are reported for each drug within a category compared with placebo. RR tables and graphs inform the reader about SE incidence differences for each drug and provide clear evidence of the wide variability in SE incidence in the FDA data. Breslow-Day and Cochran Mantel-Haenszel methods were used to test for drug-placebo SE differences and to test for significance across drugs within each category based on odds ratios (ORs). Significant drug-placebo differences were found for each drug compared with placebo, when odds were pooled across all drugs in a category compared with placebo, and between some drugs within categories. Unexpectedly, many large RR differences did not reach significance. Potential explanations are offered, including limitations of the FDA data sets and statistical and methodological issues. Future research directions are offered. The potential impact of certain SEs on school performance, mitigation strategies, and the potential role of the school psychologist is discussed, with consideration for ethical and legal limitations. (c) 2012 APA, all rights reserved.

Predicting A Drug'S Membrane Permeability: Evolution of a Computational Model Validated with in Vitro Permeability Assay Data

DOE Office of Scientific and Technical Information (OSTI.GOV)

Carpenter, Timothy S.; McNerney, M. Windy; Be, Nicholas A.

Membrane permeability is a key property to consider in drug design, especially when the drugs in question need to cross the blood-brain barrier (BBB). A comprehensive in vivo assessment of the BBB permeability of a drug takes considerable time and financial resources. A current, simplified in vitro model to investigate drug permeability is a Parallel Artificial Membrane Permeability Assay (PAMPA) that generally provides higher throughput and initial quantification of a drug's passive permeability. Computational methods can also be used to predict drug permeability. Our methods are highly advantageous as they do not require the synthesis of the desired drug, andmore » can be implemented rapidly using high-performance computing. In this study, we have used umbrella sampling Molecular Dynamics (MD) methods to assess the passive permeability of a range of compounds through a lipid bilayer. Furthermore, the permeability of these compounds was comprehensively quantified using the PAMPA assay to calibrate and validate the MD methodology. And after demonstrating a firm correlation between the two approaches, we then implemented our MD method to quantitatively predict the most permeable potential drug from a series of potential scaffolds. This permeability was then confirmed by the in vitro PAMPA methodology. Therefore, in this work we have illustrated the potential that these computational methods hold as useful tools to help predict a drug's permeability in a faster and more cost-effective manner. Release number: LLNL-ABS-677757.« less

Surveillance of Physicians Causing Potential Drug-Drug Interactions in Ambulatory Care: A Pilot Study in Switzerland

PubMed Central

Bucher, Heiner C.; Achermann, Rita; Stohler, Nadja; Meier, Christoph R.

2016-01-01

Objectives We analysed potential drug-drug interactions (DDI) in ambulatory care in Switzerland based on claims data from three large health insurers in 2010 to identify physicians with peculiar prescription behaviour differing from peers of the same specialty. Methods We analysed contraindicated or potentially contraindicated DDI from the national drug formulary and calculated for each physician the ratios of the number of patients with a potential DDI divided by the number of patients at risk and used a zero inflated binomial distribution to correct for the inflated number of observations with no DDI. We then calculated the probability that the number of caused potential DDI of physicians was unlikely (p-value < 0.05 and ≥0.01) and very unlikely (p-value <0.01) to be due to chance. Results Of 1'607'233 females and 1'525'307 males 1.3% and 1.2% were exposed to at least one potential DDI during 12 months. When analysing the 40 most common DDI, 598 and 416 of 18,297 physicians (3.3% and 2.3%) were causing potential DDI in a frequency unlikely (p<0.05 and p≥0.01) and very unlikely (p<0.01) to be explained by chance. Patients cared by general practitioners and cardiologists had the lowest probability (0.20 and 0.26) for not being exposed to DDI. Conclusions Contraindicated or potentially contraindicated DDI are frequent in ambulatory care in Switzerland, with a small proportion of physicians causing potential DDI in a frequency that is very unlikely to be explained by chance when compared to peers of the same specialty. PMID:26808430

In Vitro and Clinical Evaluations of the Drug-Drug Interaction Potential of a Metabotropic Glutamate 2/3 Receptor Agonist Prodrug with Intestinal Peptide Transporter 1

PubMed Central

Long, Amanda J.; Annes, William F.; Witcher, Jennifer W.; Knadler, Mary Pat; Ayan-Oshodi, Mosun A.; Mitchell, Malcolm I.; Leese, Phillip; Hillgren, Kathleen M.

2017-01-01

Despite peptide transporter 1 (PEPT1) being responsible for the bioavailability for a variety of drugs, there has been little study of its potential involvement in drug-drug interactions. Pomaglumetad methionil, a metabotropic glutamate 2/3 receptor agonist prodrug, utilizes PEPT1 to enhance absorption and bioavailability. In vitro studies were conducted to guide the decision to conduct a clinical drug interaction study and to inform the clinical study design. In vitro investigations determined the prodrug (LY2140023 monohydrate) is a substrate of PEPT1 with Km value of approximately 30 µM, whereas the active moiety (LY404039) is not a PEPT1 substrate. In addition, among the eight known PEPT1 substrates evaluated in vitro, valacyclovir was the most potent inhibitor (IC50 = 0.46 mM) of PEPT1-mediated uptake of the prodrug. Therefore, a clinical drug interaction study was conducted to evaluate the potential interaction between the prodrug and valacyclovir in healthy subjects. No effect of coadministration was observed on the pharmacokinetics of the prodrug, valacyclovir, or either of their active moieties. Although in vitro studies showed potential for the prodrug and valacyclovir interaction via PEPT1, an in vivo study showed no interaction between these two drugs. PEPT1 does not appear to easily saturate because of its high capacity and expression in the intestine. Thus, a clinical interaction at PEPT1 is unlikely even with a compound with high affinity for the transporter. PMID:27895114

Drug-vitamin D interactions: A systematic review of the literature

PubMed Central

Oppeneer, Sarah J.; Kelly, Julia A.; Hamilton-Reeves, Jill M.

2017-01-01

Extensive media coverage of the potential health benefits of vitamin D supplementation has translated into substantial increases in supplement sales over recent years. Yet, the potential for drug-vitamin D interactions is rarely considered. This systematic review of the literature was conducted to evaluate the extent to which drugs affect vitamin D status or supplementation alters drug effectiveness or toxicity in humans. Electronic databases were used to identify eligible peer-reviewed studies published through September 1, 2010. Study characteristics and findings were abstracted, and quality was assessed for each study. A total of 109 unique reports met the inclusion criteria. The majority of eligible studies were classified as Class C (non-randomized trials, case-control studies, or time series) or D (cross-sectional, trend, case report/series, or before-and-after studies). Only two Class C and three Class D studies were of positive quality. Insufficient evidence was available to determine whether lipase inhibitors, antimicrobial agents, antiepileptic drugs, highly active antiretroviral agents or H2 receptor antagonists alter serum 25(OH)D concentrations. Atorvastatin appears to increase 25(OH)D concentrations, while concurrent vitamin D supplementation decreases concentrations of atorvastatin. Use of thiazide diuretics in combination with calcium and vitamin D supplements may cause hypercalcemia in the elderly, or those with compromised renal function or hyperparathyroidism. Larger studies with stronger study designs are needed to clarify potential drug-vitamin D interactions, especially for drugs metabolized by cytochrome P450 3A4 (CYP3A4). Health care providers should be aware of the potential for drug-vitamin D interactions. PMID:23307906

Human abuse liability evaluation of CNS stimulant drugs.

PubMed

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

2014-12-01

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

Effects of propofol, sevoflurane, remifentanil, and (S)-ketamine in subanesthetic concentrations on visceral and somatosensory pain-evoked potentials.

PubMed

Untergehrer, Gisela; Jordan, Denis; Eyl, Sebastian; Schneider, Gerhard

2013-02-01

Although electroencephalographic parameters and auditory evoked potentials (AEP) reflect the hypnotic component of anesthesia, there is currently no specific and mechanism-based monitoring tool for anesthesia-induced blockade of nociceptive inputs. The aim of this study was to assess visceral pain-evoked potentials (VPEP) and contact heat-evoked potentials (CHEP) as electroencephalographic indicators of drug-induced changes of visceral and somatosensory pain. Additionally, AEP and electroencephalographic permutation entropy were used to evaluate sedative components of the applied drugs. In a study enrolling 60 volunteers, VPEP, CHEP (amplitude N2-P1), and AEP (latency Nb, amplitude Pa-Nb) were recorded without drug application and at two subanesthetic concentration levels of propofol, sevoflurane, remifentanil, or (s)-ketamine. Drug-induced changes of evoked potentials were analyzed. VPEP were generated by electric stimuli using bipolar electrodes positioned in the distal esophagus. For CHEP, heat pulses were given to the medial aspect of the right forearm using a CHEP stimulator. In addition to AEP, electroencephalographic permutation entropy was used to indicate level of sedation. With increasing concentrations of propofol, sevoflurane, remifentanil, and (s)-ketamine, VPEP and CHEP N2-P1 amplitudes decreased. AEP and electroencephalographic permutation entropy showed neither clinically relevant nor statistically significant suppression of cortical activity during drug application. Decreasing VPEP and CHEP amplitudes under subanesthetic concentrations of propofol, sevoflurane, remifentanil, and (s)-ketamine indicate suppressive drug effects. These effects seem to be specific for analgesia.

23 years of toxicology testing fatally injured pilots: Implications for aviation and other modes of transportation.

PubMed

McKay, Mary Pat; Groff, Loren

2016-05-01

Use of over-the-counter, prescription, and illicit drugs is increasing in the United States (US). Many of these drugs are psychoactive and can affect the user's ability to safely operate a vehicle. However, data about drug use by vehicle operators is typically limited to a small proportion of operators and a short list of drugs. For instance, required testing for commercial vehicle operators following most accidents is limited to a urine test for 11 drugs. By comparison, the Federal Aviation Administration (FAA), routinely tests fatally injured pilots' blood and tissues for hundreds of compounds. This study used the results from these tests to assess drug use in aviation. Using matched data from the FAA's Civil Aerospace Medical Institute toxicology database and the National Transportation Safety Board's (NTSB's) aviation accident database, this study examined trends in the prevalence of over-the-counter, prescription, and illicit drugs identified in toxicology tests of fatally injured pilots between 1990 and 2012. Cases that failed to match or where toxicology testing had not been performed were excluded. Pilots identified by the NTSB investigation as being the "flying pilot" at the time of the accident and results from blood or tissues were included. Toxicology results for ethanol and other alcohols were not included. Positive test results were categorized by drug type and potential for causing impairment. Analysis used SPSS Version 19.1 to perform linear by linear chi-squared statistics. The study included 6677 pilots or 87% of the eligible subjects. The large majority were male (98%) and flying general aviation operations (96%) at the time of their fatal accident. There were increasing trends in pilots' use of all drugs, potentially impairing drugs, drugs used to treat potentially impairing conditions, drugs designated as controlled substances, and illicit drugs. The most common potentially impairing drug pilots had used was diphenhydramine, a sedating antihistamine that is an active ingredient in many over-the-counter allergy formulations, cold medicines, and sleep aids in the US. Although evidence of illicit drug use was found only in a small number of cases, the percentage of pilots testing positive for marijuana use increased during the study period, mostly in the last 10 years. Published by Elsevier Ltd.

Drugged Driving: Increased Traffic Risks Involving Licit and Illicit Substances

ERIC Educational Resources Information Center

Pilkinton, Melinda W.; Robertson, Angela; McCluskey, D. Lee

2013-01-01

Driving under the influence of drugs poses risks for traffic safety. Most research attention has been focused on the most prevalent drugs of abuse, such as alcohol, illegal drugs, and prescription drugs with high abuse potential. The objectives of this study were to determine the types of drugs used by convicted DUI offenders on the day of their…

Innovative polymeric system (IPS) for solvent-free lipophilic drug transdermal delivery via dissolving microneedles.

PubMed

Dangol, Manita; Yang, Huisuk; Li, Cheng Guo; Lahiji, Shayan Fakhraei; Kim, Suyong; Ma, Yonghao; Jung, Hyungil

2016-02-10

Lipophilic drugs are potential drug candidates during drug development. However, due to the need for hazardous organic solvents for their solubilization, these drugs often fail to reach the pharmaceutical market, and in doing so highlight the importance of solvent free systems. Although transdermal drug delivery systems (TDDSs) are considered prospective safe drug delivery routes, a system involving lipophilic drugs in solvent free or powder form has not yet been described. Here, we report, for the first time, a novel approach for the delivery of every kind of lipophilic drug in powder form based on an innovative polymeric system (IPS). The phase transition of powder form of lipophilic drugs due to interior chemical bonds between drugs and biodegradable polymers and formation of nano-sized colloidal structures allowed the fabrication of dissolving microneedles (DMNs) to generate a powerful TDDS. We showed that IPS based DMN with powder capsaicin enhances the therapeutic effect for treatment of the rheumatic arthritis in a DBA/1 mouse model compared to a solvent-based system, indicating the promising potential of this new solvent-free platform for lipophilic drug delivery. Copyright © 2016 Elsevier B.V. All rights reserved.

Preparation and evaluation of a timolol maleate drug-resin ophthalmic suspension as a sustained-release formulation in vitro and in vivo.

PubMed

Qin, Fuhong; Zeng, Li; Zhu, Yongtao; Cao, Jingjing; Wang, Xiaohui; Liu, Wei

2016-01-01

The aim of this work was to assess the performance of resin as an ocular delivery system. Timolol maleate (TM) was chosen as the model drug and an ion exchange resin (IER) as the carrier. The drug-resin complex was prepared using an oscillation method and then characterized regarding particle size, zeta potential, morphology, and drug content. After in vitro drug release study and corneal permeation study were performed, in vivo studies were performed in New Zealand albino rabbits using a suspension with particles sized 4.8 ± 1.2 μm and drug loading at 43.00 ± 0.09%. The results indicate that drug released from the drug-resin ophthalmic suspension permeated the cornea and displayed a sustained-release behavior. Drug levels in the ocular tissues after administration of the drug-resin ophthalmic suspension were significantly higher than after treatment with an eye drop formulation but were lower in body tissues and in the plasma. In conclusion, resins have great potential as effective ocular drug delivery carriers to increase ocular bioavailability of timolol while simultaneously reducing systemic drug absorption.

Sex differences in drug addiction and response to exercise intervention: from human to animal studies

PubMed Central

Zhou, Yuehui; Zhao, Min; Zhou, Chenglin; Li, Rena

2015-01-01

Accumulated research supports the idea that exercise could be an option of potential prevention and treatment for drug addiction. During the past few years, there has been increased interest in investigating of sex differences in exercise and drug addiction. This demonstrates that sex-specific exercise intervention strategies may be important for preventing and treating drug addiction in men and women. However, little is known about how and why sex differences are found when doing exercise-induced interventions for drug addiction. In this review, we included both animal and human that pulled subjects from a varied age demographic, as well as neurobiological mechanisms that may highlight the sex-related differences in these potential to assess the impact of sex-specific roles in drug addiction and exercise therapies. PMID:26182835

Nanomaterials potentiating standard chemotherapy drugs' effect

NASA Astrophysics Data System (ADS)

Kazantsev, S. O.; Korovin, M. S.

2017-09-01

Application of antitumor chemotherapeutic drugs is hindered by a number of barriers, multidrug resistance that makes effective drug deposition inside cancer cells difficult is among them. Recent research shows that potential efficiency of anticancer drugs can be increased with nanoparticles. This review is devoted to the application of nanoparticles for cancer treatment. Various types of nanoparticles currently used in medicine are reviewed. The nanoparticles that have been used for cancer therapy and targeted drug delivery to damaged sites of organism are described. Also, the possibility of nanoparticles application for cancer diagnosis that could help early detection of tumors is discussed. Our investigations of antitumor activity of low-dimensional nanostructures based on aluminum oxides and hydroxides are briefly reviewed.

Emerging anti-insomnia drugs: tackling sleeplessness and the quality of wake time.

PubMed

Wafford, Keith A; Ebert, Bjarke

2008-06-01

Sleep is essential for our physical and mental well being. However, when novel hypnotic drugs are developed, the focus tends to be on the marginal and statistically significant increase in minutes slept during the night instead of the effects on the quality of wakefulness. Recent research on the mechanisms underlying sleep and the control of the sleep-wake cycle has the potential to aid the development of novel hypnotic drugs; however, this potential has not yet been realized. Here, we review the current understanding of how hypnotic drugs act, and discuss how new, more effective drugs and treatment strategies for insomnia might be achieved by taking into consideration the daytime consequences of disrupted sleep.

Implications of formulation design on lipid-based nanostructured carrier system for drug delivery to brain.

PubMed

Salunkhe, Sachin S; Bhatia, Neela M; Bhatia, Manish S

2016-05-01

The aim of present investigation was to formulate and develop lipid-based nanostructured carriers (NLCs) containing Idebenone (IDE) for delivery to brain. Attempts have been made to evaluate IDE NLCs for its pharmacokinetic and pharmacodynamic profile through the objective of enhancement in bioavailability and effectivity of drug. Nanoprecipitation technique was used for development of drug loaded NLCs. The components solid lipid Precirol ATO 5, oil Miglyol 840, surfactants Tween 80 and Labrasol have been screened out for formulation development by consideration of preformulation parameters including solubility, Required Hydrophilic lipophilic balance (HLB) of lipids and stability study. Developed IDE NLCs were subjected for particle size, zeta potential, entrapment efficiency (%EE), crystallographic investigation, transmission electron microscopy, in vitro drug release, pharmacokinetics, in vivo and stability study. Formulation under investigation has particle size 174.1 ± 2.6 nm, zeta potential -18.65 ± 1.13 mV and% EE 90.68 ± 2.90. Crystallographic studies exemplified for partial amorphization of IDE by molecularly dispersion within lipid crust. IDE NLCs showed drug release 93.56 ± 0.39% at end of 24 h by following Higuchi model which necessitates for appropriate drug delivery with enhancement in bioavailability of drug by 4.6-fold in plasma and 2.8-fold in brain over plain drug loaded aqueous dispersions. In vivo studies revealed that effect of drug was enhanced by prepared lipid nanocarriers. IDE lipid-based nanostructured carriers could have potential for efficient drug delivery to brain with enhancement in bioavailability of drug over the conventional formulations.

Nanoscale drug delivery systems and the blood-brain barrier.

PubMed

Alyautdin, Renad; Khalin, Igor; Nafeeza, Mohd Ismail; Haron, Muhammad Huzaimi; Kuznetsov, Dmitry

2014-01-01

The protective properties of the blood-brain barrier (BBB) are conferred by the intricate architecture of its endothelium coupled with multiple specific transport systems expressed on the surface of endothelial cells (ECs) in the brain's vasculature. When the stringent control of the BBB is disrupted, such as following EC damage, substances that are safe for peripheral tissues but toxic to neurons have easier access to the central nervous system (CNS). As a consequence, CNS disorders, including degenerative diseases, can occur independently of an individual's age. Although the BBB is crucial in regulating the biochemical environment that is essential for maintaining neuronal integrity, it limits drug delivery to the CNS. This makes it difficult to deliver beneficial drugs across the BBB while preventing the passage of potential neurotoxins. Available options include transport of drugs across the ECs through traversing occludins and claudins in the tight junctions or by attaching drugs to one of the existing transport systems. Either way, access must specifically allow only the passage of a particular drug. In general, the BBB allows small molecules to enter the CNS; however, most drugs with the potential to treat neurological disorders other than infections have large structures. Several mechanisms, such as modifications of the built-in pumping-out system of drugs and utilization of nanocarriers and liposomes, are among the drug-delivery systems that have been tested; however, each has its limitations and constraints. This review comprehensively discusses the functional morphology of the BBB and the challenges that must be overcome by drug-delivery systems and elaborates on the potential targets, mechanisms, and formulations to improve drug delivery to the CNS.

University of Michigan Drug Education Questionnaire.

ERIC Educational Resources Information Center

Francis, John Bruce; Patch, David J.

This questionnaire assesses attitudes toward potential drug education programs and drug use practices in college students. The 87 items (multiple choice or free response) pertain to the history and extent of usage of 27 different drugs, including two non-existent drugs which may be utilized as a validity check; attitude toward the content, format,…

Drug Sensitivity in Older Adults: The Role of Physiologic and Pharmacokinetic Factors.

ERIC Educational Resources Information Center

Cherry, Katie E.; Morton, Mark R.

1989-01-01

Notes that age-related changes in physiology and pharmacokinetics (how drugs are used in the body) lead to increased drug sensitivity and potentially harmful drug effects. Addresses heightened sensitivity to drug effects seen in older adults. Presents three examples of physiologic decline and discusses some broad considerations for geriatric…

Nature engineered diatom biosilica as drug delivery systems.

PubMed

Uthappa, U T; Brahmkhatri, Varsha; Sriram, G; Jung, Ho-Young; Yu, Jingxian; Kurkuri, Nikita; Aminabhavi, Tejraj M; Altalhi, Tariq; Neelgund, Gururaj M; Kurkuri, Mahaveer D

2018-05-14

Diatoms, unicellular photosynthetic algae covered with siliceous cell wall, are also called frustule. These are the most potential naturally available materials for the development of cost-effective drug delivery systems because of their excellent biocompatibility, high surface area, low cost and ease of surface modification. Mesoporous silica materials such as MCM-41 and SBA-15 have been extensively used in drug delivery area. Their synthesis is challenging, time consuming, requires toxic chemicals and are energy intensive, making the entire process expensive and non-viable. Therefore, it is necessary to explore alternative materials. Surprisingly, nature has provided some exciting materials called diatoms; biosilica is one such a material that can be potentially used as a drug delivery vehicle. The present review focuses on different types of diatom species used in drug delivery with respect to their structural properties, morphology, purification process and surface functionalization. In this review, recent advances along with their limitations as well as the future scope to develop them as potential drug delivery vehicles are discussed. Copyright © 2018. Published by Elsevier B.V.

Anterior eye segment drug delivery systems: current treatments and future challenges.

PubMed

Molokhia, Sarah A; Thomas, Samuel C; Garff, Kevin J; Mandell, Kenneth J; Wirostko, Barbara M

2013-03-01

New technologies for delivery of drugs, such as small molecules and biologics, are of growing interest among clinical and pharmaceutical researchers for use in treating anterior segment eye disease. The challenge is to deliver effective drugs at therapeutic concentrations to the targeted ocular tissue with minimal side effects. To achieve this, a better understanding of the unmet needs, what is required of the various methods of delivery to achieve successful delivery, and the potential challenges of anterior segment drug delivery is necessary and the primarily aim of this review. This review covers the various physiological and anatomical barriers that exist for effective delivery to the targeted tissue of the eye, the pathological conditions of the anterior segment, and the unmet needs for treatment of these ocular diseases. Second, it reviews the novel delivery technologies that have the potential to maintain and/or improve the drug's therapeutic index and improving both patient adherence for chronic therapy and potential patient outcomes. This review bridges the pharmaceutical and clinical research/challenges and provides a detailed overview of anterior segment drug delivery accomplishments thus far, for researchers and clinicians.

Alignment-independent comparison of binding sites based on DrugScore potential fields encoded by 3D Zernike descriptors.

PubMed

Nisius, Britta; Gohlke, Holger

2012-09-24

Analyzing protein binding sites provides detailed insights into the biological processes proteins are involved in, e.g., into drug-target interactions, and so is of crucial importance in drug discovery. Herein, we present novel alignment-independent binding site descriptors based on DrugScore potential fields. The potential fields are transformed to a set of information-rich descriptors using a series expansion in 3D Zernike polynomials. The resulting Zernike descriptors show a promising performance in detecting similarities among proteins with low pairwise sequence identities that bind identical ligands, as well as within subfamilies of one target class. Furthermore, the Zernike descriptors are robust against structural variations among protein binding sites. Finally, the Zernike descriptors show a high data compression power, and computing similarities between binding sites based on these descriptors is highly efficient. Consequently, the Zernike descriptors are a useful tool for computational binding site analysis, e.g., to predict the function of novel proteins, off-targets for drug candidates, or novel targets for known drugs.

Trends in GPCR drug discovery: new agents, targets and indications.

PubMed

Hauser, Alexander S; Attwood, Misty M; Rask-Andersen, Mathias; Schiöth, Helgi B; Gloriam, David E

2017-12-01

G protein-coupled receptors (GPCRs) are the most intensively studied drug targets, mostly due to their substantial involvement in human pathophysiology and their pharmacological tractability. Here, we report an up-to-date analysis of all GPCR drugs and agents in clinical trials, which reveals current trends across molecule types, drug targets and therapeutic indications, including showing that 475 drugs (~34% of all drugs approved by the US Food and Drug Administration (FDA)) act at 108 unique GPCRs. Approximately 321 agents are currently in clinical trials, of which ~20% target 66 potentially novel GPCR targets without an approved drug, and the number of biological drugs, allosteric modulators and biased agonists has increased. The major disease indications for GPCR modulators show a shift towards diabetes, obesity and Alzheimer disease, although several central nervous system disorders are also highly represented. The 224 (56%) non-olfactory GPCRs that have not yet been explored in clinical trials have broad untapped therapeutic potential, particularly in genetic and immune system disorders. Finally, we provide an interactive online resource to analyse and infer trends in GPCR drug discovery.

Drug-releasing shape-memory polymers - the role of morphology, processing effects, and matrix degradation.

PubMed

Wischke, Christian; Behl, Marc; Lendlein, Andreas

2013-09-01

Shape-memory polymers (SMPs) have gained interest for temporary drug-release systems that should be anchored in the body by self-sufficient active movements of the polymeric matrix. Based on the so far published scientific literature, this review highlights three aspects that require particular attention when combining SMPs with drug molecules: i) the defined polymer morphology as required for the shape-memory function, ii) the strong effects that processing conditions such as drug-loading methodologies can have on the drug-release pattern from SMPs, and iii) the independent control of drug release and degradation by their timely separation. The combination of SMPs with a drug-release functionality leads to multifunctional carriers that are an interesting technology for pharmaceutical sciences and can be further expanded by new materials such as thermoplastic SMPs or temperature-memory polymers. Experimental studies should include relevant molecules as (model) drugs and provide a thermomechanical characterization also in an aqueous environment, report on the potential effect of drug type and loading levels on the shape-memory functionality, and explore the potential correlation of polymer degradation and drug release.

Engineering three-dimensional cardiac microtissues for potential drug screening applications.

PubMed

Wang, L; Huang, G; Sha, B; Wang, S; Han, Y L; Wu, J; Li, Y; Du, Y; Lu, T J; Xu, F

2014-01-01

Heart disease is one of the major global health issues. Despite rapid advances in cardiac tissue engineering, limited successful strategies have been achieved to cure cardiovascular diseases. This situation is mainly due to poor understanding of the mechanism of diverse heart diseases and unavailability of effective in vitro heart tissue models for cardiovascular drug screening. With the development of microengineering technologies, three-dimensional (3D) cardiac microtissue (CMT) models, mimicking 3D architectural microenvironment of native heart tissues, have been developed. The engineered 3D CMT models hold greater potential to be used for assessing effective drugs candidates than traditional two-dimensional cardiomyocyte culture models. This review discusses the development of 3D CMT models and highlights their potential applications for high-throughput screening of cardiovascular drug candidates.

Estimation of Potential Savings Through Therapeutic Substitution.

PubMed

Johansen, Michael E; Richardson, Caroline

2016-06-01

Therapeutic substitution offers potential to decrease pharmaceutical expenditures and potentially improve the efficiency of the health care system. To estimate potential savings through therapeutic substitution in terms of both overall and out-of-pocket expenditures of branded drugs when a generic in the same class with the same indication was available. Repeated cross-sectional study using the 107 132 individuals included in the nationally representative Medical Expenditure Panel Survey (2010-2012) along with their reported prescribed medicine use. The Orange Book, company financial statements, US Food and Drug Administration records, and published research were used for adjunctive information. Estimated excess expenditure due to branded drug overuse when a lower-cost generic in the same class with the same indication was available. The study included 107 132 individuals between 2010 and 2012, of whom 62.1% (95% CI, 61.4%-62.8%) reported use of any prescribed medicine. A total of 31.5% (95% CI, 30.7%-32.2%) used a medication from an included drug class, whereas 16.6% (95% CI, 16.0%-17.1%) of the population used a branded drug from the included classes compared with 24.0% (95% CI, 23.4%-24.7%) who used a generic and 9.1% (95% CI, 8.7%-9.4%) who used both. In the included drug classes, the majority of the drugs were generics, with a total of 93.5 billion standardized doses compared with 47.4 billion standardized doses of branded drugs. Total expenditure of the branded drugs accounted for $147 (95% CI, $137-$156) billion compared with $62.7 (95% CI, $58.9-$66.5) billion for the generics. Between 2010 and 2012, an estimated $73.0 (95% CI, $67.6-$78.5) billion in total excess expenditure and $24.6 (95% CI, $22.6-$26.5) billion in out-of-pocket excess expenditure was attributable to branded drug overuse. The excess was present across numerous drug classes throughout many aspects of medicine and equates to 9.6% of total and 14.1% of out-of-pocket prescribed medicine expenses. The drug classes with the highest excess expenditure included statins ($10.9 [SE, $0.41] billion), atypical antipsychotics ($9.99 [SE, $1.03] billion), proton pump inhibitors ($6.12 [SE, $0.38] billion), selective serotonin reuptake inhibitors ($6.08 [SE, $0.49] billion), and angiotensin receptor blockers ($5.53 [SE, $0.35] billion). Although therapeutic substitution is controversial, it offers a potential mechanism to significantly decrease drug costs if it can be implemented in a way that does not negatively affect quality of care.

3,4-Methylenedioxy analogues of amphetamine: defining the risks to humans.

PubMed

Hegadoren, K M; Baker, G B; Bourin, M

1999-03-01

The 3,4-methylenedioxy analogues of amphetamine [MDMA ("Ecstasy", "Adam"), MDA ("Love") and MDE ("Eve")] are recreational drugs that produce feelings of euphoria and energy and a desire to socialize, which go far to explain their current popularity as "rave drugs". In addition to these positive effects, the drugs are relatively inexpensive to purchase and have the reputation of being safe compared to other recreational drugs. Yet there is mounting evidence that these drugs do not deserve this reputation of being safe. This review examines the relevant human and animal literature to delineate the possible risks MDMA, MDA and MDE engender with oral consumption in humans. Following a summary of the behavioral and cognitive effects of MDMA, MDA and MDE, risks will be discussed in terms of toxicity, psychopathology, neurotoxicity, abuse potential and the potential for drug-drug interactions associated with acute and chronic use.

Application of optical action potentials in human induced pluripotent stem cells-derived cardiomyocytes to predict drug-induced cardiac arrhythmias.

PubMed

Lu, H R; Hortigon-Vinagre, M P; Zamora, V; Kopljar, I; De Bondt, A; Gallacher, D J; Smith, G

2017-09-01

Human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs) are emerging as new and human-relevant source in vitro model for cardiac safety assessment that allow us to investigate a set of 20 reference drugs for predicting cardiac arrhythmogenic liability using optical action potential (oAP) assay. Here, we describe our examination of the oAP measurement using a voltage sensitive dye (Di-4-ANEPPS) to predict adverse compound effects using hiPS-CMs and 20 cardioactive reference compounds. Fluorescence signals were digitized at 10kHz and the records subsequently analyzed off-line. Cells were exposed to 30min incubation to vehicle or compound (n=5/dose, 4 doses/compound) that were blinded to the investigating laboratory. Action potential parameters were measured, including rise time (T rise ) of the optical action potential duration (oAPD). Significant effects on oAPD were sensitively detected with 11 QT-prolonging drugs, while oAPD shortening was observed with I Ca -antagonists, I Kr -activator or ATP-sensitive K + channel (K ATP )-opener. Additionally, the assay detected varied effects induced by 6 different sodium channel blockers. The detection threshold for these drug effects was at or below the published values of free effective therapeutic plasma levels or effective concentrations by other studies. The results of this blinded study indicate that OAP is a sensitive method to accurately detect drug-induced effects (i.e., duration/QT-prolongation, shortening, beat rate, and incidence of early after depolarizations) in hiPS-CMs; therefore, this technique will potentially be useful in predicting drug-induced arrhythmogenic liabilities in early de-risking within the drug discovery phase. Copyright © 2017 Elsevier Inc. All rights reserved.

Herb–drug interaction prediction based on the high specific inhibition of andrographolide derivatives towards UDP-glucuronosyltransferase (UGT) 2B7

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ma, Hai-Ying, E-mail: cmu4h-mhy@126.com; Sun, Dong-Xue; Cao, Yun-Feng

2014-05-15

Herb–drug interaction strongly limits the clinical application of herbs and drugs, and the inhibition of herbal components towards important drug-metabolizing enzymes (DMEs) has been regarded as one of the most important reasons. The present study aims to investigate the inhibition potential of andrographolide derivatives towards one of the most important phase II DMEs UDP-glucuronosyltransferases (UGTs). Recombinant UGT isoforms (except UGT1A4)-catalyzed 4-methylumbelliferone (4-MU) glucuronidation reaction and UGT1A4-catalyzed trifluoperazine (TFP) glucuronidation were employed to firstly screen the andrographolide derivatives' inhibition potential. High specific inhibition of andrographolide derivatives towards UGT2B7 was observed. The inhibition type and parameters (K{sub i}) were determined for themore » compounds exhibiting strong inhibition capability towards UGT2B7, and human liver microsome (HLMs)-catalyzed zidovudine (AZT) glucuronidation probe reaction was used to furtherly confirm the inhibition behavior. In combination of inhibition parameters (K{sub i}) and in vivo concentration of andrographolide and dehydroandrographolide, the potential in vivo inhibition magnitude was predicted. Additionally, both the in vitro inhibition data and computational modeling results provide important information for the modification of andrographolide derivatives as selective inhibitors of UGT2B7. Taken together, data obtained from the present study indicated the potential herb–drug interaction between Andrographis paniculata and the drugs mainly undergoing UGT2B7-catalyzed metabolic elimination, and the andrographolide derivatives as potential candidates for the selective inhibitors of UGT2B7. - Highlights: • Specific inhibition of andrographolide derivatives towards UGT2B7. • Herb-drug interaction related withAndrographis paniculata. • Guidance for design of UGT2B7 specific inhibitors.« less

Microbial P450 Enzymes in Bioremediation and Drug Discovery: Emerging Potentials and Challenges.

PubMed

Bhattacharya, Sukanta S; Yadav, Jagjit S

2018-01-01

Cytochrome P450 enzymes are a structurally conserved but functionally diverse group of heme-containing mixed function oxidases found across both prokaryotic and eukaryotic forms of the microbial world. Microbial P450s are known to perform diverse functions ranging from the synthesis of cell wall components to xenobiotic/drug metabolism to biodegradation of environmental chemicals. Conventionally, many microbial systems have been reported to mimic mammalian P450-like activation of drugs and were proposed as the in-vitro models of mammalian drug metabolism. Recent reports suggest that native or engineered forms of specific microbial P450s from these and other microbial systems could be employed for desired specific biotransformation reactions toward natural and synthetic (drug) compounds underscoring their emerging potential in drug improvement and discovery. On the other hand, microorganisms particularly fungi and actinomycetes have been shown to possess catabolic P450s with unusual potential to degrade toxic environmental chemicals including persistent organic pollutants (POPs). Wood-rotting basidiomycete fungi in particular have revealed the presence of exceptionally large P450 repertoire (P450ome) in their genomes, majority of which are however orphan (with no known function). Our pre- and post-genomic studies have led to functional characterization of several fungal P450s inducible in response to exposure to several environmental toxicants and demonstration of their potential in bioremediation of these chemicals. This review is an attempt to summarize the postgenomic unveiling of this versatile enzyme superfamily in microbial systems and investigation of their potential to synthesize new drugs and degrade persistent pollutants, among other biotechnological applications. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Evaluation of small molecule tuberculostats for targeting tuberculosis infections of the central nervous system.

PubMed

Bartzatt, Ronald

2012-03-01

Tuberculosis infection of the central nervous system is a serious and frequently fatal disease. Four drugs have been found to very efficiently inhibit the growth of Mycobacterium tuberculosis and are examined for molecular properties that enable penetration of the blood-brain barrier. Drugs 1, 2, and 3 are aromatic compounds having a single bromine atom in ortho, meta, and para-position, respectively, relative to the hydrazide group (-C(O)NHNH2). A paraposition for bromine enabled the strongest inhibition of Mycobacterium tuberculosis. Drug 4 is a hydrazide derivative of ciprofloxacin. All drugs showed molecular properties suitable for targeting tuberculosis infections of the central nervous system. Drugs 1, 2, 3, 4, and isoniazid showed zero violations of the Rule of 5 and potential capability for oral administration. Values of BB (Cbrain/Cblood) suggested that drugs 1, 2, and 3 will be able to penetrate the brain approximately three times greater than isoniazid. Similarly, the calculated value of BB for drug 4 is comparable to that of isoniazid. Calculated values of polar surface area for drugs 1, 2, 3, and isoniazid indicated a potential rate of intestinal absorption of greater than 75% of drug amount present. The intestinal absorption of drug 4 is predicted to be greater than 50% of total amount present. Drug concentrations necessary for achieving MIC50 for 1, 2, 3, 4, and isoniazid are determined to be 65.9 μg/mL, 29.5 μg/mL, 21.5 μg/mL, 36.4 μg/mL, and 16.7 μg/mL, respectively. The position of the bromine atom within drugs 1, 2, and 3 appears to substantially influence the effectiveness of growth inhibition. These compounds show substantial potential for targeting tuberculosis infections within the central nervous system.

Roadside drug testing: An evaluation of the Alere DDS® 2 mobile test system.

PubMed

Rohrig, Timothy P; Moore, Christine M; Stephens, Kimberly; Cooper, Kelsey; Coulter, Cynthia; Baird, Tyson; Garnier, Margaux; Miller, Samuel; Tuyay, James; Osawa, Kei; Chou, Joshua; Nuss, Carson; Collier, Jeff; Wittman, Karen Cudlin

2018-04-01

The number of drivers using drugs has increased over the last few years, and is likely to continue its upward trend. Testing drivers for alcohol use is routine and standardized, but the same is not true for the identification of driving under the influence of drugs (DUID). The Drug Evaluation and Classification Program (DECP) was developed to train police officers to recognize the signs and symptoms of recent drug use and remains an invaluable program; however, there are insufficient numbers of these highly trained drug recognition experts (DREs) available to attend every potential drug involved traffic incident. While blood and urine samples are used to test for drugs in a driver, both have disadvantages, particularly as they pertain to the length of time required after a traffic stop to sample collection. Therefore, the development of oral fluid testing devices which can be operated at the roadside and have the potential to assist officers in the identification of drug use is a major advancement in DUID cases. This project evaluated the performance of one instrumental oral fluid roadside testing device (Alere DDS®2) compared to DRE opinion, oral fluid laboratory-based analysis, and routine blood testing. The results showed that there was a good correlation with DRE observations and the device performance was >80% in all drug categories compared to laboratory-based analytical testing, both in oral fluid and blood, with few exceptions. The instrument can be considered a useful tool to assist law enforcement in identifying a drugged driver. Because the device does not test for all potentially impairing drugs, the opinion of the police officer regarding the condition of the driver should still be considered the most important aspect for arrest and further action. Copyright © 2017 John Wiley & Sons, Ltd.

Illicit drugs and the environment--a review.

PubMed

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

2013-10-01

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

The pivotal role of multimodality reporter sensors in drug discovery: from cell based assays to real time molecular imaging.

PubMed

Ray, Pritha

2011-04-01

Development and marketing of new drugs require stringent validation that are expensive and time consuming. Non-invasive multimodality molecular imaging using reporter genes holds great potential to expedite these processes at reduced cost. New generations of smarter molecular imaging strategies such as Split reporter, Bioluminescence resonance energy transfer, Multimodality fusion reporter technologies will further assist to streamline and shorten the drug discovery and developmental process. This review illustrates the importance and potential of molecular imaging using multimodality reporter genes in drug development at preclinical phases.

Early assessment of proarrhythmic risk of drugs using the in vitro data and single-cell-based in silico models: proof of concept.

PubMed

Abbasi, Mitra; Small, Ben G; Patel, Nikunjkumar; Jamei, Masoud; Polak, Sebastian

2017-02-01

To determine the predictive performance of in silico models using drug-specific preclinical cardiac electrophysiology data to investigate drug-induced arrhythmia risk (e.g. Torsade de pointes (TdP)) in virtual human subjects. To assess drug proarrhythmic risk, we used a set of in vitro electrophysiological measurements describing ion channel inhibition triggered by the investigated drugs. The Cardiac Safety Simulator version 2.0 (CSS; Simcyp, Sheffield, UK) platform was used to simulate human left ventricular cardiac myocyte action potential models. This study shows the impact of drug concentration changes on particular ionic currents by using available experimental data. The simulation results display safety threshold according to drug concentration threshold and log (threshold concentration/ effective therapeutic plasma concentration (ETPC)). We reproduced the underlying biophysical characteristics of cardiac cells resulted in effects of drugs associated with cardiac arrhythmias (action potential duration (APD) and QT prolongation and TdP) which were observed in published 3D simulations, yet with much less computational burden.

Erosive and cariogenicity potential of pediatric drugs: study of physicochemical parameters

PubMed Central

2013-01-01

Background Pediatric medications may possess a high erosive potential to dental tissues due to the existence of acid components in their formulations. The purpose was to determine the erosive and cariogenic potential of pediatric oral liquid medications through the analysis of their physicochemical properties in vitro. Methods A total of 59 substances were selected from the drug reference list of the National Health Surveillance Agency (ANVISA), which belong to 11 therapeutic classes, as follows: analgesics, non-steroidal anti-inflammatory, corticosteroids, antihistamines, antitussives, bronchodilators, antibacterials, antiparasitics, antiemetics, anticonvulsants and antipsychotics. Measurement of pH was performed by potentiometry, using a digital pH meter. For the Total Titratable Acidity (TTA) chemical assay, a 0.1 N NaOH standard solution was used, which was titrated until drug pH was neutralized. The Total Soluble Solids Contents (TSSC) quantification was carried out by refractometry using Brix scale and the analysis of Total Sugar Content was performed according to Fehling’s method. In addition, it was analyzed the information contained in the drug inserts with regard to the presence of sucrose and type of acid and sweetener added to the formulations. Results All drug classes showed acidic pH, and the lowest mean was found for antipsychotics (2.61 ± 0.08). There was a large variation in the TTA (0.1% - 1.18%) and SST (10.44% - 57.08%) values. High total sugar contents were identified in the antitussives (53.25%) and anticonvulsants (51.75%). As described in the drug inserts, sucrose was added in 47.5% of the formulations, as well as citric acid (39.0%), sodium saccharin (36.4%) and sorbitol (34.8%). Conclusion The drugs analyzed herein showed physicochemical characteristics indicative of a cariogenic and erosive potential on dental tissues. Competent bodies’ strategies should be implemented in order to broaden the knowledge of health professionals, drug manufacturers and general consuming public about the risks from the consumption of medicines potentially harmful to dental tissues. PMID:24325544

Acute drug prescribing to children on chronic antiepilepsy therapy and the potential for adverse drug interactions in primary care

PubMed Central

Novak, Philipp H; Ekins-Daukes, Suzie; Simpson, Colin R; Milne, Robert M; Helms, Peter; McLay, James S

2005-01-01

Aims To investigate the extent of acute coprescribing in primary care to children on chronic antiepileptic therapy, which could give rise to potentially harmful drug–drug interactions. Design Acute coprescribing to children on chronic antiepileptic drug therapy in primary care was assessed in 178 324 children aged 0–17 years for the year 1 November 1999 to 31 October 2000. Computerized prescribing data were retrieved from 161 representative general practices in Scotland. Setting One hundred and sixty-one general practices throughout Scotland. Results During the study year 723 (0.41%) children chronically prescribed antiepileptic therapy were identified. Fourteen antiepileptic agents were prescribed, with carbamazepine, sodium valproate and lamotrigine accounting for 80% of the total. During the year children on chronic antiepileptic therapy were prescribed 4895 acute coprescriptions for 269 different medicines. The average number of acute coprescriptions for non-epileptic drug therapy were eight, 11, six, and six for the 0–1, 2–4, 5–11, and 12–17-year-olds, respectively. Of these acute coprescriptions 72 (1.5%) prescribed to 22 (3.0%) children were identified as a potential source of clinically serious interactions. The age-adjusted prevalence rates for potentially serious coprescribing were 86, 26, 22, and 33/1000 children chronically prescribed antiepileptic therapy in the 0–1, 2–4, 5–11, and 12–17-year-old age groups, respectively. The drugs most commonly coprescribed which could give rise to such interactions were antacids, erythromycin, ciprofloxacin, theophylline and the low-dose oral contraceptive. For 10 (45.5%0 of the 20 children identified at risk of a potentially clinically serious adverse drug interaction, the acute coprescription was prescribed off label because of age or specific contraindication/warning. Conclusions In primary care, 3.0% of children on chronic antiepileptic therapy are coprescribed therapeutic agents, which could give rise to clinically serious drug–drug interactions. PMID:15948936

Exposure to antineoplastic drugs outside the hospital environment.

PubMed

Meijster, T; Fransman, W; Veldhof, R; Kromhout, H

2006-10-01

The objectives were (i) to identify occupational populations outside hospitals working with antineoplastic drugs, (ii) to determine the size of the populations 'at risk', (iii) to identify major determinants and routes of exposure outside hospitals and (iv) to estimate exposure levels and frequencies relative to levels found in hospitals. The survey consisted of two phases; (i) identification of activities with potential exposure to antineoplastic drugs by literature review, interviews, questionnaires and workplace visits, (ii) exploratory measurements of exposure and surface contamination in selected sectors. Eight sectors were identified with potential exposure to antineoplastic drugs: pharmaceutical industry, pharmacies, universities, veterinary medicine, nursing homes, home care, laundry facilities, and waste treatment. Four sectors were of primary concern: veterinary medicine, home care, nursing homes and industrial laundries. The populations potentially exposed in these sectors vary considerably (from several tens to thousands of workers), as do their levels of exposure. Exposure measurements collected in the veterinary medicine sector showed that workers are indeed exposed to antineoplastic drugs and, in some cases (on gloves after administration), levels were 15 times higher than levels measured during administration in hospitals. Workers sorting contaminated hospital laundry in industrial laundry facilities were exposed to antineoplastic drugs through inhalation. For the home care and nursing homes sectors the highest exposure levels were found when cleaning toilets and washing treated patients. These two sectors are expected to have the largest exposed population (5,000-10,000 individuals). This study has resulted in a comprehensive overview of populations with potential exposure to antineoplastic drugs. Exposure levels can potentially be high compared with the hospital environment, because exposure routes are complex and awareness of the hazard (and therefore use of protective measures) is low. The number of individuals outside hospitals in The Netherlands exposed to antineoplastic drugs is estimated to be between 5,000 and 15,000.

Erosive and cariogenicity potential of pediatric drugs: study of physicochemical parameters.

PubMed

Xavier, Alidianne Fábia C; Moura, Eline F F; Azevedo, Waldeneide F; Vieira, Fernando F; Abreu, Mauro H N G; Cavalcanti, Alessandro L

2013-12-10

Pediatric medications may possess a high erosive potential to dental tissues due to the existence of acid components in their formulations. The purpose was to determine the erosive and cariogenic potential of pediatric oral liquid medications through the analysis of their physicochemical properties in vitro. A total of 59 substances were selected from the drug reference list of the National Health Surveillance Agency (ANVISA), which belong to 11 therapeutic classes, as follows: analgesics, non-steroidal anti-inflammatory, corticosteroids, antihistamines, antitussives, bronchodilators, antibacterials, antiparasitics, antiemetics, anticonvulsants and antipsychotics. Measurement of pH was performed by potentiometry, using a digital pH meter. For the Total Titratable Acidity (TTA) chemical assay, a 0.1 N NaOH standard solution was used, which was titrated until drug pH was neutralized. The Total Soluble Solids Contents (TSSC) quantification was carried out by refractometry using Brix scale and the analysis of Total Sugar Content was performed according to Fehling's method. In addition, it was analyzed the information contained in the drug inserts with regard to the presence of sucrose and type of acid and sweetener added to the formulations. All drug classes showed acidic pH, and the lowest mean was found for antipsychotics (2.61 ± 0.08). There was a large variation in the TTA (0.1% - 1.18%) and SST (10.44% - 57.08%) values. High total sugar contents were identified in the antitussives (53.25%) and anticonvulsants (51.75%). As described in the drug inserts, sucrose was added in 47.5% of the formulations, as well as citric acid (39.0%), sodium saccharin (36.4%) and sorbitol (34.8%). The drugs analyzed herein showed physicochemical characteristics indicative of a cariogenic and erosive potential on dental tissues. Competent bodies' strategies should be implemented in order to broaden the knowledge of health professionals, drug manufacturers and general consuming public about the risks from the consumption of medicines potentially harmful to dental tissues.

Prescription of hazardous drugs during pregnancy.

PubMed

Malm, Heli; Martikainen, Jaana; Klaukka, Timo; Neuvonen, Pertti J

2004-01-01

Prescribing drugs to pregnant women requires the balancing of benefits and risks. Only a small proportion of drugs are known to be harmful to the fetus, but for the vast majority of drugs little evidence of fetal safety exists. To determine the prescription pattern of potentially and clearly harmful prescription drugs during pregnancy with reference to drug safety categorisation, and to define the drug groups primarily responsible for multiple drug use during pregnancy. A retrospective, register-based cohort study. Linkage of three nationwide registers in Finland. Data collection included prescription drugs purchased during the preconception period and each trimester in the pregnant cohort, and the corresponding time periods in the non-pregnant controls. The pregnancy safety categorisation was determined for each drug (Anatomic Therapeutic Chemical [ATC] code) by using the Swedish classification of approved medicinal products (Farmaceutiska Specialiteter i Sverige [FASS]) and if not available, the corresponding Australian (Australian Drug Evaluation Committee [ADEC]) or US categorisation (FDA). GROUPS STUDIED: Women applying for maternity support (maternal grants) during the year 1999 (n = 43 470) plus non-pregnant control women matched by age and hospital district (n = 43 470). In the pregnant cohort, 20.4% of women purchased at least one drug classified as potentially harmful during pregnancy, and 3.4% purchased at least one drug classified as clearly harmful. A significant decline occurred in the number of pregnant women purchasing potentially and clearly harmful drugs during the first trimester when compared with the preconception period, and the decline continued from the first to the second trimester. In the pregnant cohort, 107 (0.2%) women purchased at least ten different drugs during pregnancy. The drugs most commonly purchased in this group were topical corticosteroids and nasal preparations. The use of hazardous prescription drugs declines during pregnancy but prescriptions of known teratogens and the relatively frequent practice of polypharmacy in epilepsy place emphasis on the need for careful pre-pregnancy counselling. However, drug safety classifications give a very crude estimation of risk and should only be used as general guidelines when planning treatment. Risk assessment must always be made on an individual basis, and pregnant women with illnesses requiring treatment must be treated adequately.

DrugPath: a database for academic investigators to match oncology molecular targets with drugs in development.

PubMed

Shah, Eric D; Fisch, Brandon M A; Arceci, Robert J; Buckley, Jonathan D; Reaman, Gregory H; Sorensen, Poul H; Triche, Timothy J; Reynolds, C Patrick

2014-05-01

Academic laboratories are developing increasingly large amounts of data that describe the genomic landscape and gene expression patterns of various types of cancers. Such data can potentially identify novel oncology molecular targets in cancer types that may not be the primary focus of a drug sponsor's initial research for an investigational new drug. Obtaining preclinical data that point toward the potential for a given molecularly targeted agent, or a novel combination of agents requires knowledge of drugs currently in development in both the academic and commercial sectors. We have developed the DrugPath database ( http://www.drugpath.org ) as a comprehensive, free-of-charge resource for academic investigators to identify agents being developed in academics or industry that may act against molecular targets of interest. DrugPath data on molecular targets overlay the Michigan Molecular Interactions ( http://mimi.ncibi.org ) gene-gene interaction map to facilitate identification of related agents in the same pathway. The database catalogs 2,081 drug development programs representing 751 drug sponsors and 722 molecular and genetic targets. DrugPath should assist investigators in identifying and obtaining drugs acting on specific molecular targets for biological and preclinical therapeutic studies.

Development and feasibility of the misuse, abuse, and diversion drug event reporting system (MADDERS®).

PubMed

Treister, Roi; Trudeau, Jeremiah J; Van Inwegen, Richard; Jones, Judith K; Katz, Nathaniel P

2016-12-01

Inappropriate use of analgesic drugs has become increasingly pervasive over the past decade. Currently, drug abuse potential is primarily assessed post-marketing; no validated tools are available to assess this potential in phase II and III clinical trials. This paper describes the development and feasibility testing of a Misuse, Abuse, and Diversion Drug Event Reporting System (MADDERS), which aims to identify potentially abuse-related events and classify them according to a recently developed classification scheme, allowing the quantification of these events in clinical trials. The system was initially conceived and designed with input from experts and patients, followed by field-testing to assess its feasibility and content validity in both completed and ongoing clinical trials. The results suggest that MADDERS is a feasible system with initial validity. It showed higher rates of the triggering events in subjects taking medications with known abuse potential than in patients taking medications without abuse potential. Additionally, experts agreed on the classification of most abuse-related events in MADDERS. MADDERS is a new systematic approach to collect information on potentially abuse-related events in clinical trials and classify them. The system has demonstrated feasibility for implementation. Additional research is ongoing to further evaluate its validity. Currently, there are no validated tools to assess drug abuse potential during clinical trials. Because of its ease of implementation, its systematic approach, and its preliminary validation results, MADDERS could provide such a tool for clinical trials. (Am J Addict 2016;25:641-651). © 2016 American Academy of Addiction Psychiatry.

Potential Role of Extracellular Vesicles in the Pathophysiology of Drug Addiction.

PubMed

Rao, P S S; O'Connell, Kelly; Finnerty, Thomas Kyle

2018-01-23

Extracellular vesicles (EVs) are small vesicles secreted by cells and are known to carry sub-cellular components including microRNA, proteins, and lipids. Due to their ability to transport cargo between cells, EVs have been identified as important regulators of various pathophysiological conditions and can therefore influence treatment outcomes. In particular, the significance of microRNAs in EV-mediated cell-cell communication is well-documented. While the influence of EVs and the cargo delivered by EVs has been extensively reviewed in other neurological disorders, the available literature on the potential role of EVs in the pathophysiology of drug addiction has not been reviewed. Hence, in this article, the known effects of commonly abused drugs (ethanol, nicotine, opiates, cocaine, and cannabinoids) on EV secretion have been reviewed. In addition, the potential role of drugs of abuse in affecting the delivery of EV-packaged microRNAs, and the subsequent impact on neuronal health and continued drug dependence, has been discussed.

Age factors potentiating drug toxicity in the reproductive axis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Walker, R.F.

Traditionally, the drug toxicity in the reproductive system has been a concern only as it affects fertility and fecundity in young individuals. The purpose of this report is to address the potential problem of synergy between drug actions and abnormal secretion of reproductive hormones that together produce disease in older individuals. Thus, reproductive toxicity has different, but no less serious implications in aging individuals. During aging, the coordinated function of elements within the reproductive neuroendocrine axis degrades. This change promotes atypical secretion of hormones producing abnormal responses in target organs and thus creates a condition with pathogenic potential. Certain drugsmore » may contribute to reproductive toxicity in aging individuals either by accelerating the process of dysregulation and/or by synergizing with hormones to stimulate pathologic changes in target tissues. The geriatric population or the world is increasing, and since it consumes a proportionately larger percentage of drugs than younger groups, this novel form of reproductive toxicity may represent a problem in drug safety that warrants serious consideration.« less

Falcipain inhibitors as potential therapeutics for resistant strains of malaria: a patent review.

PubMed

Mane, Uttam Rajaram; Gupta, Ramesh C; Nadkarni, Sunil Sadanand; Giridhar, Rajani R; Naik, Prashant Prakash; Yadav, Mange R

2013-02-01

There is an urgent need to discover new antimalarial drugs due to emergence of resistance in the parasite to the existing drugs. Malarial cysteine proteases falcipin-2 (FP-2) and falcipain-3 (FP-3) are attractive targets for antimalarial chemotherapy. The structures and functions of FP-2/3, their binding domains and their interactions with small- and macro-molecules are well studied. These studies could provide important insight into rational designing of FP inhibitors as potential antimalarial drugs. This review is focused on a selection of interesting patents published during 1999 - 2011 on peptidic and nonpeptidic chemotypes of the FP-2/FP-3 inhibitors. It is a known fact that malaria is a serious health problem worldwide due to the emergence of resistant strains. Hence, development of novel, potent and affordable antimalarial drugs devoid of side effects is of great significance and in great demand. FPs, the malarial cysteine proteases are potential targets for development of new antimalarial drugs. Assessing the available literature on FP-2/3 and their inhibitors it could be speculated that these inhibitors have the potential to enter the clinical stages of development for the treatment of malaria in the years to come.

Chitosan-Acrylic Polymeric Nanoparticles with Dynamic Covalent Bonds. Synthesis and Stimuli Behavior.

PubMed

Palacio, Herman; Otálvaro, Felipe; Giraldo, Luis Fernando; Ponchel, Gilles; Segura-Sánchez, Freimar

2017-12-01

Drug delivery represents one of the most important research fields within the pharmaceutical industry. Different strategies are reported every day in a dynamic search for carriers with the ability to transport drugs across the body, avoiding or decreasing toxic issues and improving therapeutic activity. One of the most interesting strategies currently under research is the development of drug delivery systems sensitive to different stimuli, due to the high potential attributed to the selective delivery of the payload. In this work, a stimuli-sensitive nanocarrier was built with a bifunctional acrylic polymer, linked by imine and disulfide bonds to thiolate chitosan, the latter being a biopolymer widely known in the field of tissue engineering and drug delivery by its biodegradability and biocompatibility. These polymer nanoparticles were exposed to different changes in pH and redox potential, which are environments commonly found inside cancer cells. The results proof the ability of the nanoparticles to keep the original structure when either changes in pH or redox potential were applied individually. However, when both stimuli were applied simultaneously, a disassembly of the nanoparticles was evident. These special characteristics make these nanoparticles suitable nanocarriers with potential for the selective delivery of anticancer drugs.

Drug-using and nonusing women: potential for child abuse, child-rearing attitudes, social support, and affection for expected baby.

PubMed

Williams-Petersen, M G; Myers, B J; Degen, H M; Knisely, J S; Elswick, R K; Schnoll, S S

1994-10-01

Eighty pregnant women (25 substance using, 55 nonusing) from an American prenatal clinic serving lower-income to working-class women responded to questionnaire measures of child-rearing attitudes. The drug users' primary substance of misuse was cocaine (68%), alcohol (16%), amphetamines (12%), or sedatives (4%); polydrug use was documented for 80% of the women. The two (user and nonuser) groups were not different on demographic (age, race, marital status, education, SES, source of income) or obstetrical factors (number of pregnancies, number of children). Drug-using women scored significantly higher on a measure of child abuse potential; more than half scored in the range of clinical criterion for extreme risk. As their babies were not yet born, no actual physical abuse was documented, only a higher potential for abuse. The subgroup who were both drug users and had lower social support scored higher on child abuse potential than all other subgroups. The drug users also had lower self-esteem scores than the nonusers. The two groups did not differ on measures of overall social support, authoritarian/democratic child-rearing beliefs, or affection for the expected baby.

Enhancement of oral bioavailability of atorvastatin calcium by self-emulsifying drug delivery systems (SEDDS).

PubMed

Kadu, Pawan J; Kushare, Sachin S; Thacker, Dhaval D; Gattani, Surendra G

2011-02-01

The aim of the present study was to formulate a self-emulsifying drug delivery system of atorvastatin calcium and its characterization including in vitro and in vivo potential. The solubility of atorvastatin calcium was determined in various vehicles such as Captex 355, Captex 355 EP/NF, Ethyl oleate, Capmul MCM, Capmul PG-8, Gelucire 44/14, Tween 80, Tween 20, and PEG 400. Pseudoternary phase diagrams were plotted on the basis of solubility data of drug in various components to evaluate the microemulsification region. Formulation development and screening was carried out based on results obtained from phase diagrams and characteristics of resultant microemulsion. Prepared formulations were tested for microemulsifying properties and evaluated for clarity, precipitation, viscosity determination, drug content and in vitro dissolution. The optimized formulation further evaluated for particle size distribution, zeta potential, stability studies and in vivo potential. In vivo performance of the optimized formulation was evaluated using a Triton-induced hypercholesterolemia model in male Albino Wistar rats. The formulation significantly reduced serum lipid levels as compared with atorvastatin calcium. Thus studies illustrated the potential use for the delivery of hydrophobic drug such as atorvastatin calcium by oral route.

Investigation of the host-guest complexation between 4-sulfocalix[4]arene and nedaplatin for potential use in drug delivery

NASA Astrophysics Data System (ADS)

Fahmy, Sherif Ashraf; Ponte, Fortuna; Abd El-Rahman, Mohamed K.; Russo, Nino; Sicilia, Emilia; Shoeib, Tamer

2018-03-01

Macromolecules including macrocyclic species have been reported to have the potential to encapsulate biologically active compounds such as drugs through host-guest complexation to increase their solubility, stability and bioavailability. In this paper the first experimental and theoretical investigation of the complexation between nedaplatin, a second generation antineoplastic drug, and p-4-sulfocalix[4]arene, a macromolecule possessing a bipolar amphiphilic structure with good biocompatibility and relatively low haemolytic toxicity for potential use as a drug delivery system is presented. Data from 1H NMR, UV, Job's plot analysis, HPLC and DFT calculations are detailed and suggest the formation of a 1:1 complex. The stability constant of the complex was experimentally estimated to be 3.6 × 104 M- 1 and 2.1 × 104 M- 1 which correspond to values of - 6.2 and - 5.9 kcal mol- 1, respectively for the free energy of complexation while the interaction free energy is calculated to be - 4.9 kcal mol- 1. The formed species is shown to be stabilised in solution through hydrogen bonding between the host and the guest which may allow for this strategy to be effective for potential use in drug delivery.

Predicting Drug Combination Index and Simulating the Network-Regulation Dynamics by Mathematical Modeling of Drug-Targeted EGFR-ERK Signaling Pathway

NASA Astrophysics Data System (ADS)

Huang, Lu; Jiang, Yuyang; Chen, Yuzong

2017-01-01

Synergistic drug combinations enable enhanced therapeutics. Their discovery typically involves the measurement and assessment of drug combination index (CI), which can be facilitated by the development and applications of in-silico CI predictive tools. In this work, we developed and tested the ability of a mathematical model of drug-targeted EGFR-ERK pathway in predicting CIs and in analyzing multiple synergistic drug combinations against observations. Our mathematical model was validated against the literature reported signaling, drug response dynamics, and EGFR-MEK drug combination effect. The predicted CIs and combination therapeutic effects of the EGFR-BRaf, BRaf-MEK, FTI-MEK, and FTI-BRaf inhibitor combinations showed consistent synergism. Our results suggest that existing pathway models may be potentially extended for developing drug-targeted pathway models to predict drug combination CI values, isobolograms, and drug-response surfaces as well as to analyze the dynamics of individual and combinations of drugs. With our model, the efficacy of potential drug combinations can be predicted. Our method complements the developed in-silico methods (e.g. the chemogenomic profile and the statistically-inferenced network models) by predicting drug combination effects from the perspectives of pathway dynamics using experimental or validated molecular kinetic constants, thereby facilitating the collective prediction of drug combination effects in diverse ranges of disease systems.

Identifying high risk medications causing potential drug-drug interactions in outpatients: A prescription database study based on an online surveillance system.

PubMed

Toivo, T M; Mikkola, J A V; Laine, K; Airaksinen, M

2016-01-01

Drug-drug interactions (DDIs) are a significant cause for adverse drug events (ADEs). DDIs are often predictable and preventable, but their prevention and management require systematic service development. Most DDI studies focus on interaction rates in hospitalized patients. Less is known of DDIs in outpatients, particularly how community pharmacists could contribute to DDI management by applying their surveillance systems for identifying high-risk medications. The study was related to the implementation of the first online DDI surveillance system in Finnish community pharmacies. The goal was to demonstrate how community pharmacies can utilize their prospective surveillance system 1) for identifying high risk medications causing potential DDIs in outpatients, 2) for collaborative service development with local physicians, and 3) for academic risk management research purposes. All DDI alerts given by the online surveillance system were collected during a one-month period in 16 out of 17 University Pharmacy outlets in Finland, covering approximately 10% of the national outpatient prescription volume. The surveillance system was based on the FASS database, which categorizes DDIs into four classes (A-D) according to their clinical significance. Potential drug-drug DDIs were analyzed for 276,891 dispensed community pharmacy prescriptions. Potential DDIs were associated with 10.8%, or 31,110 of these prescriptions. Clinically significant interaction alerts categorized as FASS classes D (most severe, should be avoided) and C (clinically significant but controllable) were associated with 0.5% and 7.0% of the prescriptions, respectively. Methotrexate and warfarin had the highest risk of causing potentially serious (class D) interactions. These interaction alerts were most frequently between methotrexate and NSAIDs and warfarin and NSAIDs. In general, NSAIDs were the most commonly interacting drugs in this study. This study demonstrates that community pharmacies can actively contribute to DDI risk management and systematically use their surveillance systems for identifying patients having clinically significant DDIs. The findings also indicate that the majority of potentially serious interactions in outpatients involve a limited number of drugs, particularly NSAIDs, warfarin and methotrexate. Further research should focus on community pharmacists' involvement in DDI risk management in collaboration with local health care providers. Copyright © 2015 Elsevier Inc. All rights reserved.

Anticoagulant Medicine: Potential for Drug-Food Interactions

MedlinePlus

... Medications Anticoagulants and Drug-Food Interactions Anticoagulants and Drug-Food Interactions Make an Appointment Ask a Question ... care provider before making the change. Anticoagulants and Medicine There are many medicines that can interact with ...

[Adverse Effect Predictions Based on Computational Toxicology Techniques and Large-scale Databases].

PubMed

Uesawa, Yoshihiro

2018-01-01

　Understanding the features of chemical structures related to the adverse effects of drugs is useful for identifying potential adverse effects of new drugs. This can be based on the limited information available from post-marketing surveillance, assessment of the potential toxicities of metabolites and illegal drugs with unclear characteristics, screening of lead compounds at the drug discovery stage, and identification of leads for the discovery of new pharmacological mechanisms. This present paper describes techniques used in computational toxicology to investigate the content of large-scale spontaneous report databases of adverse effects, and it is illustrated with examples. Furthermore, volcano plotting, a new visualization method for clarifying the relationships between drugs and adverse effects via comprehensive analyses, will be introduced. These analyses may produce a great amount of data that can be applied to drug repositioning.

DUE (drug usage evaluation) of ticarcillin and clavulanate potassium: determining appropriate and cost-effective therapeutic options.

PubMed

Lomaestro, B M; Lesar, T S

1988-11-01

The initial 46 patients who were prescribed the combination drug ticarcillin disodium and clavulanate potassium in a 640-bed teaching hospital were evaluated to determine the potential usefulness of the drug in the institution. The review revealed frequent use of the drug for inappropriate indications and in situations for which less expensive antimicrobials were appropriate. The results demonstrate that an increase in costs can occur when an agent that is being considered for formulary addition--because of its cost-saving potential--is not used as expected. In order to optimally utilize the clinical or cost advantages of newer antimicrobials, a program of prescriber education, drug use controls or guidelines, and a concurrent monitoring program may be required and should be implemented at the time of initial drug use within an institution.

Rechargeable infection-responsive antifungal denture materials.

PubMed

Cao, Z; Sun, X; Yeh, C-K; Sun, Y

2010-12-01

Candida-associated denture stomatitis (CADS) is a significant clinical concern. We developed rechargeable infection-responsive antifungal denture materials for potentially managing the disease. Polymethacrylic acid (PMAA) was covalently bound onto diurethane dimethacrylate denture resins in the curing step. The PMAA resins bound cationic antifungal drugs such as miconazole and chlorhexidine digluconate (CG) through ionic interactions. The anticandidal activities of the drug-containing PMAA-resin discs were sustained for a prolonged period of time (weeks and months). Drug release was much faster at acidic conditions (pH 5) than at pH 7. Drugs bound to the denture materials could be "washed out" by treatment with EDTA, and the drug-depleted resins could be recharged with the same or a different class of anticandidal drugs. These results suggest clinical potential of the newly developed antifungal denture materials in the management of CADS and other infectious conditions.

Sex differences in drug addiction and response to exercise intervention: From human to animal studies.

PubMed

Zhou, Yuehui; Zhao, Min; Zhou, Chenglin; Li, Rena

2016-01-01

Accumulated research supports the idea that exercise could be an option of potential prevention and treatment for drug addiction. During the past few years, there has been increased interest in investigating of sex differences in exercise and drug addiction. This demonstrates that sex-specific exercise intervention strategies may be important for preventing and treating drug addiction in men and women. However, little is known about how and why sex differences are found when doing exercise-induced interventions for drug addiction. In this review, we included both animal and human that pulled subjects from a varied age demographic, as well as neurobiological mechanisms that may highlight the sex-related differences in these potential to assess the impact of sex-specific roles in drug addiction and exercise therapies. Copyright © 2015 Elsevier Inc. All rights reserved.

Improving specialist drug prescribing in primary care using task and error analysis: an observational study.

PubMed

Chana, Narinder; Porat, Talya; Whittlesea, Cate; Delaney, Brendan

2017-03-01

Electronic prescribing has benefited from computerised clinical decision support systems (CDSSs); however, no published studies have evaluated the potential for a CDSS to support GPs in prescribing specialist drugs. To identify potential weaknesses and errors in the existing process of prescribing specialist drugs that could be addressed in the development of a CDSS. Semi-structured interviews with key informants followed by an observational study involving GPs in the UK. Twelve key informants were interviewed to investigate the use of CDSSs in the UK. Nine GPs were observed while performing case scenarios depicting requests from hospitals or patients to prescribe a specialist drug. Activity diagrams, hierarchical task analysis, and systematic human error reduction and prediction approach analyses were performed. The current process of prescribing specialist drugs by GPs is prone to error. Errors of omission due to lack of information were the most common errors, which could potentially result in a GP prescribing a specialist drug that should only be prescribed in hospitals, or prescribing a specialist drug without reference to a shared care protocol. Half of all possible errors in the prescribing process had a high probability of occurrence. A CDSS supporting GPs during the process of prescribing specialist drugs is needed. This could, first, support the decision making of whether or not to undertake prescribing, and, second, provide drug-specific parameters linked to shared care protocols, which could reduce the errors identified and increase patient safety. © British Journal of General Practice 2017.

Potential geographic "hotspots" for drug-injection related transmission of HIV and HCV and for initiation into injecting drug use in New York City, 2011-2015, with implications for the current opioid epidemic in the US

PubMed Central

Cooper, H. L. F.; Arasteh, K.; Feelemyer, J.; McKnight, C.; Ross, Z.

2018-01-01

Objective We identified potential geographic “hotspots” for drug-injecting transmission of HIV and hepatitis C virus (HCV) among persons who inject drugs (PWID) in New York City. The HIV epidemic among PWID is currently in an “end of the epidemic” stage, while HCV is in a continuing, high prevalence (> 50%) stage. Methods We recruited 910 PWID entering Mount Sinai Beth Israel substance use treatment programs from 2011–2015. Structured interviews and HIV/ HCV testing were conducted. Residential ZIP codes were used as geographic units of analysis. Potential “hotspots” for HIV and HCV transmission were defined as 1) having relatively large numbers of PWID 2) having 2 or more HIV (or HCV) seropositive PWID reporting transmission risk—passing on used syringes to others, and 3) having 2 or more HIV (or HCV) seronegative PWID reporting acquisition risk—injecting with previously used needles/syringes. Hotspots for injecting drug use initiation were defined as ZIP codes with 5 or more persons who began injecting within the previous 6 years. Results Among PWID, 96% injected heroin, 81% male, 34% White, 15% African-American, 47% Latinx, mean age 40 (SD = 10), 7% HIV seropositive, 62% HCV seropositive. Participants resided in 234 ZIP codes. No ZIP codes were identified as potential hotspots due to small numbers of HIV seropositive PWID reporting transmission risk. Four ZIP codes were identified as potential hotspots for HCV transmission. 12 ZIP codes identified as hotspots for injecting drug use initiation. Discussion For HIV, the lack of potential hotspots is further validation of widespread effectiveness of efforts to reduce injecting-related HIV transmission. Injecting-related HIV transmission is likely to be a rare, random event. HCV prevention efforts should include focus on potential hotspots for transmission and on hotspots for initiation into injecting drug use. We consider application of methods for the current opioid epidemic in the US. PMID:29596464

21 CFR 516.3 - Definitions.

Code of Federal Regulations, 2011 CFR

2011-04-01

... translation or transcription or were minor differences in amino acid sequence; other potentially important... 21 Food and Drugs 6 2011-04-01 2011-04-01 false Definitions. 516.3 Section 516.3 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS...

21 CFR 516.3 - Definitions.

Code of Federal Regulations, 2010 CFR

2010-04-01

... transcription or were minor differences in amino acid sequence; other potentially important differences, such as... 21 Food and Drugs 6 2010-04-01 2010-04-01 false Definitions. 516.3 Section 516.3 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS...

Drug Abuse: A Challenge for Education.

ERIC Educational Resources Information Center

Conte, Anthony E.; Mason, Eugene R.

This report provides comprehensive information regarding drug use/abuse. The first chapter describes drugs -- those generally accepted by society as well as those less accepted -- and discusses potential psychic and physical dangers inherent in their abuse. The second chapter explains the reasons offered by drug users for their generally…

75 FR 5798 - National Institute on Drug Abuse; Notice of Closed Meetings

Federal Register 2010, 2011, 2012, 2013, 2014

2010-02-04

... DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health National Institute on Drug..., Targeted Library Synthesis and Screening at Novel Targets for Potential Drug Addiction (R21/R33). Date... Panel, Diversity-promoting Institutions' Drug Abuse Research Development Program. Date: February 25...

Drug Testing of Public Employees: An Introduction.

ERIC Educational Resources Information Center

Jascourt, Hugh D.

1988-01-01

The Federal Government has pushed employers to establish programs to test applicants and employees for drug use. The accompanying articles discuss legal barriers to drug testing and test administration and practical problems that limit the feasibility of drug testing and carry with them potential legal problems. (MLF)

Predicting Drug-Target Interactions With Multi-Information Fusion.

PubMed

Peng, Lihong; Liao, Bo; Zhu, Wen; Li, Zejun; Li, Keqin

2017-03-01

Identifying potential associations between drugs and targets is a critical prerequisite for modern drug discovery and repurposing. However, predicting these associations is difficult because of the limitations of existing computational methods. Most models only consider chemical structures and protein sequences, and other models are oversimplified. Moreover, datasets used for analysis contain only true-positive interactions, and experimentally validated negative samples are unavailable. To overcome these limitations, we developed a semi-supervised based learning framework called NormMulInf through collaborative filtering theory by using labeled and unlabeled interaction information. The proposed method initially determines similarity measures, such as similarities among samples and local correlations among the labels of the samples, by integrating biological information. The similarity information is then integrated into a robust principal component analysis model, which is solved using augmented Lagrange multipliers. Experimental results on four classes of drug-target interaction networks suggest that the proposed approach can accurately classify and predict drug-target interactions. Part of the predicted interactions are reported in public databases. The proposed method can also predict possible targets for new drugs and can be used to determine whether atropine may interact with alpha1B- and beta1- adrenergic receptors. Furthermore, the developed technique identifies potential drugs for new targets and can be used to assess whether olanzapine and propiomazine may target 5HT2B. Finally, the proposed method can potentially address limitations on studies of multitarget drugs and multidrug targets.

From the Test Tube to the Treatment Room: Fundamentals of Boron-containing Compounds and their Relevance to Dermatology.

PubMed

Del Rosso, James Q; Plattner, Jacob J

2014-02-01

The development of new drug classes and novel molecules that are brought to the marketplace has been a formidable challenge, especially for dermatologic drugs. The relative absence of new classes of antimicrobial agents is also readily apparent. Several barriers account for slow drug development, including regulatory changes, added study requirements, commercial pressures to bring drugs to market quickly by developing new generations of established compounds, and the greater potential for failure and higher financial risk when researching new drug classes. In addition, the return on investment is usually much lower with dermatologic drugs as compared to the potential revenue from "blockbuster" drugs for cardiovascular or gastrointestinal disease, hypercholesterolemia, and mood disorders. Nevertheless, some researchers are investigating new therapeutic platforms, one of which is boron-containing compounds. Boron-containing compounds offer a wide variety of potential applications in dermatology due to their unique physical and chemical properties, with several in formal phases of development. Tavaborole, a benzoxaborole compound, has been submitted to the United States Food and Drug Administration for approval for treatment of onychomycosis. This article provides a thorough overview of the history of boron-based compounds in medicine, their scientific rationale, physiochemical and pharmacologic properties, and modes of actions including therapeutic targets. A section dedicated to boron-based compounds in development for treatment of various skin disorders is also included.

Prediction of phospholipidosis-inducing potential of drugs by in vitro biochemical and physicochemical assays followed by multivariate analysis.

PubMed

Kuroda, Yukihiro; Saito, Madoka

2010-03-01

An in vitro method to predict phospholipidosis-inducing potential of cationic amphiphilic drugs (CADs) was developed using biochemical and physicochemical assays. The following parameters were applied to principal component analysis, as well as physicochemical parameters: pK(a) and clogP; dissociation constant of CADs from phospholipid, inhibition of enzymatic phospholipid degradation, and metabolic stability of CADs. In the score plot, phospholipidosis-inducing drugs (amiodarone, propranolol, imipramine, chloroquine) were plotted locally forming the subspace for positive CADs; while non-inducing drugs (chlorpromazine, chloramphenicol, disopyramide, lidocaine) were placed scattering out of the subspace, allowing a clear discrimination between both classes of CADs. CADs that often produce false results by conventional physicochemical or cell-based assay methods were accurately determined by our method. Basic and lipophilic disopyramide could be accurately predicted as a nonphospholipidogenic drug. Moreover, chlorpromazine, which is often falsely predicted as a phospholipidosis-inducing drug by in vitro methods, could be accurately determined. Because this method uses the pharmacokinetic parameters pK(a), clogP, and metabolic stability, which are usually obtained in the early stages of drug development, the method newly requires only the two parameters, binding to phospholipid, and inhibition of lipid degradation enzyme. Therefore, this method provides a cost-effective approach to predict phospholipidosis-inducing potential of a drug. Copyright (c) 2009 Elsevier Ltd. All rights reserved.

From the Test Tube to the Treatment Room

PubMed Central

Del Rosso, James Q.; Plattner, Jacob J.

2014-01-01

The development of new drug classes and novel molecules that are brought to the marketplace has been a formidable challenge, especially for dermatologic drugs. The relative absence of new classes of antimicrobial agents is also readily apparent. Several barriers account for slow drug development, including regulatory changes, added study requirements, commercial pressures to bring drugs to market quickly by developing new generations of established compounds, and the greater potential for failure and higher financial risk when researching new drug classes. In addition, the return on investment is usually much lower with dermatologic drugs as compared to the potential revenue from “blockbuster” drugs for cardiovascular or gastrointestinal disease, hypercholesterolemia, and mood disorders. Nevertheless, some researchers are investigating new therapeutic platforms, one of which is boron-containing compounds. Boron-containing compounds offer a wide variety of potential applications in dermatology due to their unique physical and chemical properties, with several in formal phases of development. Tavaborole, a benzoxaborole compound, has been submitted to the United States Food and Drug Administration for approval for treatment of onychomycosis. This article provides a thorough overview of the history of boron-based compounds in medicine, their scientific rationale, physiochemical and pharmacologic properties, and modes of actions including therapeutic targets. A section dedicated to boron-based compounds in development for treatment of various skin disorders is also included. PMID:24578778

Diatom silica microparticles for sustained release and permeation enhancement following oral delivery of prednisone and mesalamine.

PubMed

Zhang, Hongbo; Shahbazi, Mohammad-Ali; Mäkilä, Ermei M; da Silva, Tiago H; Reis, Rui L; Salonen, Jarno J; Hirvonen, Jouni T; Santos, Hélder A

2013-12-01

Diatoms are porous silica-based materials obtained from single cell photosynthetic algae. Despite low cost, easy purification process, environmentally safe properties, and rapidly increasing potentials for medical applications, the cytotoxicity of diatoms and the effect on drug permeation of oral formulations have not been studied so far. Herein, we have evaluated the potential of diatom silica microparticles (DSMs) for the delivery of mesalamine and prednisone, which are two commonly prescribed drugs for gastrointestinal (GI) diseases. Transmission electron microscopy analysis of the morphological surface changes of Caco-2/HT-29 monolayers and the cell viability data in colon cancer cells (Caco-2, HT-29 and HCT-116) showed very low toxicity of diatoms at concentrations up to 1000 μg/mL. The mesalamine and prednisone release under simulated GI conditions indicated prolonged release of both drugs from the diatoms. Furthermore, drug permeation across Caco-2/HT-29 co-culture monolayers demonstrated that diatoms are capable to enhance the drug permeability. Overall, this study evaluated DSMs' cytotoxicity in colon cancer cells and the effect of DSMs on drug permeability across Caco-2/HT-29 monolayers. Our results demonstrate that DSMs can be considered as a non-cytotoxic biomaterial with high potential to improve the mesalamine and prednisone bioavailability by sustaining the drug release and enhancing drug permeability. Copyright © 2013 Elsevier Ltd. All rights reserved.

Point-of-care detection and real-time monitoring of intravenously delivered drugs via tubing with an integrated SERS sensor

NASA Astrophysics Data System (ADS)

Wu, Hsin-Yu; Cunningham, Brian T.

2014-04-01

We demonstrate an approach for detection, identification, and kinetic monitoring of drugs flowing within tubing, through the use of a plasmonic nanodome array (PNA) surface. The PNA structures are fabricated using a low-cost nanoreplica molding process upon a flexible plastic substrate that is subsequently integrated with a flow cell that connects in series with ordinary intravenous (IV) drug delivery tubing. To investigate the potential clinical applications for point-of-care detection and real-time monitoring, we perform SERS detection of ten pharmaceutical compounds (hydrocodone, levorphanol, morphine, oxycodone, methadone, phenobarbital, dopamine, diltiazem, promethazine, and mitoxantrone). We demonstrate dose-dependent SERS signal magnitude, resulting in detection limits (ng ml-1) well below typical administered dosages (mg ml-1). Further, we show that the detected drugs are not permanently attached to the PNA surface, and thus our approach is capable of performing continuous monitoring of drug delivery as materials flow through IV tubing that is connected in series with the sensor. Finally, we demonstrate the potential co-detection of multiple drugs when they are mixed together, and show excellent reproducibility and stability of SERS measurements for periods extending at least five days. The capabilities reported here demonstrate the potential to use PNA SERS surfaces for enhancing the safety of IV drug delivery.We demonstrate an approach for detection, identification, and kinetic monitoring of drugs flowing within tubing, through the use of a plasmonic nanodome array (PNA) surface. The PNA structures are fabricated using a low-cost nanoreplica molding process upon a flexible plastic substrate that is subsequently integrated with a flow cell that connects in series with ordinary intravenous (IV) drug delivery tubing. To investigate the potential clinical applications for point-of-care detection and real-time monitoring, we perform SERS detection of ten pharmaceutical compounds (hydrocodone, levorphanol, morphine, oxycodone, methadone, phenobarbital, dopamine, diltiazem, promethazine, and mitoxantrone). We demonstrate dose-dependent SERS signal magnitude, resulting in detection limits (ng ml-1) well below typical administered dosages (mg ml-1). Further, we show that the detected drugs are not permanently attached to the PNA surface, and thus our approach is capable of performing continuous monitoring of drug delivery as materials flow through IV tubing that is connected in series with the sensor. Finally, we demonstrate the potential co-detection of multiple drugs when they are mixed together, and show excellent reproducibility and stability of SERS measurements for periods extending at least five days. The capabilities reported here demonstrate the potential to use PNA SERS surfaces for enhancing the safety of IV drug delivery. Electronic supplementary information (ESI) available: Fabrication of PNA substrates, fabrication details of the flow cell, details of FDTD simulation, characterization of the scattering volume, and detection of diltiazem diluted in DI water and PBS. See DOI: 10.1039/c4nr00027g

Molecular, Cellular, and Structural Mechanisms of Cocaine Addiction: A Key Role for MicroRNAs

PubMed Central

Jonkman, Sietse; Kenny, Paul J

2013-01-01

The rewarding properties of cocaine play a key role in establishing and maintaining the drug-taking habit. However, as exposure to cocaine increases, drug use can transition from controlled to compulsive. Importantly, very little is known about the neurobiological mechanisms that control this switch in drug use that defines addiction. MicroRNAs (miRNAs) are small non-protein coding RNA transcripts that can regulate the expression of messenger RNAs that code for proteins. Because of their highly pleiotropic nature, each miRNA has the potential to regulate hundreds or even thousands of protein-coding RNA transcripts. This property of miRNAs has generated considerable interest in their potential involvement in complex psychiatric disorders such as addiction, as each miRNA could potentially influence the many different molecular and cellular adaptations that arise in response to drug use that are hypothesized to drive the emergence of addiction. Here, we review recent evidence supporting a key role for miRNAs in the ventral striatum in regulating the rewarding and reinforcing properties of cocaine in animals with limited exposure to the drug. Moreover, we discuss evidence suggesting that miRNAs in the dorsal striatum control the escalation of drug intake in rats with extended cocaine access. These findings highlight the central role for miRNAs in drug-induced neuroplasticity in brain reward systems that drive the emergence of compulsive-like drug use in animals, and suggest that a better understanding of how miRNAs control drug intake will provide new insights into the neurobiology of drug addiction. PMID:22968819

Can Untargeted Metabolomics Be Utilized in Drug Discovery/Development?

PubMed

Caldwell, Gary W; Leo, Gregory C

2017-01-01

Untargeted metabolomics is a promising approach for reducing the significant attrition rate for discovering and developing drugs in the pharmaceutical industry. This review aims to highlight the practical decision-making value of untargeted metabolomics for the advancement of drug candidates in drug discovery/development including potentially identifying and validating novel therapeutic targets, creating alternative screening paradigms, facilitating the selection of specific and translational metabolite biomarkers, identifying metabolite signatures for the drug efficacy mechanism of action, and understanding potential drug-induced toxicity. The review provides an overview of the pharmaceutical process workflow to discover and develop new small molecule drugs followed by the metabolomics process workflow that is involved in conducting metabolomics studies. The pros and cons of the major components of the pharmaceutical and metabolomics workflows are reviewed and discussed. Finally, selected untargeted metabolomics literature examples, from primarily 2010 to 2016, are used to illustrate why, how, and where untargeted metabolomics can be integrated into the drug discovery/preclinical drug development process. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Sperm-Hybrid Micromotor for Targeted Drug Delivery.

PubMed

Xu, Haifeng; Medina-Sánchez, Mariana; Magdanz, Veronika; Schwarz, Lukas; Hebenstreit, Franziska; Schmidt, Oliver G

2018-01-23

A sperm-driven micromotor is presented as a targeted drug delivery system, which is appealing to potentially treat diseases in the female reproductive tract. This system is demonstrated to be an efficient drug delivery vehicle by first loading a motile sperm cell with an anticancer drug (doxorubicin hydrochloride), guiding it magnetically, to an in vitro cultured tumor spheroid, and finally freeing the sperm cell to deliver the drug locally. The sperm release mechanism is designed to liberate the sperm when the biohybrid micromotor hits the tumor walls, allowing it to swim into the tumor and deliver the drug through the sperm-cancer cell membrane fusion. In our experiments, the sperm cells exhibited a high drug encapsulation capability and drug carrying stability, conveniently minimizing  toxic side effects and unwanted drug accumulation in healthy tissues. Overall, sperm cells are excellent candidates to operate in physiological environments, as they neither express pathogenic proteins nor proliferate to form undesirable colonies, unlike other cells or microorganisms. This sperm-hybrid micromotor is a biocompatible platform with potential application in gynecological healthcare, treating or detecting cancer or other diseases in the female reproductive system.

Potential and problems in ultrasound-responsive drug delivery systems

PubMed Central

Zhao, Ying-Zheng; Du, Li-Na; Lu, Cui-Tao; Jin, Yi-Guang; Ge, Shu-Ping

2013-01-01

Ultrasound is an important local stimulus for triggering drug release at the target tissue. Ultrasound-responsive drug delivery systems (URDDS) have become an important research focus in targeted therapy. URDDS include many different formulations, such as microbubbles, nanobubbles, nanodroplets, liposomes, emulsions, and micelles. Drugs that can be loaded into URDDS include small molecules, biomacromolecules, and inorganic substances. Fields of clinical application include anticancer therapy, treatment of ischemic myocardium, induction of an immune response, cartilage tissue engineering, transdermal drug delivery, treatment of Huntington’s disease, thrombolysis, and disruption of the blood–brain barrier. This review focuses on recent advances in URDDS, and discusses their formulations, clinical application, and problems, as well as a perspective on their potential use in the future. PMID:23637531

Fetal effects of psychoactive drugs.

PubMed

Salisbury, Amy L; Ponder, Kathryn L; Padbury, James F; Lester, Barry M

2009-09-01

Psychoactive drug use by pregnant women has the potential to effect fetal development; the effects are often thought to be drug-specific and gestational age dependent. This article describes the effects of three drugs with similar molecular targets that involve monoaminergic transmitter systems: cocaine, methamphetamine, and selective serotonin re-uptake inhibitors (SSRIs) used to treat maternal depression during pregnancy. We propose a possible common epigenetic mechanism for their potential effects on the developing child. We suggest that exposure to these substances acts as a stressor that affects fetal programming, disrupts fetal placental monoamine transporter expression and alters neuroendocrine and neurotransmitter system development. We also discuss neurobehavioral techniques that may be useful in the early detection of the effects of in utero drug exposure.

Personalized Cancer Medicine: An Organoid Approach.

PubMed

Aboulkheyr Es, Hamidreza; Montazeri, Leila; Aref, Amir Reza; Vosough, Massoud; Baharvand, Hossein

2018-04-01

Personalized cancer therapy applies specific treatments to each patient. Using personalized tumor models with similar characteristics to the original tumors may result in more accurate predictions of drug responses in patients. Tumor organoid models have several advantages over pre-existing models, including conserving the molecular and cellular composition of the original tumor. These advantages highlight the tremendous potential of tumor organoids in personalized cancer therapy, particularly preclinical drug screening and predicting patient responses to selected treatment regimens. Here, we highlight the advantages, challenges, and translational potential of tumor organoids in personalized cancer therapy and focus on gene-drug associations, drug response prediction, and treatment selection. Finally, we discuss how microfluidic technology can contribute to immunotherapy drug screening in tumor organoids. Copyright © 2017 Elsevier Ltd. All rights reserved.

Novel Non-Peptide Inhibitors against SmCL1 of Schistosoma mansoni: In Silico Elucidation, Implications and Evaluation via Knowledge Based Drug Discovery

PubMed Central

Zafar, Atif; Ahmad, Sabahuddin; Rizvi, Asim; Ahmad, Masood

2015-01-01

Schistosomiasis is a major endemic disease known for excessive mortality and morbidity in developing countries. Because praziquantel is the only drug available for its treatment, the risk of drug resistance emphasizes the need to discover new drugs for this disease. Cathepsin SmCL1 is the critical target for drug design due to its essential role in the digestion of host proteins for growth and development of Schistosoma mansoni. Inhibiting the function of SmCL1 could control the wide spread of infections caused by S. mansoni in humans. With this objective, a homology modeling approach was used to obtain theoretical three-dimensional (3D) structure of SmCL1. In order to find the potential inhibitors of SmCL1, a plethora of in silico techniques were employed to screen non-peptide inhibitors against SmCL1 via structure-based drug discovery protocol. Receiver operating characteristic (ROC) curve analysis and molecular dynamics (MD) simulation were performed on the results of docked protein-ligand complexes to identify top ranking molecules against the modelled 3D structure of SmCL1. MD simulation results suggest the phytochemical Simalikalactone-D as a potential lead against SmCL1, whose pharmacophore model may be useful for future screening of potential drug molecules. To conclude, this is the first report to discuss the virtual screening of non-peptide inhibitors against SmCL1 of S. mansoni, with significant therapeutic potential. Results presented herein provide a valuable contribution to identify the significant leads and further derivatize them to suitable drug candidates for antischistosomal therapy. PMID:25933436

Drug Targeting and Biomarkers in Head and Neck Cancers: Insights from Systems Biology Analyses.

PubMed

Islam, Tania; Rahman, Rezanur; Gov, Esra; Turanli, Beste; Gulfidan, Gizem; Haque, Anwarul; Arga, Kazım Yalçın; Haque Mollah, Nurul

2018-06-01

The head and neck squamous cell carcinoma (HNSCC) is one of the most common cancers in the world, but robust biomarkers and diagnostics are still not available. This study provides in-depth insights from systems biology analyses to identify molecular biomarker signatures to inform systematic drug targeting in HNSCC. Gene expression profiles from tumors and normal tissues of 22 patients with histological confirmation of nonmetastatic HNSCC were subjected to integrative analyses with genome-scale biomolecular networks (i.e., protein-protein interaction and transcriptional and post-transcriptional regulatory networks). We aimed to discover molecular signatures at RNA and protein levels, which could serve as potential drug targets for therapeutic innovation in the future. Eleven proteins, 5 transcription factors, and 20 microRNAs (miRNAs) came into prominence as potential drug targets. The differential expression profiles of these reporter biomolecules were cross-validated by independent RNA-Seq and miRNA-Seq datasets, and risk discrimination performance of the reporter biomolecules, BLNK, CCL2, E4F1, FOSL1, ISG15, MMP9, MYCN, MYH11, miR-1252, miR-29b, miR-29c, miR-3610, miR-431, and miR-523, was also evaluated. Using the transcriptome guided drug repositioning tool, geneXpharma, several candidate drugs were repurposed, including antineoplastic agents (e.g., gemcitabine and irinotecan), antidiabetics (e.g., rosiglitazone), dermatological agents (e.g., clocortolone and acitretin), and antipsychotics (e.g., risperidone), and binding affinities of the drugs to their potential targets were assessed using molecular docking analyses. The molecular signatures and repurposed drugs presented in this study warrant further attention for experimental studies since they offer significant potential as biomarkers and candidate therapeutics for precision medicine approaches to clinical management of HNSCC.

Herbal medicines in Brazil: pharmacokinetic profile and potential herb-drug interactions

PubMed Central

Mazzari, Andre L. D. A.; Prieto, Jose M.

2014-01-01

A plethora of active compounds found in herbal medicines can serve as substrate for enzymes involved in the metabolism of xenobiotics. When a medicinal plant is co-administered with a conventional drug and little or no information is known about the pharmacokinetics of the plant metabolites, there is an increased risk of potential herb-drug interactions. Moreover, genetic polymorphisms in a population may act to predispose individuals to adverse reactions. The use of herbal medicines is rapidly increasing in many countries, particularly Brazil where the vast biodiversity is a potential source of new and more affordable treatments for numerous conditions. Accordingly, the Brazilian Unified Public Health System (SUS) produced a list of 71 plant species of interest, which could be made available to the population in the near future. Physicians at SUS prescribe a number of essential drugs and should herbal medicines be added to this system the chance of herb-drug interactions further increases. A review of the effects of these medicinal plants on Phase 1 and Phase 2 metabolic mechanisms and the transporter P-glycoprotein was conducted. The results have shown that approximately half of these medicinal plants lack any pharmacokinetic data. Moreover, most of the studies carried out are in vitro. Only a few reports on herb-drug interactions with essential drugs prescribed by SUS were found, suggesting that very little attention is being given to the safety of herbal medicines. Here we have taken this information to discuss the potential interactions between herbal medicines and essential drugs prescribed to Brazilian patients whilst taking into account the most common polymorphisms present in the Brazilian population. A number of theoretical interactions are pinpointed but more pharmacokinetic studies and pharmacovigilance data are needed to ascertain their clinical significance. PMID:25071580

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

NASA Astrophysics Data System (ADS)

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

2018-05-01

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

Classification of drugs with different risk profiles.

PubMed

Saedder, Eva Aggerholm; Brock, Birgitte; Nielsen, Lars Peter; Bonnerup, Dorthe Krogsgaard; Lisby, Marianne

2015-08-01

A risk stratification approach is needed to identify patients at high risk of medication errors and a resulting high need of medication review. The aim of this study was to perform risk stratification (distinguishing between low-risk, medium-risk and high-risk drugs) for drugs found to cause serious adverse reactions due to medication errors. The study employed a modified Delphi technique. Drugs from a systematic literature search were included into two rounds of a Delphi process. A panel of experts was asked to evaluate each identified drug's potential for harm and for clinically relevant drug-drug interactions on a scale from 1 (low risk) to 9 (high risk). A total of 36 experts were appointed to serve on the panel. Consensus was reached for 29/57 (51%) drugs or drug classes that cause harm, and for 32/57 (56%) of the drugs or drug classes that cause interactions. For the remaining drugs, a decision was made based on the median score. Two lists, one stating the drugs' potential for causing harm and the other stating clinically relevant drug-drug interactions, were stratified into low-risk, medium-risk and high-risk drugs. Based on a modified Delphi technique, we created two lists of drugs stratified into a low-risk, a medium-risk and a high-risk group of clinically relevant interactions or risk of harm to patients. The lists could be incorporated into a risk-scoring tool that stratifies the performance of medication reviews according to patients' risk of experiencing adverse reactions. none. not relevant.

Occupational exposure to cytotoxic drugs in two UK oncology wards

PubMed Central

Ziegler, E; Mason, H; Baxter, P

2002-01-01

Aims: To investigate the potential exposure to cytotoxic drugs of staff on two oncology wards in a large district, UK hospital under normal working conditions. Methods: Cytotoxic drug exposure was monitored in urine samples, surface wipes, and on disposable gloves by using a number of commonly used marker drugs, namely cyclophosphamide, ifosfamide, methotrexate, and the platino coordinated drugs. Questionnaire data on their work practices, potential exposure, use of protective personal equipment, and relevant training were collected from nursing, domestic, and clerical staff on two oncology wards. Results: The majority of staff were female with a mean age of 31 years. Roughly half of the staff studied were specifically trained nurses with an average of 3.5 years experience of administering cytotoxic drugs. No cytotoxic drug preparation or reconstitution was carried out on the wards. Disposable gloves, plastic armlets and aprons, but not eye protection, were invariably worn where there was potential exposure to cytotoxics. No cytotoxic drug was detected in any of the staff's urine samples. Isolated disposable latex gloves from nurses administering drugs showed some contamination, as did some surfaces within the wards' sluice rooms, but not in the ward areas where the drugs were stored and checked prior to administration. Conclusions: The risk management strategies in place, including use of personal protective equipment, staff training, and other organisational measures, have ensured that internal exposure is lower than the detection limits for the current biological monitoring methods. Levels of contamination appear significantly lower than earlier, non-UK published studies where different risk management strategies were in place and, in particular, ward staff may have been involved in some degree of cytotoxic drug reconstitution. PMID:12205233

Nanoscale drug delivery systems and the blood–brain barrier

PubMed Central

Alyautdin, Renad; Khalin, Igor; Nafeeza, Mohd Ismail; Haron, Muhammad Huzaimi; Kuznetsov, Dmitry

2014-01-01

The protective properties of the blood–brain barrier (BBB) are conferred by the intricate architecture of its endothelium coupled with multiple specific transport systems expressed on the surface of endothelial cells (ECs) in the brain’s vasculature. When the stringent control of the BBB is disrupted, such as following EC damage, substances that are safe for peripheral tissues but toxic to neurons have easier access to the central nervous system (CNS). As a consequence, CNS disorders, including degenerative diseases, can occur independently of an individual’s age. Although the BBB is crucial in regulating the biochemical environment that is essential for maintaining neuronal integrity, it limits drug delivery to the CNS. This makes it difficult to deliver beneficial drugs across the BBB while preventing the passage of potential neurotoxins. Available options include transport of drugs across the ECs through traversing occludins and claudins in the tight junctions or by attaching drugs to one of the existing transport systems. Either way, access must specifically allow only the passage of a particular drug. In general, the BBB allows small molecules to enter the CNS; however, most drugs with the potential to treat neurological disorders other than infections have large structures. Several mechanisms, such as modifications of the built-in pumping-out system of drugs and utilization of nanocarriers and liposomes, are among the drug-delivery systems that have been tested; however, each has its limitations and constraints. This review comprehensively discusses the functional morphology of the BBB and the challenges that must be overcome by drug-delivery systems and elaborates on the potential targets, mechanisms, and formulations to improve drug delivery to the CNS. PMID:24550672

Leveraging existing data for prioritization of the ecological risks of human and veterinary pharmaceuticals to aquatic organisms

PubMed Central

LaLone, Carlie A.; Berninger, Jason P.; Villeneuve, Daniel L.; Ankley, Gerald T.

2014-01-01

Medicinal innovation has led to the discovery and use of thousands of human and veterinary drugs. With this comes the potential for unintended effects on non-target organisms exposed to pharmaceuticals inevitably entering the environment. The impracticality of generating whole-organism chronic toxicity data representative of all species in the environment has necessitated prioritization of drugs for focused empirical testing as well as field monitoring. Current prioritization strategies typically emphasize likelihood for exposure (i.e. predicted/measured environmental concentrations), while incorporating only rather limited consideration of potential effects of the drug to non-target organisms. However, substantial mammalian pharmacokinetic and mechanism/mode of action (MOA) data are produced during drug development to understand drug target specificity and efficacy for intended consumers. An integrated prioritization strategy for assessing risks of human and veterinary drugs would leverage available pharmacokinetic and toxicokinetic data for evaluation of the potential for adverse effects to non-target organisms. In this reiview, we demonstrate the utility of read-across approaches to leverage mammalian absorption, distribution, metabolism and elimination data; analyse cross-species molecular target conservation and translate therapeutic MOA to an adverse outcome pathway(s) relevant to aquatic organisms as a means to inform prioritization of drugs for focused toxicity testing and environmental monitoring. PMID:25405975

Point-of-care detection and real-time monitoring of intravenously delivered drugs via tubing with an integrated SERS sensor.

PubMed

Wu, Hsin-Yu; Cunningham, Brian T

2014-05-21

We demonstrate an approach for detection, identification, and kinetic monitoring of drugs flowing within tubing, through the use of a plasmonic nanodome array (PNA) surface. The PNA structures are fabricated using a low-cost nanoreplica molding process upon a flexible plastic substrate that is subsequently integrated with a flow cell that connects in series with ordinary intravenous (IV) drug delivery tubing. To investigate the potential clinical applications for point-of-care detection and real-time monitoring, we perform SERS detection of ten pharmaceutical compounds (hydrocodone, levorphanol, morphine, oxycodone, methadone, phenobarbital, dopamine, diltiazem, promethazine, and mitoxantrone). We demonstrate dose-dependent SERS signal magnitude, resulting in detection limits (ng ml(-1)) well below typical administered dosages (mg ml(-1)). Further, we show that the detected drugs are not permanently attached to the PNA surface, and thus our approach is capable of performing continuous monitoring of drug delivery as materials flow through IV tubing that is connected in series with the sensor. Finally, we demonstrate the potential co-detection of multiple drugs when they are mixed together, and show excellent reproducibility and stability of SERS measurements for periods extending at least five days. The capabilities reported here demonstrate the potential to use PNA SERS surfaces for enhancing the safety of IV drug delivery.

Impact of concomitant medications on obstructive sleep apnoea

PubMed Central

Jullian‐Desayes, Ingrid; Revol, Bruno; Chareyre, Elisa; Camus, Philippe; Villier, Céline; Borel, Jean‐Christian; Pepin, Jean‐Louis

2016-01-01

Obstructive sleep apnoea (OSA) is characterized by repeated episodes of apnoea and hypopnoea during sleep. Little is known about the potential impact of therapy drugs on the underlying respiratory disorder. Any influence should be taken into account and appropriate action taken, including drug withdrawal if necessary. Here, we review drugs in terms of their possible impact on OSA; drugs which (1) may worsen OSA; (2) are unlikely to have an impact on OSA; (3) those for which data are scarce or contradictory; and (4) drugs with a potentially improving effect. The level of evidence is ranked according to three grades: A – randomized controlled trials (RCTs) with high statistical power; B – RCTs with lower power, non‐randomized comparative studies and observational studies; C – retrospective studies and case reports. Our review enabled us to propose clinical recommendations. Briefly, agents worsening OSA or inducing weight gain, that must be avoided, are clearly identified. Drugs such as ‘Z drugs’ and sodium oxybate should be used with caution as the literature contains conflicting results. Finally, larger trials are needed to clarify the potential positive impact of certain drugs on OSA. In the meantime, some, such as diuretics or other antihypertensive medications, are helpful in reducing OSA‐associated cardiovascular morbidity. PMID:27735059

Drug-device combination products in the twenty-first century: epinephrine auto-injector development using human factors engineering.

PubMed

Edwards, Eric S; Edwards, Evan T; Simons, F Estelle R; North, Robert

2015-05-01

The systematic application of human factors engineering (HFE) principles to the development of drug-device combination products, including epinephrine auto-injectors (EAIs), has the potential to improve the effectiveness and safety of drug administration. A PubMed search was performed to assess the role of HFE in the development of drug-device combination products. The following keywords were used in different combinations: 'human factors engineering,' 'human factors,' 'medical products,' 'epinephrine/adrenaline auto-injector,' 'healthcare' and 'patient safety.' This review provides a summary of HFE principles and their application to the development of drug-device combination products as advised by the US FDA. It also describes the HFE process that was applied to the development of Auvi-Q, a novel EAI, highlighting specific steps that occurred during the product-development program. For drug-device combination products, device labeling and usability are critical and have the potential to impact clinical outcomes. Application of HFE principles to the development of drug-delivery devices has the potential to improve product quality and reliability, reduce risk and improve patient safety when applied early in the development process. Additional clinical and real-world studies will confirm whether the application of HFE has helped to develop an EAI that better meets the needs of patients at risk of anaphylaxis.

E-learning in order to improve drug prescription for hospitalized older patients: a cluster-randomized controlled study.

PubMed

Franchi, Carlotta; Tettamanti, Mauro; Djade, Codjo Dgnefa; Pasina, Luca; Mannucci, Pier Mannuccio; Onder, Graziano; Gussoni, Gualberto; Manfellotto, Dario; Bonassi, Stefano; Salerno, Francesco; Nobili, Alessandro

2016-07-01

The aim of the study was to evaluate the effect of an e-learning educational program meant to foster the quality of drug prescription in hospitalized elderly patients. Twenty geriatric and internal medicine wards were randomized to intervention (e-learning educational program) or control (basic geriatric pharmacology notions). Logistic regression analysis was used in order to assess the effect of the intervention on the use of potentially inappropriate medication (PIM, primary outcome) at hospital discharge. Secondary outcomes were a reduced prevalence of at least one potential drug-drug interaction (DDI) and potentially severe DDI at discharge. Mortality rate and incidence of re-hospitalizations were other secondary outcomes assessed at the 12-month follow-up. A total of 697 patients (347 in the intervention and 350 in the control arms) were enrolled. No difference in the prevalence of PIM at discharge was found between arms (OR 1.29 95%CI 0.87-1.91). We also found no decrease in the prevalence of DDI (OR 0.67 95%CI 0.34-1.28) and potentially severe DDI (OR 0.86 95%CI 0.63-1.15) at discharge, nor in mortality rates and incidence of re-hospitalization at 12-month follow-up. This e-learning educational program had no clear effect on the quality of drug prescription and clinical outcomes in hospitalized elderly patients. Given the high prevalence of PIMs and potential DDIs recorded in the frame of this study, other approaches should be developed in order to improve the quality of drug prescription in this population. © 2016 The British Pharmacological Society.

Carboxyl-terminated PAMAM dendrimer interaction with 1-palmitoyl-2-oleoyl phosphocholine bilayers

USDA-ARS?s Scientific Manuscript database

Polycationic polymers and liposomes have a great potential use as individual drug delivery systems and greater potential as a combined drug delivery system. Thus, it is important to better understand the interactions of polymers with phospholipid bilayers. A mechanistic study of carboxyl-terminate...

Indolealkylamines: biotransformations and potential drug-drug interactions.

PubMed

Yu, Ai-Ming

2008-06-01

Indolealkylamine (IAA) drugs are 5-hydroxytryptamine (5-HT or serotonin) analogs that mainly act on the serotonin system. Some IAAs are clinically utilized for antimigraine therapy, whereas other substances are notable as drugs of abuse. In the clinical evaluation of antimigraine triptan drugs, studies on their biotransformations and pharmacokinetics would facilitate the understanding and prevention of unwanted drug-drug interactions (DDIs). A stable, principal metabolite of an IAA drug of abuse could serve as a useful biomarker in assessing intoxication of the IAA substance. Studies on the metabolism of IAA drugs of abuse including lysergic acid amides, tryptamine derivatives and beta-carbolines are therefore emerging. An important role for polymorphic cytochrome P450 2D6 (CYP2D6) in the metabolism of IAA drugs of abuse has been revealed by recent studies, suggesting that variations in IAA metabolism, pharmaco- or toxicokinetics and dynamics can arise from distinct CYP2D6 status, and CYP2D6 polymorphism may represent an additional risk factor in the use of these IAA drugs. Furthermore, DDIs with IAA agents could occur additively at the pharmaco/toxicokinetic and dynamic levels, leading to severe or even fatal serotonin toxicity. In this review, the metabolism and potential DDIs of these therapeutic and abused IAA drugs are described.

Drug–drug interactions between anti-retroviral therapies and drugs of abuse in HIV systems

PubMed Central

Rao, PSS; Earla, Ravindra; Kumar, Anil

2015-01-01

Introduction Substance abuse is a common problem among HIV-infected individuals. Importantly, addictions as well as moderate use of alcohol, smoking, or other illicit drugs have been identified as major reasons for non-adherence to antiretroviral therapy (ART) among HIV patients. The literature also suggests a decrease in the response to ART among HIV patients who use these substances, leading to failure to achieve optimal virological response and increased disease progression. Areas covered This review discusses the challenges with adherence to ART as well as observed drug interactions and known toxicities with major drugs of abuse, such as alcohol, smoking, methamphetamine, cocaine, marijuana, and opioids. The lack of adherence and drug interactions potentially lead to decreased efficacy of ART drugs and increased ART, and drugs of abuse-mediated toxicity. As CYP is the common pathway in metabolizing both ART and drugs of abuse, we discuss the possible involvement of CYP pathways in such drug interactions. Expert opinion We acknowledge that further studies focusing on common metabolic pathways involving CYP and advance research in this area would help to potentially develop novel/alternate interventions and drug dose/regimen adjustments to improve medication outcomes in HIV patients who consume drugs of abuse. PMID:25539046

Lipid drug conjugate nanoparticle as a potential nanocarrier for the oral delivery of pemetrexed diacid: Formulation design, characterization, ex vivo, and in vivo assessment.

PubMed

Soni, Kriti; Mujtaba, Ali; Kohli, Kanchan

2017-10-01

The present work was to develop lipid drug conjugated (LDC) nanoparticles for the potential oral delivery of pemetrexed diacid (PTX) and evaluation of its in vitro, ex vivo and in vivo potentials. The LDC was prepared by salt formation of PTX with stearic acid and followed by cold homogenization technique to produce the LDC nanoparticles. FTIR analysis of LDC proved the presence of amide bond in LDC powder indicating the conjugation between drug and lipid. LDC nanoparticles was found to have particle size 121.9±1.85nm and zeta potential -51.6mV±1.23 and entrapment efficiency 81.0±0.89%. TEM images revealed spherical morphology and were in corroboration with particle size measurements. Ex vivo gut permeation studies revealed a very good enhancement in permeation of drug present in the LDC as compared to plain drug solution and were confirmed by CLSM. MTT assay conformed significant% toxicity at the end of 24h and 48h. Furthermore, the AUC 0-24 of PTX from the optimized LDC nanoparticels was found to be 4.22 folds higher than that from PTX suspension on oral administration. Thus, LDC has high potential for the oral delivery of PTX in cancer therapy and future prospects for the industrial purpose. Copyright © 2017 Elsevier B.V. All rights reserved.

Evaluation of P-Glycoprotein Inhibitory Potential Using a Rhodamine 123 Accumulation Assay

PubMed Central

Jouan, Elodie; Le Vée, Marc; Mayati, Abdullah; Denizot, Claire; Parmentier, Yannick; Fardel, Olivier

2016-01-01

In vitro evaluation of P-glycoprotein (P-gp) inhibitory potential is now a regulatory issue during drug development, in order to predict clinical inhibition of P-gp and subsequent drug–drug interactions. Assays for this purpose, commonly based on P-gp-expressing cell lines and digoxin as a reference P-gp substrate probe, unfortunately exhibit high variability, raising thus the question of developing alternative or complementary tests for measuring inhibition of P-gp activity. In this context, the present study was designed to investigate the use of the fluorescent dye rhodamine 123 as a reference P-gp substrate probe for characterizing P-gp inhibitory potential of 16 structurally-unrelated drugs known to interact with P-gp. 14/16 of these P-gp inhibitors were found to increase rhodamine 123 accumulation in P-gp-overexpressing MCF7R cells, thus allowing the determination of their P-gp inhibitory potential, i.e., their half maximal inhibitor concentration (IC50) value towards P-gp-mediated transport of the dye. These IC50 values were in the range of variability of previously reported IC50 for P-gp and can be used for the prediction of clinical P-gp inhibition according to Food and Drug Administration (FDA) criteria, with notable sensitivity (80%). Therefore, the data demonstrated the feasibility of the use of rhodamine 123 for evaluating the P-gp inhibitory potential of drugs. PMID:27077878

21 CFR 516.121 - Meetings.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 6 2012-04-01 2012-04-01 false Meetings. 516.121 Section 516.121 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS... attending on behalf of the requestor or potential requestor, and contain a proposed agenda for the meeting...

21 CFR 516.121 - Meetings.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 6 2013-04-01 2013-04-01 false Meetings. 516.121 Section 516.121 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS... attending on behalf of the requestor or potential requestor, and contain a proposed agenda for the meeting...

21 CFR 516.121 - Meetings.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 6 2014-04-01 2014-04-01 false Meetings. 516.121 Section 516.121 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS... attending on behalf of the requestor or potential requestor, and contain a proposed agenda for the meeting...

21 CFR 516.121 - Meetings.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 6 2011-04-01 2011-04-01 false Meetings. 516.121 Section 516.121 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS... attending on behalf of the requestor or potential requestor, and contain a proposed agenda for the meeting...

Drug research methodology. Volume 2, The identification of drugs of interest in highway safety

DOT National Transportation Integrated Search

1980-03-01

This report presents findings of a workshop on the identification of drugs that should be the focus of near-term highway safety research. Drugs of interest are those that have a potential to increase the likelihood of traffic crashes and their attend...

21 CFR 312.81 - Scope.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 5 2013-04-01 2013-04-01 false Scope. 312.81 Section 312.81 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS FOR HUMAN USE... with potentially fatal outcomes, where the end point of clinical trial analysis is survival. (b) For...

RAS - Screens & Assays - Drug Discovery

Cancer.gov

The RAS Drug Discovery group aims to develop assays that will reveal aspects of RAS biology upon which cancer cells depend. Successful assay formats are made available for high-throughput screening programs to yield potentially effective drug compounds.

42 CFR 418.54 - Condition of participation: Initial and comprehensive assessment of the patient.

Code of Federal Regulations, 2010 CFR

2010-10-01

... potential drug interactions. (iv) Duplicate drug therapy. (v) Drug therapy currently associated with... family and other individuals focusing on the social, spiritual, and cultural factors that may impact...

Medicinal electronomics bricolage design of hypoxia-targeting antineoplastic drugs and invention of boron tracedrugs as innovative future-architectural drugs.

PubMed

Hori, Hitoshi; Uto, Yoshihiro; Nakata, Eiji

2010-09-01

We describe herein for the first time our medicinal electronomics bricolage design of hypoxia-targeting antineoplastic drugs and boron tracedrugs as newly emerging drug classes. A new area of antineoplastic drugs and treatments has recently focused on neoplastic cells of the tumor environment/microenvironment involving accessory cells. This tumor hypoxic environment is now considered as a major factor that influences not only the response to antineoplastic therapies but also the potential for malignant progression and metastasis. We review our medicinal electronomics bricolage design of hypoxia-targeting drugs, antiangiogenic hypoxic cell radiosensitizers, sugar-hybrid hypoxic cell radiosensitizers, and hypoxia-targeting 10B delivery agents, in which we design drug candidates based on their electronic structures obtained by molecular orbital calculations, not based solely on pharmacophore development. These drugs include an antiangiogenic hypoxic cell radiosensitizer TX-2036, a sugar-hybrid hypoxic cell radiosensitizer TX-2244, new hypoxia-targeting indoleamine 2,3-dioxygenase (IDO) inhibitors, and a hypoxia-targeting BNCT agent, BSH (sodium borocaptate-10B)-hypoxic cytotoxin tirapazamine (TPZ) hybrid drug TX-2100. We then discuss the concept of boron tracedrugs as a new drug class having broad potential in many areas.

Novel catalytic micromotor of porous zeolitic imidazolate framework-67 for precise drug delivery.

PubMed

Wang, Linlin; Zhu, Hongli; Shi, Ying; Ge, You; Feng, Xiaomiao; Liu, Ruiqing; Li, Yi; Ma, Yanwen; Wang, Lianhui

2018-06-07

Micromotors hold promise as drug carriers for targeted drug delivery owing to the characteristics of self-propulsion and directional navigation. However, several defects still exist, including high cost, short movement life, low drug loading and slow release rate. Herein, a novel catalytic micromotor based on porous zeolitic imidazolate framework-67 (ZIF-67) synthesized by a greatly simplified wet chemical method assisted with ultrasonication is described as an efficient anticancer drug carrier. These porous micromotors display effective autonomous motion in hydrogen peroxide and long durable movement life of up to 90 min. Moreover, the multifunctional micromotor ZIF-67/Fe3O4/DOX exhibits excellent performance in precise drug delivery under external magnetic field with high drug loading capacity of fluorescent anticancer drug DOX up to 682 μg mg-1 owing to its porous nature, high surface area and rapid drug release based on dual stimulus of catalytic reaction and solvent effects. Therefore, these porous ZIF-67-based catalytic micromotors combine the domains of metal-organic frameworks (MOFs) and micomotors, thus developing potential resources for micromotors and holding great potential as label-free and precisely controlled high-quality candidates of drug delivery systems for biomedical applications.

Effect of generic drug competition on the price of prescription drugs in Ontario.

PubMed Central

Lexchin, J

1993-01-01

OBJECTIVE: To analyse the potential effect of generic drug competition on prices in Ontario to assess the costs and benefits associated with Bill C-22 (An Act to amend the Patent Act). DESIGN: Comparison of the cost of the least and most expensive versions of all products sold by more than one manufacturer in 1991. The number of brand-name and generic drug companies marketing each of the products was recorded. RESULTS: Of 1599 products 437 (27.3%) were made by more than one company. Almost half (44.6%) of the 437 were sold by two companies. The more companies that sold a drug the greater the difference in price between the least and most expensive versions. Similarly, as the proportion of generic drug companies in competition increased, the greater the price difference. When competition was between generic drug companies only, the price spread was smaller than when it was between brand-name drug companies only. CONCLUSIONS: Generic drug competition can result in savings to the Ontario Drug Benefit Plan. A more in-depth analysis of the potential savings is necessary to fully assess the costs and benefits associated with Bill C-22. PMID:8439888

Drug Target Protein-Protein Interaction Networks: A Systematic Perspective

PubMed Central

2017-01-01

The identification and validation of drug targets are crucial in biomedical research and many studies have been conducted on analyzing drug target features for getting a better understanding on principles of their mechanisms. But most of them are based on either strong biological hypotheses or the chemical and physical properties of those targets separately. In this paper, we investigated three main ways to understand the functional biomolecules based on the topological features of drug targets. There are no significant differences between targets and common proteins in the protein-protein interactions network, indicating the drug targets are neither hub proteins which are dominant nor the bridge proteins. According to some special topological structures of the drug targets, there are significant differences between known targets and other proteins. Furthermore, the drug targets mainly belong to three typical communities based on their modularity. These topological features are helpful to understand how the drug targets work in the PPI network. Particularly, it is an alternative way to predict potential targets or extract nontargets to test a new drug target efficiently and economically. By this way, a drug target's homologue set containing 102 potential target proteins is predicted in the paper. PMID:28691014

A Mapping of Drug Space from the Viewpoint of Small Molecule Metabolism

PubMed Central

Basuino, Li; Chambers, Henry F.; Lee, Deok-Sun; Wiest, Olaf G.; Babbitt, Patricia C.

2009-01-01

Small molecule drugs target many core metabolic enzymes in humans and pathogens, often mimicking endogenous ligands. The effects may be therapeutic or toxic, but are frequently unexpected. A large-scale mapping of the intersection between drugs and metabolism is needed to better guide drug discovery. To map the intersection between drugs and metabolism, we have grouped drugs and metabolites by their associated targets and enzymes using ligand-based set signatures created to quantify their degree of similarity in chemical space. The results reveal the chemical space that has been explored for metabolic targets, where successful drugs have been found, and what novel territory remains. To aid other researchers in their drug discovery efforts, we have created an online resource of interactive maps linking drugs to metabolism. These maps predict the “effect space” comprising likely target enzymes for each of the 246 MDDR drug classes in humans. The online resource also provides species-specific interactive drug-metabolism maps for each of the 385 model organisms and pathogens in the BioCyc database collection. Chemical similarity links between drugs and metabolites predict potential toxicity, suggest routes of metabolism, and reveal drug polypharmacology. The metabolic maps enable interactive navigation of the vast biological data on potential metabolic drug targets and the drug chemistry currently available to prosecute those targets. Thus, this work provides a large-scale approach to ligand-based prediction of drug action in small molecule metabolism. PMID:19701464

Preparation and in vitro characterization of pluronic-attached polyamidoamine dendrimers for drug delivery.

PubMed

Gu, Zhuojun; Wang, Meng; Fang, Qiongyan; Zheng, Huaiyu; Wu, Feiyue; Lin, Dai; Xu, Ying; Jin, Yi

2015-05-01

Polyamidoamine (PAMAM) dendrimers have attracted lots of interest as drug carriers. And little study about whether pluronic-attached PAMAM dendrimers could be potential drug delivery systems has been carried on. Pluronic F127 (PF127) attached PAMAM dendrimers were designed as novel drug carriers. Two conjugation ratios of PF127-attached PAMAM dendrimers were synthesized. (1)H nuclear magnetic resonance ((1)H-NMR), Fourier transform infrared spectrum (FTIR), element analysis and ninhydrin assay were used to characterize the conjugates. Size, zeta potential and critical micelle concentrations (CMC) were also detected. And DOX was incorporated into the hydrophobic interior of the conjugates. Studies on their drug loading and drug release were carried on. Furthermore, hemolysis and cytotoxicity assay were used to evaluate the toxicity of the conjugates. PF127 was successfully conjugated to the fifth generation PAMAM dendrimer at two molar ratios of 19% and 57% (PF127 to surface amine per PAMAM dendrimer molecular). The conjugates showed an increased size and a reduced zeta potential. And higher CMC values were obtained than pure PF127. Compared with unconjugated PAMAM dendrimer, PF127 conjugation significantly reduced the hemolytic toxicity and cytotoxicity of PAMAM dendrimer in vitro. The encapsulation results showed that the ability to encapsulate DOX by the conjugate of 19% conjugation ratio was better than that of 57% conjugation ratio. And the maximum is ∼12.87 DOX molecules per conjugate molecule. Moreover, the complexes showed a sustained release behavior compared to pure DOX. Findings from the in vitro study show that the PF127-attached PAMAM dendrimers may be potential carriers for drug delivery.

Drug interactions and risk of acute bleeding leading to hospitalisation or death in patients with chronic atrial fibrillation treated with warfarin.

PubMed

Gasse, Christiane; Hollowell, Jennifer; Meier, Christoph R; Haefeli, Walter E

2005-09-01

Although drug interactions with warfarin are an important cause of excessive anticoagulation, their impact on the risk of serious bleeding is unknown. We therefore performed a cohort study and a nested case-control analysis to determine the risk of serious bleeding in 4152 patients (aged 40-84 years) with nonvalvular atrial fibrillation (AF) taking long-term warfarin (> 3 months). The study population was drawn from the UK General Practice Research Database. More than half (58%) of eligible patients used potentially interacting drugs during continuous warfarin treatment. Among 45 identified cases of incident idiopathic bleeds (resulting in hospitalisation within 30 days or death within 7 days) and 143 matched controls, more cases than controls took > or = 1 potentially interacting drug within the preceding 30 days (62.2% vs. 35.7%) and used > 4 drugs (polypharmacy) within the preceding 90 days (80.0% vs. 66.4%). Conditional logistic regression analysis yielded an odds ratio (OR) of 3.4 (95% confidence interval [CI]: 1.4-8.5) for the risk of serious bleeding in patients treated with warfarin and > or = 1 drugs potentially increasing the effect of warfarin vs. warfarin alone adjusted for polypharmacy, diabetes, hypertension, heart failure, and thyroid disease; the adjusted OR for the combined use of warfarin and aspirin vs. warfarin alone was 4.5 (95% CI: 1.1-18.1). We conclude that concurrent use of potentially interacting drugs with warfarin is associated with a 3 to 4.5-fold increased risk of serious bleeding in long-term warfarin users.

Effect of Bar-code Technology on the Incidence of Medication Dispensing Errors and Potential Adverse Drug Events in a Hospital Pharmacy

PubMed Central

Poon, Eric G; Cina, Jennifer L; Churchill, William W; Mitton, Patricia; McCrea, Michelle L; Featherstone, Erica; Keohane, Carol A; Rothschild, Jeffrey M; Bates, David W; Gandhi, Tejal K

2005-01-01

We performed a direct observation pre-post study to evaluate the impact of barcode technology on medication dispensing errors and potential adverse drug events in the pharmacy of a tertiary-academic medical center. We found that barcode technology significantly reduced the rate of target dispensing errors leaving the pharmacy by 85%, from 0.37% to 0.06%. The rate of potential adverse drug events (ADEs) due to dispensing errors was also significantly reduced by 63%, from 0.19% to 0.069%. In a 735-bed hospital where 6 million doses of medications are dispensed per year, this technology is expected to prevent about 13,000 dispensing errors and 6,000 potential ADEs per year. PMID:16779372

Adrenergic modulation of hepatotoxicity.

PubMed

Roberts, S M; DeMott, R P; James, R C

1997-01-01

Summaries of the interactions caused by altering adrenoreceptor activity in conjunction with the administration of selected hepatotoxicants are provided in Table 2 and Fig. 1. These hepatotoxicants can be divided into two groups, one whose toxicity is increased by adrenergic agonist drugs (group I) and the other whose toxicity is decreased by adrenergic antagonists (group II). Group I includes carbon tetrachloride, acetaminophen, and methylphenidate. Perhaps the most remarkable aspect these chemicals have in common is the striking potentiation that occurs with cotreatment with certain adrenergic agonist drugs. For each of these, cotreatment with the appropriate adrenergic agent can result in massive hepatocellular necrosis from an otherwise nontoxic dose. In terms of the specific adrenoreceptors involved and mechanisms of potentiation, however, they have little in common. Potentiation of carbon tetrachloride hepatotoxicity appears to be mediated by alpha(2)-adrenoceptor stimulation, acetaminophen is potentiated by alpha(1)-adrenoreceptor agonists, and methylphenidate responds to beta(2)-adrenoreceptor stimulation. Studies of the potentiation of carbon tetrachloride and acetaminophen agree that the timing of adrenergic stimulation relative to the hepatotoxicant dose is critically important to the interaction but markedly different for these two toxicants. Acetaminophen was potentiated only when the adrenergic drug was administered as a 3-h pretreatment. This is apparently a consequence of a mechanism of potentiation that involves adrenergic depression of hepatic glutathione content and a requirement that peak effects on glutathione of both the adrenergic agent and acetaminophen be coincident. The mechanism of potentiation of carbon tetrachloride hepatotoxicity is uncertain but clearly does not involve hepatic glutathione content. In contrast to acetaminophen, adrenergic effects must occur within a time window a few hours after the carbon tetrachloride dose for potentiation to occur. The importance of dose timing has not been evaluated for adrenergic potentiation of methylphenidate hepatotoxicity, but it is clear that this interaction is based on yet a third mechanism. While only three hepatotoxicants of the group I type have been examined in detail, the diversity of receptor types and mechanisms involved suggest that this phenomenon may be relevant for a wide variety of hepatotoxic drugs and chemicals. This interaction is also of interest because factors or events that lead to increased adrenergic stimulation are common in everyday life. Most over-the-counter cold and allergy preparations contain sympathomimetic drugs, and many prescription drugs produce adrenergic effects as either an extension of the intended therapeutic effect or as a side effect. Stress and some disease states can also lead to significant increases in peripheral adrenergic activity, creating the potential for increased susceptibility to hepatic injury from exposure to certain drugs or chemicals. Cocaine and bromobenzene represent group II, chemicals whose hepatotoxicity is diminished by cotreatment with adrenergic antagonist drugs. In the case of cocaine, adrenergic antagonist cotreatment was capable of reducing serum alanine aminotransferase activities by approximately 50%. For bromobenzene, the protection afforded by adrenergic antagonist cotreatment was more profound, with minimal hepatic lesions resulting from doses of bromobenzene that otherwise produced lethal hepatic necrosis. For the chemicals in group II, experimental observations are consistent with a phenomenon in which adrenergic potentiation of toxicity is supplied by the hepatotoxicant itself. Both cocaine and bromobenzene, in hepatotoxic doses increase endogenous catecholamine levels. When the effects of the elevated catecholamines are removed with the appropriate adrenergic antagonist, much lower toxicity (presumably due only to the direct hepatotoxic effects of the drug or chemical) is obse

Availability of Oral Formulations Labeled for Use in Young Children in Serbia, Germany and the USA.

PubMed

Bajcetic, Milica; Kearns, Gregory L; Jovanovic, Ida; Brajovic, Milan; van den Anker, John N

2015-01-01

The paucity of marketed drug products that have been adequately studied in infants and children and subsequently, licensed (or labeled) for pediatric use has caused abundant use of off-label and unauthorized products in this patient population. In those instances where insufficient pharmacologic or therapeutic information exists for children, the potential for off-label use of medicines to result in therapeutic misadventure does as well. In the USA, a series of regulatory measures have been introduced since 1997 which have increased both the number and scope of pediatric drug trials and also, fostered the development of ageappropriate drug formulations by pharmaceutical companies. Provisions of these regulations for previously marketed drugs include the potential for a company to be granted 6 months of marketing exclusivity, thereby providing them with a financial incentive. For new drugs being developed that have potential pediatric use, the regulations mandate the inclusion of children in the drug development process. In the EU comparable measures have been very recently (Jan 2007) signed into European law to overcome the therapeutic orphan status of the infants and children of Europe. The aims of this study was to compare the availability of age-appropriate oral formulations labeled for use in children less than 12 years of age in Serbia, Germany and USA in 2007, and to investigate if certain drug groups of therapeutic importance to children had fewer medicines appropriately labeled for pediatric patients available. The primary sources of information for determining the ageappropriate oral dosage forms, and their licensing and labeling status were the official manuals on drug information and national formularies in 2007. The general availability of oral drugs was the highest in the USA (304), followed by Germany (235) and Serbia (156). From all these oral drugs the availability of labeled age-appropriate pediatric dosage formulations was only between 21.2% and 47.7%. Moreover, there were striking differences between the three countries in the availability of labeled age-appropriate formulations for certain drug groups such as cardiovascular (absent in Serbia) and antiparasitic drugs (absent in Serbia and Germany). Our data suggest that significant country-to-country differences continue to exist in both the number and type of oral drug formulations that have pediatric labeling. Potential contributing factors include country-specific differences in the drug regulatory process, capacity for pharmaceutical development and the regulatory lag time associated with the implementation of drug regulation specifically addressing pediatric product development and labeling. We hypothesize that the new European regulation concerning medicines and children will improve the current unacceptable situation.

Advantageous use of HepaRG cells for the screening and mechanistic study of drug-induced steatosis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tolosa, Laia

Only a few in vitro assays have been proposed to evaluate the steatotic potential of new drugs. The present study examines the utility of HepaRG cells as a cell-based assay system for screening drug-induced liver steatosis. A high-content screening assay was run to evaluate multiple toxicity-related cell parameters in HepaRG cells exposed to 28 compounds, including drugs reported to cause steatosis through different mechanisms and non-steatotic compounds. Lipid content was the most sensitive parameter for all the steatotic drugs, whereas no effects on lipid levels were produced by non-steatotic compounds. Apart from fat accumulation, increased ROS production and altered mitochondrialmore » membrane potential were also found in the cells exposed to steatotic drugs, which indicates that all these cellular events contributed to drug-induced hepatotoxicity. These findings are of clinical relevance as most effects were observed at drug concentrations under 100-fold of the therapeutic peak plasmatic concentration. HepaRG cells showed increased lipid overaccumulation vs. HepG2 cells, which suggests greater sensitivity to drug-induced steatosis. An altered expression profile of transcription factors and the genes that code key proteins in lipid metabolism was also found in the cells exposed to drugs capable of inducing liver steatosis. Our results generally indicate the value of HepaRG cells for assessing the risk of liver damage associated with steatogenic compounds and for investigating the molecular mechanisms involved in drug-induced steatosis. - Highlights: • HepaRG cells were explored as an in vitro model to detect steatogenic potential. • Multiple toxicity-related endpoints were analysed by HCS. • HepaRG showed a greater sensitivity to drug-induced steatosis than HepG2 cells. • Changes in the expression of genes related to lipid metabolism were revealed. • HepaRG allow mechanistic understanding of liver damage induced by steatogenic drugs.« less

Harnessing the potential of natural products in drug discovery from a cheminformatics vantage point.

PubMed

Rodrigues, Tiago

2017-11-15

Natural products (NPs) present a privileged source of inspiration for chemical probe and drug design. Despite the biological pre-validation of the underlying molecular architectures and their relevance in drug discovery, the poor accessibility to NPs, complexity of the synthetic routes and scarce knowledge of their macromolecular counterparts in phenotypic screens still hinder their broader exploration. Cheminformatics algorithms now provide a powerful means of circumventing the abovementioned challenges and unlocking the full potential of NPs in a drug discovery context. Herein, I discuss recent advances in the computer-assisted design of NP mimics and how artificial intelligence may accelerate future NP-inspired molecular medicine.

PEGylated Silk Nanoparticles for Anticancer Drug Delivery.

PubMed

Wongpinyochit, Thidarat; Uhlmann, Petra; Urquhart, Andrew J; Seib, F Philipp

2015-11-09

Silk has a robust clinical track record and is emerging as a promising biopolymer for drug delivery, including its use as nanomedicine. However, silk-based nanomedicines still require further refinements for full exploitation of their potential; the application of "stealth" design principals is especially necessary to support their evolution. The aim of this study was to develop and examine the potential of PEGylated silk nanoparticles as an anticancer drug delivery system. We first generated B. mori derived silk nanoparticles by driving β-sheet assembly (size 104 ± 1.7 nm, zeta potential -56 ± 5.6 mV) using nanoprecipitation. We then surface grafted polyethylene glycol (PEG) to the fabricated silk nanoparticles and verified the aqueous stability and morphology of the resulting PEGylated silk nanoparticles. We assessed the drug loading and release behavior of these nanoparticles using clinically established and emerging anticancer drugs. Overall, PEGylated silk nanoparticles showed high encapsulation efficiency (>93%) and a pH-dependent release over 14 days. Finally, we demonstrated significant cytotoxicity of drug loaded silk nanoparticles applied as single and combination nanomedicines to human breast cancer cells. In conclusion, these results, taken together with prior silk nanoparticle data, support a viable future for silk-based nanomedicines.

Retrieval of Enterobacteriaceae drug targets using singular value decomposition.

PubMed

Silvério-Machado, Rita; Couto, Bráulio R G M; Dos Santos, Marcos A

2015-04-15

The identification of potential drug target proteins in bacteria is important in pharmaceutical research for the development of new antibiotics to combat bacterial agents that cause diseases. A new model that combines the singular value decomposition (SVD) technique with biological filters composed of a set of protein properties associated with bacterial drug targets and similarity to protein-coding essential genes of Escherichia coli (strain K12) has been created to predict potential antibiotic drug targets in the Enterobacteriaceae family. This model identified 99 potential drug target proteins in the studied family, which exhibit eight different functions and are protein-coding essential genes or similar to protein-coding essential genes of E.coli (strain K12), indicating that the disruption of the activities of these proteins is critical for cells. Proteins from bacteria with described drug resistance were found among the retrieved candidates. These candidates have no similarity to the human proteome, therefore exhibiting the advantage of causing no adverse effects or at least no known adverse effects on humans. rita_silverio@hotmail.com. Supplementary data are available at Bioinformatics online. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Platform for Lipid Based Nanocarriers' Formulation Components and their Potential Effects: A Literature Review.

PubMed

Farid, Ragwa Mohamed; Youssef, Nancy Abdel Hamid Abou; Kassem, Abeer Ahmed

2017-11-27

Lipid based nanocarriers have gained recently enormous interest for pharmaceutical application. They have the potential to provide controlled drug release and to target the drug to a specific area. In addition, lipid based nanocarriers can improve the bioavailability of drugs suffering from high hepatic first-pass metabolism, by enhancing their transport via the lymphatic system. The main components of lipid based nanocarriers are lipids and surfactants. Both have great influence on the prepared lipid based systems characteristics. The criteria for their selection are much related to physicochemical properties of the drug and the required administration route. This work gives an overview on the effect of both the type and amount of lipids and surfactants used in the manufacture of lipid based nanocarriers on their behavior and characteristics. Recent studies revealed that the properties of the final product including; particle size, homogeneity, drug loading capacity, zeta potential, drug release profile, stability, permeability, pharmacokinetic properties, crystallinity and cytotoxicity, may be significantly influenced not only by the type but also the amount of the lipids and/or surfactants included in the formulation of the lipid based nanocarriers. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

In Silico Knockout Screening of Plasmodium falciparum Reactions and Prediction of Novel Essential Reactions by Analysing the Metabolic Network

PubMed Central

Isewon, Itunuoluwa; Aromolaran, Olufemi; Oladipupo, Olufunke

2018-01-01

Malaria is an infectious disease that affects close to half a million individuals every year and Plasmodium falciparum is a major cause of malaria. The treatment of this disease could be done effectively if the essential enzymes of this parasite are specifically targeted. Nevertheless, the development of the parasite in resisting existing drugs now makes discovering new drugs a core responsibility. In this study, a novel computational model that makes the prediction of new and validated antimalarial drug target cheaper, easier, and faster has been developed. We have identified new essential reactions as potential targets for drugs in the metabolic network of the parasite. Among the top seven (7) predicted essential reactions, four (4) have been previously identified in earlier studies with biological evidence and one (1) has been with computational evidence. The results from our study were compared with an extensive list of seventy-seven (77) essential reactions with biological evidence from a previous study. We present a list of thirty-one (31) potential candidates for drug targets in Plasmodium falciparum which includes twenty-four (24) new potential candidates for drug targets. PMID:29789805

Pharmacogenetic aspects of drug-induced torsade de pointes: potential tool for improving clinical drug development and prescribing.

PubMed

Shah, Rashmi R

2004-01-01

Drug-induced torsade de pointes (TdP) has proved to be a significant iatro-genic cause of morbidity and mortality and a major reason for the withdrawal of a number of drugs from the market in recent times. Enzymes that metabolise many of these drugs and the potassium channels that are responsible for cardiac repolarisation display genetic polymorphisms. Anecdotal reports have suggested that in many cases of drug-induced TdP, there may be a concealed genetic defect of either these enzymes or the potassium channels, giving rise to either high plasma drug concentrations or diminished cardiac repolarisation reserve, respectively. The presence of either of these genetic defects may predispose a patient to TdP, a potentially fatal adverse reaction, even at therapeutic dosages of QT-prolonging drugs and in the absence of other risk factors. Advances in pharmacogenetics of drug metabolising enzymes and pharmacological targets, together with the prospects of rapid and inexpensive genotyping procedures, promise to individualise and improve the benefit/risk ratio of therapy with drugs that have the potential to cause TdP. The qualitative and the quantitative contributions of these genetic defects in clinical cases of TdP are unclear because not all of the patients with TdP are routinely genotyped and some relevant genetic mutations still remain to be discovered. There are regulatory guidelines that recommend strategies aimed at uncovering the risk of TdP associated with new chemical entities during their development. There are also a number of guidelines that recommend integrating pharmacogenetics in this process. This paper proposes a strategy for integrating pharmacogenetics into drug development programmes to optimise association studies correlating genetic traits and endpoints of clinical interest, namely failure of efficacy or development of repolarisation abnormalities. Until pharmacogenetics is carefully integrated into all phases of development of QT-prolonging drugs and large-scale studies are undertaken during their post-marketing use to determine the genetic components involved in induction of TdP, routine genotyping of patients remains unrealistic. Even without this pharmacogenetic data, the clinical risk of TdP can already be greatly minimised. Clinically, a substantial proportion of cases of TdP are due to the use of either high or usual dosages of drugs with potential to cause TdP in the presence of factors that inhibit drug metabolism. Therefore, choosing the lowest effective dose and identifying patients with these non-genetic risk factors are important means of minimising the risk of TdP. In view of the common secondary pharmacology shared by these drugs, a standard set of contraindications and warnings have evolved over the last decade. These include factors responsible for pharmacokinetic or pharmacodynamic drug interactions. Among the latter, the more important ones are bradycardia, electrolyte imbalance, cardiac disease and co-administration of two or more QT-prolonging drugs. In principle, if large scale prospective studies can demonstrate a substantial genetic component, pharmacogenetically driven prescribing ought to reduce the risk further. However, any potential benefits of pharmacogenetics will be squandered without any reduction in the clinical risk of TdP if physicians do not follow prescribing and monitoring recommendations.

Effect of the market withdrawal of carisoprodol on use of other prescribed drugs with abuse potential.

PubMed

Bramness, J G; Furu, K; Skurtveit, S; Engeland, A

2012-03-01

Carisoprodol, a centrally acting muscle relaxant indicated for acute lower back pain, has been available in Europe and the United States since 1959. Studies indicating increased risk of abuse or addiction led to withdrawal of the drug from the market in Norway and other EU countries in 2008. In this nationwide longitudinal prescription study of 53,116 individuals in Norway, previous users of carisoprodol switched, to a limited extent, to other prescribed drugs with abuse potential after the withdrawal.

Preventable drug waste among anesthesia providers: opportunities for efficiency.

PubMed

Atcheson, Carrie Leigh Hamby; Spivack, John; Williams, Robert; Bryson, Ethan O

2016-05-01

Health care service bundling experiments at the state and regional levels have showed reduced costs by providing a single lump-sum reimbursement for anesthesia services, surgery, and postoperative care. Potential for cost savings related to the provision of anesthesia care has the potential to significantly impact sustainability. This study defines and quantifies routine and preventable anesthetic drug waste and the patient, procedure, and anesthesia provider characteristics associated with increased waste. Over a 12-month period, the type and quantity of clean drugs prepared by the anesthesia team for the first case of the day were recorded. The amount of each drug administered was obtained from the computerized anesthesia record, and data were analyzed to determine the incidence and cost of routine and preventable drug waste. The monthly and yearly cost of preventable waste, including the cost of pharmacy tech labor and materials where applicable, was estimated based on surgical case volume at the study institution. All analyses were performed using SAS software v9.2. Anesthetic drugs prepared for 543 separate surgical cases were observed. Less than 20% of cases generated routine waste. Preventable waste was generated most frequently for ephedrine (59.5% of cases), succinylcholine (33.7%), and lidocaine (25.1%), and least frequently for ondansetron (1.3%), phenylephrine (2.6%), and dexamethasone (2.8%). The estimated yearly cost of preventable anesthetic drug waste was $185,250. Significant potential savings with little impact on clinically significant availability may be achieved through the use of prefilled syringes for some commonly used anesthetic drugs. An intelligently implemented switch to prefilled syringes for select drugs is a potential cost saving measure, but savings might be diminished by disposal of prefilled syringes when they expire, hidden costs in the hospital pharmacy, and inability to supply some medications in prefilled syringes due to stability or manufacturing issues. Copyright © 2016 Elsevier Inc. All rights reserved.

Updates on drug-target network; facilitating polypharmacology and data integration by growth of DrugBank database.

PubMed

Barneh, Farnaz; Jafari, Mohieddin; Mirzaie, Mehdi

2016-11-01

Network pharmacology elucidates the relationship between drugs and targets. As the identified targets for each drug increases, the corresponding drug-target network (DTN) evolves from solely reflection of the pharmaceutical industry trend to a portrait of polypharmacology. The aim of this study was to evaluate the potentials of DrugBank database in advancing systems pharmacology. We constructed and analyzed DTN from drugs and targets associations in the DrugBank 4.0 database. Our results showed that in bipartite DTN, increased ratio of identified targets for drugs augmented density and connectivity of drugs and targets and decreased modular structure. To clear up the details in the network structure, the DTNs were projected into two networks namely, drug similarity network (DSN) and target similarity network (TSN). In DSN, various classes of Food and Drug Administration-approved drugs with distinct therapeutic categories were linked together based on shared targets. Projected TSN also showed complexity because of promiscuity of the drugs. By including investigational drugs that are currently being tested in clinical trials, the networks manifested more connectivity and pictured the upcoming pharmacological space in the future years. Diverse biological processes and protein-protein interactions were manipulated by new drugs, which can extend possible target combinations. We conclude that network-based organization of DrugBank 4.0 data not only reveals the potential for repurposing of existing drugs, also allows generating novel predictions about drugs off-targets, drug-drug interactions and their side effects. Our results also encourage further effort for high-throughput identification of targets to build networks that can be integrated into disease networks. © The Author 2015. Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.

Targeting the latest hallmark of cancer: another attempt at 'magic bullet' drugs targeting cancers' metabolic phenotype.

PubMed

Cuperlovic-Culf, M; Culf, A S; Touaibia, M; Lefort, N

2012-10-01

The metabolism of tumors is remarkably different from the metabolism of corresponding normal cells and tissues. Metabolic alterations are initiated by oncogenes and are required for malignant transformation, allowing cancer cells to resist some cell death signals while producing energy and fulfilling their biosynthetic needs with limiting resources. The distinct metabolic phenotype of cancers provides an interesting avenue for treatment, potentially with minimal side effects. As many cancers show similar metabolic characteristics, drugs targeting the cancer metabolic phenotype are, perhaps optimistically, expected to be 'magic bullet' treatments. Over the last few years there have been a number of potential drugs developed to specifically target cancer metabolism. Several of these drugs are currently in clinical and preclinical trials. This review outlines examples of drugs developed for different targets of significance to cancer metabolism, with a focus on small molecule leads, chemical biology and clinical results for these drugs.

Nanostructured porous Si-based nanoparticles for targeted drug delivery

PubMed Central

Shahbazi, Mohammad-Ali; Herranz, Barbara; Santos, Hélder A.

2012-01-01

One of the backbones in nanomedicine is to deliver drugs specifically to unhealthy cells. Drug nanocarriers can cross physiological barriers and access different tissues, which after proper surface biofunctionalization can enhance cell specificity for cancer therapy. Recent developments have highlighted the potential of mesoporous silica (PSiO2) and silicon (PSi) nanoparticles for targeted drug delivery. In this review, we outline and discuss the most recent advances on the applications and developments of cancer therapies by means of PSiO2 and PSi nanomaterials. Bio-engineering and fine tuning of anti-cancer drug vehicles, high flexibility and potential for sophisticated release mechanisms make these nanostructures promising candidates for “smart” cancer therapies. As a result of their physicochemical properties they can be controllably loaded with large amounts of drugs and coupled to homing molecules to facilitate active targeting. The main emphasis of this review will be on the in vitro and in vivo studies. PMID:23507894

Delivering safer immunotherapies for cancer

PubMed Central

Milling, Lauren; Zhang, Yuan; Irvine, Darrell J.

2017-01-01

Cancer immunotherapy is now a powerful clinical reality, with a steady progression of new drug approvals and a massive pipeline of additional treatments in clinical and preclinical development. However, modulation of the immune system can be a double-edged sword: Drugs that activate immune effectors are prone to serious non-specific systemic inflammation and autoimmune side effects. Drug delivery technologies have an important role to play in harnessing the power of immune therapeutics while avoiding on-target/off-tumor toxicities. Here we review mechanisms of toxicity for clinically-relevant immunotherapeutics, and discuss approaches based in drug delivery technology to enhance the safety and potency of these treatments. These include strategies to merge drug delivery with adoptive cellular therapies, targeting immunotherapies to tumors or select immune cells, and localizing therapeutics intratumorally. Rational design employing lessons learned from the drug delivery and nanomedicine fields has the potential to facilitate immunotherapy reaching its full potential. PMID:28545888

Polymeric Micelles and Alternative Nanonized Delivery Vehicles for Poorly Soluble Drugs

PubMed Central

Lu, Ying; Park, Kinam

2013-01-01

Poorly soluble drugs often encounter low bioavailability and erratic absorption patterns in the clinical setting. Due to the rising number of compounds having solubility issues, finding ways to enhance the solubility of drugs is one of the major challenges in the pharmaceutical industry today. Polymeric micelles, which form upon self-assembly of amphiphilic macromolecules, can act as solubilizing agents for delivery of poorly soluble drugs. This manuscript examines the fundamentals of polymeric micelles through reviews of representative literature and demonstrates possible applications through recent examples of clinical trial developments. In particular, the potential of polymeric micelles for delivery of poorly water-soluble drugs, especially in the areas of oral delivery and in cancer therapy, is discussed. Key considerations in utilizing polymeric micelles’ advantages and overcoming potential disadvantages have been highlighted. Lastly, other possible strategies related to particle size reduction for enhancing solubilization of poorly water-soluble drugs are introduced. PMID:22944304

Rechargeable Infection-responsive Antifungal Denture Materials

PubMed Central

Cao, Z.; Sun, X.; Yeh, C.-K.; Sun, Y.

2010-01-01

Candida-associated denture stomatitis (CADS) is a significant clinical concern. We developed rechargeable infection-responsive antifungal denture materials for potentially managing the disease. Polymethacrylic acid (PMAA) was covalently bound onto diurethane dimethacrylate denture resins in the curing step. The PMAA resins bound cationic antifungal drugs such as miconazole and chlorhexidine digluconate (CG) through ionic interactions. The anticandidal activities of the drug-containing PMAA-resin discs were sustained for a prolonged period of time (weeks and months). Drug release was much faster at acidic conditions (pH 5) than at pH 7. Drugs bound to the denture materials could be “washed out” by treatment with EDTA, and the drug-depleted resins could be recharged with the same or a different class of anticandidal drugs. These results suggest clinical potential of the newly developed antifungal denture materials in the management of CADS and other infectious conditions. PMID:20940361

The role of interleukin-18 in glioblastoma pathology implies therapeutic potential of two old drugs-disulfiram and ritonavir.

PubMed

Kast, Richard E

2015-04-09

Based on reporting in the last several years, an impressive but dismal list of cytotoxic chemotherapies that fail to prolong the median overall survival of patients with glioblastoma has prompted the development of treatment protocols designed to interfere with growth-facilitating signaling systems by using non-cytotoxic, non-oncology drugs. Recent recognition of the pro-mobility stimulus, interleukin-18, as a driver of centrifugal glioblastoma cell migration allows potential treatment adjuncts with disulfiram and ritonavir. Disulfiram and ritonavir are well-tolerated, non-cytotoxic, non-oncology chemotherapeutic drugs that are marketed for the treatment of alcoholism and human immunodeficiency virus (HIV) infection, respectively. Both drugs exhibit an interleukin-18-inhibiting function. Given the favorable tolerability profile of disulfiram and ritonavir, the unlikely drug-drug interaction with temozolomide, and the poor prognosis of glioblastoma, trials of addition of disulfiram and ritonavir to current standard initial treatment of glioblastoma would be warranted.

Comparison of drug delivery potentials of surface functionalized cobalt and zinc ferrite nanohybrids for curcumin in to MCF-7 breast cancer cells

NASA Astrophysics Data System (ADS)

Sawant, V. J.; Bamane, S. R.; Shejwal, R. V.; Patil, S. B.

2016-11-01

The functionalization and surface engineering of CoFe2O4 and ZnFe2O4 nanoparticles were performed by coating with PEG and Chitosan respectively using simple wet co-precipitation. Then multiactive therapeutic drug curcumin was loaded to form drug delivery nanohybrids by precipitation. These nanohybrids were characterized separately using UV-vis, FTIR, PL spectroscopy, XRD, VSM, SEM and TEM analysis. The moderate antibacterial activities of the nanohybrids were elaborated by in vitro antibacterial screening on Escherichia coli and Staphylococcus aureus. The anticancer potentials, apoptotic effects and enhanced drug delivery properties of these nanohybrids were confirmed and compared on MCF-7 cells by in vitro MTT assay. The drug delivery activities for hydrophobic drug and anticancer effects of chitosan coated zinc ferrite functionalized nanoparticles were higher than PEG coated cobalt ferrite nanohybrids.

MDMA: interactions with other psychoactive drugs.

PubMed

Mohamed, Wael M Y; Ben Hamida, Sami; Cassel, Jean-Christophe; de Vasconcelos, Anne Pereira; Jones, Byron C

2011-10-01

3,4-Methylenedioxymethamphetamine (MDMA, ecstasy) is one of the most widely abused illegal drugs. Some users self-report euphoria and an increased perception and feeling of closeness to others. When taken in warm environments, MDMA users may develop acute complications with potential fatal consequences. In rodents, MDMA increases locomotor activity and, depending on ambient temperature, may produce a dose-dependent, potentially lethal hyperthermia. Like most other recreational drugs, MDMA is frequently taken in combination with other substances including tobacco, EtOH, marijuana, amphetamines, cocaine and, caffeine. Although polydrug use is very common, the understanding of the effects of this multiple substance use, as well as the analysis of consequences of different drug-drug associations, received rather little attention. The purpose of this review is to summarize our current knowledge about the changes on MDMA-related behavior, pharmacology, and neurotoxicity associated with co-consumption of other drugs of abuse and psychoactive agents. Copyright © 2011 Elsevier B.V. All rights reserved.

Growing PAINS in academic drug discovery.

PubMed

Whitty, Adrian

2011-05-01

In a recent article it was argued that compounds published as drug leads by academic laboratories commonly contain functionality that identifies them as nonspecific 'pan-assay interference compounds' (PAINS). The article raises broad questions about why best practices for hit and lead qualification that are well known in industry are not more widely employed in academia, as well as about the role of journals in publishing manuscripts that report drug leads of little potential value. Barriers to adoption of best practices for some academic drug-discovery researchers include knowledge gaps and infrastructure deficiencies, but they also arise from fundamental differences in how academic research is structured and how success is measured. Academic drug discovery should not seek to become identical to commercial pharmaceutical research, but we can do a better job of assessing and communicating the true potential of the drug leads we publish, thereby reducing the wastage of resources on nonviable compounds.

Accelerating drug development for neuroblastoma - New Drug Development Strategy: an Innovative Therapies for Children with Cancer, European Network for Cancer Research in Children and Adolescents and International Society of Paediatric Oncology Europe Neuroblastoma project.

PubMed

Moreno, Lucas; Caron, Hubert; Geoerger, Birgit; Eggert, Angelika; Schleiermacher, Gudrun; Brock, Penelope; Valteau-Couanet, Dominique; Chesler, Louis; Schulte, Johannes H; De Preter, Katleen; Molenaar, Jan; Schramm, Alexander; Eilers, Martin; Van Maerken, Tom; Johnsen, John Inge; Garrett, Michelle; George, Sally L; Tweddle, Deborah A; Kogner, Per; Berthold, Frank; Koster, Jan; Barone, Giuseppe; Tucker, Elizabeth R; Marshall, Lynley; Herold, Ralf; Sterba, Jaroslav; Norga, Koen; Vassal, Gilles; Pearson, Andrew Dj

2017-08-01

Neuroblastoma, the commonest paediatric extra-cranial tumour, remains a leading cause of death from cancer in children. There is an urgent need to develop new drugs to improve cure rates and reduce long-term toxicity and to incorporate molecularly targeted therapies into treatment. Many potential drugs are becoming available, but have to be prioritised for clinical trials due to the relatively small numbers of patients. Areas covered: The current drug development model has been slow, associated with significant attrition, and few new drugs have been developed for neuroblastoma. The Neuroblastoma New Drug Development Strategy (NDDS) has: 1) established a group with expertise in drug development; 2) prioritised targets and drugs according to tumour biology (target expression, dependency, pre-clinical data; potential combinations; biomarkers), identifying as priority targets ALK, MEK, CDK4/6, MDM2, MYCN (druggable by BET bromodomain, aurora kinase, mTORC1/2) BIRC5 and checkpoint kinase 1; 3) promoted clinical trials with target-prioritised drugs. Drugs showing activity can be rapidly transitioned via parallel randomised trials into front-line studies. Expert opinion: The Neuroblastoma NDDS is based on the premise that optimal drug development is reliant on knowledge of tumour biology and prioritisation. This approach will accelerate neuroblastoma drug development and other poor prognosis childhood malignancies.

DR2DI: a powerful computational tool for predicting novel drug-disease associations

NASA Astrophysics Data System (ADS)

Lu, Lu; Yu, Hua

2018-05-01

Finding the new related candidate diseases for known drugs provides an effective method for fast-speed and low-risk drug development. However, experimental identification of drug-disease associations is expensive and time-consuming. This motivates the need for developing in silico computational methods that can infer true drug-disease pairs with high confidence. In this study, we presented a novel and powerful computational tool, DR2DI, for accurately uncovering the potential associations between drugs and diseases using high-dimensional and heterogeneous omics data as information sources. Based on a unified and extended similarity kernel framework, DR2DI inferred the unknown relationships between drugs and diseases using Regularized Kernel Classifier. Importantly, DR2DI employed a semi-supervised and global learning algorithm which can be applied to uncover the diseases (drugs) associated with known and novel drugs (diseases). In silico global validation experiments showed that DR2DI significantly outperforms recent two approaches for predicting drug-disease associations. Detailed case studies further demonstrated that the therapeutic indications and side effects of drugs predicted by DR2DI could be validated by existing database records and literature, suggesting that DR2DI can be served as a useful bioinformatic tool for identifying the potential drug-disease associations and guiding drug repositioning. Our software and comparison codes are freely available at https://github.com/huayu1111/DR2DI.

DR2DI: a powerful computational tool for predicting novel drug-disease associations

NASA Astrophysics Data System (ADS)

Lu, Lu; Yu, Hua

2018-04-01

Finding the new related candidate diseases for known drugs provides an effective method for fast-speed and low-risk drug development. However, experimental identification of drug-disease associations is expensive and time-consuming. This motivates the need for developing in silico computational methods that can infer true drug-disease pairs with high confidence. In this study, we presented a novel and powerful computational tool, DR2DI, for accurately uncovering the potential associations between drugs and diseases using high-dimensional and heterogeneous omics data as information sources. Based on a unified and extended similarity kernel framework, DR2DI inferred the unknown relationships between drugs and diseases using Regularized Kernel Classifier. Importantly, DR2DI employed a semi-supervised and global learning algorithm which can be applied to uncover the diseases (drugs) associated with known and novel drugs (diseases). In silico global validation experiments showed that DR2DI significantly outperforms recent two approaches for predicting drug-disease associations. Detailed case studies further demonstrated that the therapeutic indications and side effects of drugs predicted by DR2DI could be validated by existing database records and literature, suggesting that DR2DI can be served as a useful bioinformatic tool for identifying the potential drug-disease associations and guiding drug repositioning. Our software and comparison codes are freely available at https://github.com/huayu1111/DR2DI.

Microwave-aided skin drug penetration and retention of 5-fluorouracil-loaded ethosomes.

PubMed

Khan, Nauman Rahim; Wong, Tin Wui

2016-09-01

Skin drug retention is required in local treatment of skin cancer. This study investigated the interplay effects of ethosomes and microwave in transdermal drug delivery. Skin pre-treatment by microwave and applied with liquified medicine is deemed to 'cement' the skin thereby raising skin drug deposition. 5-fluorouracil-loaded ethosomes were prepared and subjected to size, zeta potential, morphology, drug content, drug release and skin permeation tests. The molecular characteristics of untreated, microwave and/or ethosome-treated skins were examined by Fourier transform infrared and raman spectroscopy, thermal and electron microscopy techniques. The skin drug retention was promoted using larger ethosomes with negative zeta potentials that repelled anionic lipids of skin and hindered vesicle permeation into deep layers. These ethosomes had low ethanol content. They were less able to fluidize the lipid and defluidize the protein domains at epidermis to enlarge aqueous pores for drug permeation. Pre-treatment of skin by 2450 MHz microwave for 2.5 min further increased skin drug penetration and retention of low ethanol ethosomes and provided lower drug permeation than cases treated for 1.15 min and 5 min. A 2.5 min treatment might be accompanied by specific dermal protein fluidization via C=O moiety which translated to macromolecular swelling, narrowing of intercellular spaces at lower skin layers, increased drug retention and reduced drug permeation. Ethosomes and microwave synergized to promote skin drug retention.

Harm Reduction Agencies as a Potential Site for Buprenorphine Treatment.

PubMed

Fox, Aaron D; Chamberlain, Adam; Frost, Taeko; Cunningham, Chinazo O

2015-01-01

Harm reduction agencies complement addiction treatment by providing diverse services that improve the health of people who use drugs. Buprenorphine maintenance treatment (BMT) is an effective opioid addiction treatment that may be provided from flexible settings, potentially including harm reduction agencies. This study investigated attitudes toward different potential sites for BMT (harm reduction agencies, general medical clinics, and drug treatment programs) among harm reduction clients. Using computer-based interviews, participants indicated preferred potential site for BMT (harm reduction agency, drug treatment program, or general medical clinic), interest in BMT by potential site, motivation for treatment, and barriers to BMT. Multivariable logistic regression was used to determine factors associated with harm reduction agency preference. Of 102 opioid users, the most preferred potential site for BMT was a harm reduction agency (51%), whereas fewer preferred general medical clinics (13%), drug treatment programs (12%), or were not interested in BMT (25%). In multivariable analysis, experiencing ≥1 barrier to BMT was strongly associated with preferring harm reduction agencies (adjusted odds ratio [aOR] = 3.39, 95% confidence interval [CI]: 1.00-11.43). The potential to initiate BMT at harm reduction agencies is highly favorable among harm reduction clients, especially among those experiencing barriers to BMT. Offering BMT at harm reduction agencies could improve access to treatment, but studies are needed to determine safety and efficacy of this approach.

A biomimetic hybrid nanoplatform for encapsulation and precisely controlled delivery of therasnostic agents

NASA Astrophysics Data System (ADS)

Wang, Hai; Agarwal, Pranay; Zhao, Shuting; Yu, Jianhua; Lu, Xiongbin; He, Xiaoming

2015-12-01

Nanoparticles have demonstrated great potential for enhancing drug delivery. However, the low drug encapsulation efficiency at high drug-to-nanoparticle feeding ratios and minimal drug loading content in nanoparticle at any feeding ratios are major hurdles to their widespread applications. Here we report a robust eukaryotic cell-like hybrid nanoplatform (EukaCell) for encapsulation of theranostic agents (doxorubicin and indocyanine green). The EukaCell consists of a phospholipid membrane, a cytoskeleton-like mesoporous silica matrix and a nucleus-like fullerene core. At high drug-to-nanoparticle feeding ratios (for example, 1:0.5), the encapsulation efficiency and loading content can be improved by 58 and 21 times, respectively, compared with conventional silica nanoparticles. Moreover, release of the encapsulated drug can be precisely controlled via dosing near infrared laser irradiation. Ultimately, the ultra-high (up to ~87%) loading content renders augmented anticancer capacity both in vitro and in vivo. Our EukaCell is valuable for drug delivery to fight against cancer and potentially other diseases.

Design and development of hyaluronan-functionalized polybenzofulvene nanoparticles as CD44 receptor mediated drug delivery system

NASA Astrophysics Data System (ADS)

Licciardi, Mariano; Scialabba, Cinzia; Giammona, Gaetano; Paolino, Marco; Razzano, Vincenzo; Grisci, Giorgio; Giuliani, Germano; Makovec, Francesco; Cappelli, Andrea

2017-06-01

A tri-component polymer brush (TCPB ), composed of a polybenzofulvene copolymer bearing low molecular weight hyaluronic acid (HA) on the surface of its cylindrical brush-like backbone and oligo-PEG fractions, was employed in the preparation of 350 nm nanostructured drug delivery systems capable of delivering the anticancer drug doxorubicin. The obtained drug delivery systems were characterized on the basis of drug loading and release, dimensions and zeta potential, morphology and in vitro cell activity, and uptake on three different human cell lines, namely the bronchial epithelial 16HBE, the breast adenocarcinoma MCF-7, and the colon cancer HCT116 cells. Finally, the ability of doxorubicin-loaded TCPB nanoparticles (DOXO-TCPB) to be internalized into cancer cells by CD44 receptor mediated uptake was assessed by means of uptake studies in HCT cells. These data were supported by anti-CD44-FITC staining assay. The proposed TCPB nanostructured drug delivery systems have many potential applications in nanomedicine, including cancer targeted drug delivery.

Drug interactions with the dietary fiber Plantago ovata husk.

PubMed

Fernandez, Nelida; Lopez, Cristina; Díez, Raquel; Garcia, Juan J; Diez, Maria Jose; Sahagun, Ana; Sierra, Matilde

2012-11-01

Plantago ovata husk is a viscous water-soluble fiber obtained by milling the seed of Plantago ovata. The increased use of this compound for the treatment of diseases makes it necessary to know of its potential drug interactions. The present paper reviews the literature concerning interactions between drugs and the dietary fiber Plantago ovata husk. All publications which might describe interactions between the dietetic fiber Plantago ovata husk and other drugs were identified by searches using databases such as MEDLINE or EMBASE. Drug interactions have been the subject of numerous studies, but few of them have been carried out with dietary fiber and the results obtained have often been variable. The incidence and importance of interactions between fiber and drugs has increased due to a worldwide rise in the use of dietary fiber. Plantago ovata husk has the potential for producing both benefits and risks with both desirable and undesirable effects when coadministered with drugs. More clinical studies are justifiably needed to improve treatments and to better evaluate patient safety.

A hadoop-based method to predict potential effective drug combination.

PubMed

Sun, Yifan; Xiong, Yi; Xu, Qian; Wei, Dongqing

2014-01-01

Combination drugs that impact multiple targets simultaneously are promising candidates for combating complex diseases due to their improved efficacy and reduced side effects. However, exhaustive screening of all possible drug combinations is extremely time-consuming and impractical. Here, we present a novel Hadoop-based approach to predict drug combinations by taking advantage of the MapReduce programming model, which leads to an improvement of scalability of the prediction algorithm. By integrating the gene expression data of multiple drugs, we constructed data preprocessing and the support vector machines and naïve Bayesian classifiers on Hadoop for prediction of drug combinations. The experimental results suggest that our Hadoop-based model achieves much higher efficiency in the big data processing steps with satisfactory performance. We believed that our proposed approach can help accelerate the prediction of potential effective drugs with the increasing of the combination number at an exponential rate in future. The source code and datasets are available upon request.

A Hadoop-Based Method to Predict Potential Effective Drug Combination

PubMed Central

Xiong, Yi; Xu, Qian; Wei, Dongqing

2014-01-01

Combination drugs that impact multiple targets simultaneously are promising candidates for combating complex diseases due to their improved efficacy and reduced side effects. However, exhaustive screening of all possible drug combinations is extremely time-consuming and impractical. Here, we present a novel Hadoop-based approach to predict drug combinations by taking advantage of the MapReduce programming model, which leads to an improvement of scalability of the prediction algorithm. By integrating the gene expression data of multiple drugs, we constructed data preprocessing and the support vector machines and naïve Bayesian classifiers on Hadoop for prediction of drug combinations. The experimental results suggest that our Hadoop-based model achieves much higher efficiency in the big data processing steps with satisfactory performance. We believed that our proposed approach can help accelerate the prediction of potential effective drugs with the increasing of the combination number at an exponential rate in future. The source code and datasets are available upon request. PMID:25147789

KCa 3.1-a microglial target ready for drug repurposing?

PubMed

Dale, Elena; Staal, Roland G W; Eder, Claudia; Möller, Thomas

2016-10-01

Over the past decade, glial cells have attracted attention for harboring unexploited targets for drug discovery. Several glial targets have attracted de novo drug discovery programs, as highlighted in this GLIA Special Issue. Drug repurposing, which has the objective of utilizing existing drugs as well as abandoned, failed, or not yet pursued clinical development candidates for new indications, might provide a faster opportunity to bring drugs for glial targets to patients with unmet needs. Here, we review the potential of the intermediate-conductance calcium-activated potassium channels KCa 3.1 as the target for such a repurposing effort. We discuss the data on KCa 3.1 expression on microglia in vitro and in vivo and review the relevant literature on the two KCa 3.1 inhibitors TRAM-34 and Senicapoc. Finally, we provide an outlook of what it might take to harness the potential of KCa 3.1 as a bona fide microglial drug target. GLIA 2016;64:1733-1741. © 2016 Wiley Periodicals, Inc.

Tissue Chips to aid drug development and modeling for rare diseases

PubMed Central

Low, Lucie A.; Tagle, Danilo A.

2016-01-01

Introduction The technologies used to design, create and use microphysiological systems (MPS, “tissue chips” or “organs-on-chips”) have progressed rapidly in the last 5 years, and validation studies of the functional relevance of these platforms to human physiology, and response to drugs for individual model organ systems, are well underway. These studies are paving the way for integrated multi-organ systems that can model diseases and predict drug efficacy and toxicology of multiple organs in real-time, improving the potential for diagnostics and development of novel treatments of rare diseases in the future. Areas covered This review will briefly summarize the current state of tissue chip research and highlight model systems where these microfabricated (or bioengineered) devices are already being used to screen therapeutics, model disease states, and provide potential treatments in addition to helping elucidate the basic molecular and cellular phenotypes of rare diseases. Expert opinion Microphysiological systems hold great promise and potential for modeling rare disorders, as well as for their potential use to enhance the predictive power of new drug therapeutics, plus potentially increase the statistical power of clinical trials while removing the inherent risks of these trials in rare disease populations. PMID:28626620

Multi-target drugs: the trend of drug research and development.

PubMed

Lu, Jin-Jian; Pan, Wei; Hu, Yuan-Jia; Wang, Yi-Tao

2012-01-01

Summarizing the status of drugs in the market and examining the trend of drug research and development is important in drug discovery. In this study, we compared the drug targets and the market sales of the new molecular entities approved by the U.S. Food and Drug Administration from January 2000 to December 2009. Two networks, namely, the target-target and drug-drug networks, have been set up using the network analysis tools. The multi-target drugs have much more potential, as shown by the network visualization and the market trends. We discussed the possible reasons and proposed the rational strategies for drug research and development in the future.

PCP and hallucinogens.

PubMed

Carroll, M E

1990-01-01

In this review phencyclidine and related arylcyclohexylamines and hallucinogens, using LSD as the prototype, are considered as two distinct classes of abused drugs. Within these classes drugs that are found on the street are discussed, and a current epidemiological summary is provided. The abuse liability and dependence potential of these drugs are evaluated by considering four major determinants of their abuse. First, is the ability of a drug to function as a positive reinforcer and increase the probability of operant behavior leading to its delivery. Animal data describing the reinforcing effects of PCP are reviewed with respect to the influence of variables controlling drug-reinforced behavior; however, there are no animal models of hallucinogen-reinforced behavior. Several methods of quantifying reinforcing efficacy are discussed. A second determinant is the subjective effects of the respective drugs. These effects are described and compared across drugs based on clinical reports in humans and drug discrimination studies in animals. A third determinant is the behavioral and physiological toxicity that results from acute and chronic use of these drugs. Clinical reports and results of sensitive tests that have been developed for laboratory animals are reviewed. A fourth determinant is the dependence potential that exists with these drugs, measured by tolerance development and the extent to which behavioral and physiological disturbances occur when drug use is terminated.

Magnetically guided release of ciprofloxacin from superparamagnetic polymer nanocomposites.

PubMed

Gupta, Rashmi; Bajpai, A K

2011-01-01

Tailored with superparamagnetic properties the magnetic nanocomposites have been thoroughly investigated in recent past because of their potential applications in the fields of biomedicine and bioengineering such as protein detection, magnetic targeted drug carriers, bioseparation, magnetic resonance imaging contrast agents and hyperthermia. Magnetic drug targeting has come up as a safe and effective drug-delivery technology, i.e., with the least amount of magnetic particles a maximum of drug may be easily administered and transported to the site of choice. In the present work novel magnetic drug-targeting carriers consisting of magnetic nanoparticles encapsulated within a smart polymer matrix with potential of controlled drug release is described. To make such magnetic polymeric drug-delivery systems, both the magnetic nanoparticles and antibiotic drug (ciprofloxacin) were incorporated into the hydrogel. The controlled release process and release profiles were investigated as a function of experimental protocols such as percent loading of drug, chemical composition of the nanocomposite, pH of release media and strength of magnetic field on the release profiles. The structure, morphology and compositions of magnetic hydrogel nanocomposites were characterized by FT-IR, TEM, XRD and VSM techniques. It was found that magnetic nanocomposites were biocompatible and superparamagnetic in nature and could be used as a smart drug carrier for controlled and targeted drug delivery.

Glutamatergic synaptic plasticity in the mesocorticolimbic system in addiction

PubMed Central

van Huijstee, Aile N.; Mansvelder, Huibert D.

2015-01-01

Addictive drugs remodel the brain’s reward circuitry, the mesocorticolimbic dopamine (DA) system, by inducing widespread adaptations of glutamatergic synapses. This drug-induced synaptic plasticity is thought to contribute to both the development and the persistence of addiction. This review highlights the synaptic modifications that are induced by in vivo exposure to addictive drugs and describes how these drug-induced synaptic changes may contribute to the different components of addictive behavior, such as compulsive drug use despite negative consequences and relapse. Initially, exposure to an addictive drug induces synaptic changes in the ventral tegmental area (VTA). This drug-induced synaptic potentiation in the VTA subsequently triggers synaptic changes in downstream areas of the mesocorticolimbic system, such as the nucleus accumbens (NAc) and the prefrontal cortex (PFC), with further drug exposure. These glutamatergic synaptic alterations are then thought to mediate many of the behavioral symptoms that characterize addiction. The later stages of glutamatergic synaptic plasticity in the NAc and in particular in the PFC play a role in maintaining addiction and drive relapse to drug-taking induced by drug-associated cues. Remodeling of PFC glutamatergic circuits can persist into adulthood, causing a lasting vulnerability to relapse. We will discuss how these neurobiological changes produced by drugs of abuse may provide novel targets for potential treatment strategies for addiction. PMID:25653591