Candesartan: widening indications for this angiotensin II receptor blocker?

PubMed

Mendis, B; Page, S R

2009-08-01

Candesartan cilexetil is one of a number of drugs of the angiotensin II receptor blocker (ARB) class. Their principal mode of action involves competitive blockade of the angiotensin II type 1 receptor, thereby modulating the activity of the rennin-angiotensin-aldosterone system. Angiotensin II receptor blocker therapy has been proven to be well tolerated and effective in the management of hypertension, chronic heart failure with left ventricular dysfunction and the prevention and progression of diabetic renal disease. Candesartan is a highly potent, long-acting and selective angiotensin II type 1 receptor blocker. It was launched in 1998 for the treatment of hypertension. Its use has increased dramatically, with recently published data suggesting benefit in the treatment of stroke, heart failure, diabetic renal disease and most recently in preventing the development of or delaying the progression of diabetic retinopathy. In this article we review the literature on the use of ARB drugs in general before focusing on candesartan.

Memory Disrupting Effects of Nonmuscle Myosin II Inhibition Depend on the Class of Abused Drug and Brain Region

ERIC Educational Resources Information Center

Briggs, Sherri B.; Blouin, Ashley M.; Young, Erica J.; Rumbaugh, Gavin; Miller, Courtney A.

2017-01-01

Depolymerizing actin in the amygdala through nonmuscle myosin II inhibition (NMIIi) produces a selective, lasting, and retrieval-independent disruption of the storage of methamphetamine-associated memories. Here we report a similar disruption of memories associated with amphetamine, but not cocaine or morphine, by NMIIi. Reconsolidation appeared…

Chitinosans as tableting excipients for modified release delivery systems.

PubMed

Rege, P R; Shukla, D J; Block, L H

1999-04-20

The term 'chitinosans' embraces the spectrum of acetylated poly(N-glucosamines) ranging from chitin to chitosan. Chitinosans (I), at acidic pH, have protonated amines which can interact with oppositely charged drug ions and, thereby, modify drug release from drug delivery systems. Tablets were compressed from a physical mixture containing salicylic acid (II) as the model drug, I, and magnesium stearate. Five commercial I compounds, varying in degree of deacetylation and molecular weight, were selected. Tablets were compressed at 5000, 10 000, and 15 000 psig using a Carver and a single punch tablet press. The differential scanning calorimetry thermograms provided evidence of I-II interaction in the powder blend. Analysis of variance (ANOVA) indicated that the compression pressure did not significantly affect the crushing strength (CS) or the release profile of II from the I-matrix tablets (P?0.05). Furthermore, the ANOVA also indicated that the tablet press used during manufacture did not affect the above properties (P?0.05); however, the chitinosans significantly affected the CS as well as the release profile of II from I-matrix tablets (P<0.05). This study provides further evidence for the use of commercial I compounds as excipients for use in modified release drug delivery systems. Copyright.

Clinical Variants of New Delhi Metallo-β-Lactamase Are Evolving To Overcome Zinc Scarcity.

PubMed

Stewart, Alesha C; Bethel, Christopher R; VanPelt, Jamie; Bergstrom, Alex; Cheng, Zishuo; Miller, Callie G; Williams, Cameron; Poth, Robert; Morris, Matthew; Lahey, Olivia; Nix, Jay C; Tierney, David L; Page, Richard C; Crowder, Michael W; Bonomo, Robert A; Fast, Walter

2017-12-08

Use and misuse of antibiotics have driven the evolution of serine β-lactamases to better recognize new generations of β-lactam drugs, but the selective pressures driving evolution of metallo-β-lactamases are less clear. Here, we present evidence that New Delhi metallo-β-lactamase (NDM) is evolving to overcome the selective pressure of zinc(II) scarcity. Studies of NDM-1, NDM-4 (M154L), and NDM-12 (M154L, G222D) demonstrate that the point mutant M154L, contained in 50% of clinical NDM variants, selectively enhances resistance to the penam ampicillin at low zinc(II) concentrations relevant to infection sites. Each of the clinical variants is shown to be progressively more thermostable and to bind zinc(II) more tightly than NDM-1, but a selective enhancement of penam turnover at low zinc(II) concentrations indicates that most of the improvement derives from catalysis rather than stability. X-ray crystallography of NDM-4 and NDM-12, as well as bioinorganic spectroscopy of dizinc(II), zinc(II)/cobalt(II), and dicobalt(II) metalloforms probe the mechanism of enhanced resistance and reveal perturbations of the dinuclear metal cluster that underlie improved catalysis. These studies support the proposal that zinc(II) scarcity, rather than changes in antibiotic structure, is driving the evolution of new NDM variants in clinical settings.

Antifungal Activity of Eupolauridine and Its Action on DNA Topoisomerases

PubMed Central

Khan, Shabana I.; Nimrod, Alison C.; Mehrpooya, Mohammed; Nitiss, John L.; Walker, Larry A.; Clark, Alice M.

2002-01-01

The azafluoranthene alkaloid eupolauridine has previously been shown to have in vitro antifungal activity and selective inhibition of fungal topoisomerase I. The present study was undertaken to examine further its selectivity and mode of action. Eupolauridine completely inhibits the DNA relaxation activity of purified fungal topoisomerase I at 50 μg/ml, but it does not stabilize the cleavage complex of either human or fungal topoisomerase I. Cleavage complex stabilization is the mode of action of topoisomerase I targeting drugs of the camptothecin family. Also, unlike camptothecin, eupolauridine does not cause significant cytotoxicity in mammalian cells. To determine if the inhibition of topoisomerase I is the principal mode of antifungal action of eupolauridine, Saccharomyces cerevisiae strains with alterations in topoisomerase genes were used in clonogenic assays. The antifungal activity of eupolauridine was not diminished in the absence of topoisomerase I; rather, the cells lacking the enzyme were more sensitive to the drug. Cell-killing activity of eupolauridine was also more pronounced in cells that overexpressed topoisomerase II. In vitro assays with the purified yeast enzyme confirmed that eupolauridine stabilized topoisomerase II covalent complexes. These results indicate that a major target for fungal cell killing by eupolauridine is DNA topoisomerase II rather than topoisomerase I, but does not exclude the possibility that the drug also acts against other targets. PMID:12019091

Antifungal activity of eupolauridine and its action on DNA topoisomerases.

PubMed

Khan, Shabana I; Nimrod, Alison C; Mehrpooya, Mohammed; Nitiss, John L; Walker, Larry A; Clark, Alice M

2002-06-01

The azafluoranthene alkaloid eupolauridine has previously been shown to have in vitro antifungal activity and selective inhibition of fungal topoisomerase I. The present study was undertaken to examine further its selectivity and mode of action. Eupolauridine completely inhibits the DNA relaxation activity of purified fungal topoisomerase I at 50 microg/ml, but it does not stabilize the cleavage complex of either human or fungal topoisomerase I. Cleavage complex stabilization is the mode of action of topoisomerase I targeting drugs of the camptothecin family. Also, unlike camptothecin, eupolauridine does not cause significant cytotoxicity in mammalian cells. To determine if the inhibition of topoisomerase I is the principal mode of antifungal action of eupolauridine, Saccharomyces cerevisiae strains with alterations in topoisomerase genes were used in clonogenic assays. The antifungal activity of eupolauridine was not diminished in the absence of topoisomerase I; rather, the cells lacking the enzyme were more sensitive to the drug. Cell-killing activity of eupolauridine was also more pronounced in cells that overexpressed topoisomerase II. In vitro assays with the purified yeast enzyme confirmed that eupolauridine stabilized topoisomerase II covalent complexes. These results indicate that a major target for fungal cell killing by eupolauridine is DNA topoisomerase II rather than topoisomerase I, but does not exclude the possibility that the drug also acts against other targets.

Identification of precision treatment strategies for relapsed/refractory multiple myeloma by functional drug sensitivity testing.

PubMed

Majumder, Muntasir Mamun; Silvennoinen, Raija; Anttila, Pekka; Tamborero, David; Eldfors, Samuli; Yadav, Bhagwan; Karjalainen, Riikka; Kuusanmäki, Heikki; Lievonen, Juha; Parsons, Alun; Suvela, Minna; Jantunen, Esa; Porkka, Kimmo; Heckman, Caroline A

2017-08-22

Novel agents have increased survival of multiple myeloma (MM) patients, however high-risk and relapsed/refractory patients remain challenging to treat and their outcome is poor. To identify novel therapies and aid treatment selection for MM, we assessed the ex vivo sensitivity of 50 MM patient samples to 308 approved and investigational drugs. With the results we i) classified patients based on their ex vivo drug response profile; ii) identified and matched potential drug candidates to recurrent cytogenetic alterations; and iii) correlated ex vivo drug sensitivity to patient outcome. Based on their drug sensitivity profiles, MM patients were stratified into four distinct subgroups with varied survival outcomes. Patients with progressive disease and poor survival clustered in a drug response group exhibiting high sensitivity to signal transduction inhibitors. Del(17p) positive samples were resistant to most drugs tested with the exception of histone deacetylase and BCL2 inhibitors. Samples positive for t(4;14) were highly sensitive to immunomodulatory drugs, proteasome inhibitors and several targeted drugs. Three patients treated based on the ex vivo results showed good response to the selected treatments. Our results demonstrate that ex vivo drug testing may potentially be applied to optimize treatment selection and achieve therapeutic benefit for relapsed/refractory MM.

Developing Anticancer Copper(II) Pro-drugs Based on the Nature of Cancer Cells and the Human Serum Albumin Carrier IIA Subdomain.

PubMed

Gou, Yi; Qi, Jinxu; Ajayi, Joshua-Paul; Zhang, Yao; Zhou, Zuping; Wu, Xiaoyang; Yang, Feng; Liang, Hong

2015-10-05

To synergistically enhance the selectivity and efficiency of anticancer copper drugs, we proposed and built a model to develop anticancer copper pro-drugs based on the nature of human serum albumin (HSA) IIA subdomain and cancer cells. Three copper(II) compounds of a 2-hydroxy-1-naphthaldehyde benzoyl hydrazone Schiff-base ligand in the presence pyridine, imidazole, or indazole ligands were synthesized (C1-C3). The structures of three HSA complexes revealed that the Cu compounds bind to the hydrophobic cavity in the HSA IIA subdomain. Among them, the pyridine and imidazole ligands of C1 and C2 are replaced by Lys199, and His242 directly coordinates with Cu(II). The indazole and Br ligands of C3 are replaced by Lys199 and His242, respectively. Compared with the Cu(II) compounds alone, the HSA complexes enhance cytotoxicity in MCF-7 cells approximately 3-5-fold, but do not raise cytotoxicity levels in normal cells in vitro through selectively accumulating in cancer cells to some extent. We find that the HSA complex has a stronger capacity for cell cycle arrest in the G2/M phase of MCF-7 by targeting cyclin-dependent kinase 1 (CDK1) and down-regulating the expression of CDK1 and cyclin B1. Moreover, the HSA complex promotes MCF-7 cell apoptosis possibly through the intrinsic reactive oxygen species (ROS) mediated mitochondrial pathway, accompanied by the regulation of Bcl-2 family proteins.

Native State Mass Spectrometry, Surface Plasmon Resonance, and X-ray Crystallography Correlate Strongly as a Fragment Screening Combination.

PubMed

Woods, Lucy A; Dolezal, Olan; Ren, Bin; Ryan, John H; Peat, Thomas S; Poulsen, Sally-Ann

2016-03-10

Fragment-based drug discovery (FBDD) is contingent on the development of analytical methods to identify weak protein-fragment noncovalent interactions. Herein we have combined an underutilized fragment screening method, native state mass spectrometry, together with two proven and popular fragment screening methods, surface plasmon resonance and X-ray crystallography, in a fragment screening campaign against human carbonic anhydrase II (CA II). In an initial fragment screen against a 720-member fragment library (the "CSIRO Fragment Library") seven CA II binding fragments, including a selection of nonclassical CA II binding chemotypes, were identified. A further 70 compounds that comprised the initial hit chemotypes were subsequently sourced from the full CSIRO compound collection and screened. The fragment results were extremely well correlated across the three methods. Our findings demonstrate that there is a tremendous opportunity to apply native state mass spectrometry as a complementary fragment screening method to accelerate drug discovery.

Factors associated with failure of oncology drugs in late-stage clinical development: A systematic review.

PubMed

Jardim, Denis L; Groves, Eric S; Breitfeld, Philip P; Kurzrock, Razelle

2017-01-01

We aimed to describe the reasons for failure of experimental anticancer drugs in late-stage clinical development. We searched the PharmaProjects database (https://citeline.com/products/pharmaprojects/) for anticancer drugs discontinued between 01/01/2009 and 06/30/2014. Drug programs that reached phase III trials, but never gained Food and Drug Administration (FDA) approval were compared to 37 anti-cancer drugs achieving FDA approval in this time period. Forty-two drugs fit our criteria for development failures. These failed drugs (49% targeted, 23% cytotoxics, and 28% other) were tested in 43 cancer indications (drug programs). Only 16% (7/43) of failed drug programs adopted a biomarker-driven rationale for patient selection versus 57% (21/37) of successful drug programs (P<0.001). Phase II trial information was available in 32 of 43 failed drug programs and in 32 of 37 successful programs. Nine of the 32 trials (28%) of failed drugs versus 28 of 32 trials (87%) of successful drugs (P<0.001) achieved proof of concept (single agent response rate (RR) ⩾20% or combination therapy showing a ⩾20% RR increase above the median historical RR without the experimental agent (with a minimal absolute increase of 5%) or a randomized phase II trial showing significance (P⩽0.05) for its primary outcome). No pattern of study sites, trial design or funding characteristics emerged from the failed drug analysis. For drugs that reached Phase III, lack of a biomarker-driven strategy and failure to attain proof of concept in phase II are potential risk factors for later discontinuation, especially for targeted agents. Copyright © 2016 Elsevier Ltd. All rights reserved.

Computer simulations for bioequivalence trials: Selection of analyte in BCS class II and IV drugs with first-pass metabolism, two metabolic pathways and intestinal efflux transporter.

PubMed

Mangas-Sanjuan, Victor; Navarro-Fontestad, Carmen; García-Arieta, Alfredo; Trocóniz, Iñaki F; Bermejo, Marival

2018-05-30

A semi-physiological two compartment pharmacokinetic model with two active metabolites (primary (PM) and secondary metabolites (SM)) with saturable and non-saturable pre-systemic efflux transporter, intestinal and hepatic metabolism has been developed. The aim of this work is to explore in several scenarios which analyte (parent drug or any of the metabolites) is the most sensitive to changes in drug product performance (i.e. differences in in vivo dissolution) and to make recommendations based on the simulations outcome. A total of 128 scenarios (2 Biopharmaceutics Classification System (BCS) drug types, 2 levels of K M Pgp , in 4 metabolic scenarios at 2 dose levels in 4 quality levels of the drug product) were simulated for BCS class II and IV drugs. Monte Carlo simulations of all bioequivalence studies were performed in NONMEM 7.3. Results showed the parent drug (PD) was the most sensitive analyte for bioequivalence trials in all the studied scenarios. PM and SM revealed less or the same sensitivity to detect differences in pharmaceutical quality as the PD. Another relevant result is that mean point estimate of C max and AUC methodology from Monte Carlo simulations allows to select more accurately the most sensitive analyte compared to the criterion on the percentage of failed or successful BE studies, even for metabolites which frequently show greater variability than PD. Copyright © 2018 Elsevier B.V. All rights reserved.

21 CFR 333.350 - Labeling of acne drug products.

Code of Federal Regulations, 2014 CFR

2014-04-01

... allows skin to heal.” (ii) “Penetrates pores to” (select one of the following: “eliminate most,” “control... pimples,” “blackheads,” or “whiteheads”). (iii) “Helps keep skin clear of new” (select one or more of the... labeling states “When using this product [bullet] skin irritation and dryness is more likely to occur if...

21 CFR 333.350 - Labeling of acne drug products.

Code of Federal Regulations, 2013 CFR

2013-04-01

... allows skin to heal.” (ii) “Penetrates pores to” (select one of the following: “eliminate most,” “control... pimples,” “blackheads,” or “whiteheads”). (iii) “Helps keep skin clear of new” (select one or more of the... labeling states “When using this product [bullet] skin irritation and dryness is more likely to occur if...

21 CFR 333.350 - Labeling of acne drug products.

Code of Federal Regulations, 2012 CFR

2012-04-01

... allows skin to heal.” (ii) “Penetrates pores to” (select one of the following: “eliminate most,” “control... pimples,” “blackheads,” or “whiteheads”). (iii) “Helps keep skin clear of new” (select one or more of the... labeling states “When using this product [bullet] skin irritation and dryness is more likely to occur if...

Nebivolol and valsartan as a fixed-dose combination for the treatment of hypertension.

PubMed

Sander, Gary E; Giles, Thomas D

2015-04-01

The fixed-dose combination of nebivolol and valsartan drug has been clinically evaluated and demonstrated to represent a unique combination of nebivolol, a selective β1-adrenoceptor antagonist and a β3-adrenoceptor agonist; β3 receptor activation increases endothelial nitric oxide and produces vasodilation. Valsartan is highly selective angiotensin AT1 receptor blocker and exerts its major pharmacological effect by decreasing angiotensin II-induced vasoconstriction and production of aldosterone. The addition of nebivolol counteracts the effects of increased angiotensin II concentrations resulting from potent AT1 blockade. This review describes a recently completed trial establishing the efficacy of the nebivolol/valsartan combination. This review provides a literature search of pertinent pharmacological and clinical data that describes the mechanisms of both drugs individually and the results of a clinical trial comparing fixed-dose combinations of nebivolol with valsartan as compared with each drug as monotherapy. Fixed-dose combination drugs are intended to improve patient compliance and reduce drug costs, as well as to reduce long-term cardiovascular event rates and block counter-regulatory effects due to monotherapy. The vast majority of hypertensive patients will require at least two medications. We believe that the clinical evidence suggests that the combination of nebivolol with valsartan offers a definite clinical benefit, combining β1-adrenoceptor and angiotensin AT1 receptor blockade with β3 receptor activation and resultant increase in nitric oxide and vasodilation.

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

PubMed

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

2012-10-01

The FDA Biopharmaceutical Classification System guidance allows waivers for in vivo bioavailability and bioequivalence studies for immediate-release solid oral dosage forms only for BCS class I. Extensions of the in vivo biowaiver for a number of drugs in BCS class III and BCS class II have been proposed, in particular, BCS class II weak acids. However, a discrepancy between the in vivo BE results and in vitro dissolution results for BCS class II acids was recently observed. The objectives of this study were to determine the oral absorption of BCS class II weak acids via simulation software and to determine if the in vitro dissolution test with various dissolution media could be sufficient for in vitro bioequivalence studies of ibuprofen and ketoprofen as models of carboxylic acid drugs. The oral absorption of these BCS class II acids from the gastrointestinal tract was predicted by GastroPlus™. Ibuprofen did not satisfy the bioequivalence criteria at lower settings of intestinal pH of 6.0. Further the experimental dissolution of ibuprofen tablets in a low concentration phosphate buffer at pH 6.0 (the average buffer capacity 2.2 mmol l (-1) /pH) was dramatically reduced compared with the dissolution in SIF (the average buffer capacity 12.6 mmol l (-1) /pH). Thus these predictions for the oral absorption of BCS class II acids indicate that the absorption patterns depend largely on the intestinal pH and buffer strength and must be considered carefully for a bioequivalence test. Simulation software may be a very useful tool to aid the selection of dissolution media that may be useful in setting an in vitro bioequivalence dissolution standard. Copyright © 2012 John Wiley & Sons, Ltd.

In Silico Prediction of Drug Dissolution and Absorption with variation in Intestinal pH for BCS Class II Weak Acid Drugs: Ibuprofen and Ketoprofen§

PubMed Central

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

2012-01-01

The FDA Biopharmaceutical Classification System guidance allows waivers for in vivo bioavailability and bioequivalence studies for immediate-release solid oral dosage forms only for BCS class I. Extensions of the in vivo biowaiver for a number of drugs in BCS Class III and BCS class II have been proposed, particularly, BCS class II weak acids. However, a discrepancy between the in vivo- BE results and in vitro- dissolution results for a BCS class II acids was recently observed. The objectives of this study were to determine the oral absorption of BCS class II weak acids via simulation software and to determine if the in vitro dissolution test with various dissolution media could be sufficient for in vitro bioequivalence studies of ibuprofen and ketoprofen as models of carboxylic acid drugs. The oral absorption of these BCS class II acids from the gastrointestinal tract was predicted by GastroPlus™. Ibuprofen did not satisfy the bioequivalence criteria at lower settings of intestinal pH=6.0. Further the experimental dissolution of ibuprofen tablets in the low concentration phosphate buffer at pH 6.0 (the average buffer capacity 2.2 mmol L-1/pH) was dramatically reduced compared to the dissolution in SIF (the average buffer capacity 12.6 mmol L -1/pH). Thus these predictions for oral absorption of BCS class II acids indicate that the absorption patterns largely depend on the intestinal pH and buffer strength and must be carefully considered for a bioequivalence test. Simulation software may be very useful tool to aid the selection of dissolution media that may be useful in setting an in vitro bioequivalence dissolution standard. PMID:22815122

Modified multiple drug resistance phenotype of Chinese hamster ovary cells selected with X-rays and vincristine versus X-rays only.

PubMed Central

McClean, S.; Hill, B. T.

1994-01-01

Exposure of Chinese hamster ovary (CHO) cells to fractionated X-irradiation [ten fractions of 9 Gray (Gy)] resulted in the expression of a multiple drug resistance phenotype which was distinct from that of drug-selected cells in two features: (i) resistance to vinca alkaloids and epipodophyllotoxins but sensitivity to anthracyclines was retained; (ii) overexpression of P-glycoprotein (Pgp) but regulated by post-translational stability rather than by any elevation in Pgp mRNA (Hill et al., 1990). It was also reported that when these cells (designated DXR-10) were subsequently exposed to another ten fractions of 9 Gy (20 x 9 Gy in total), no further increases in drug resistance or in the extent of Pgp expression were observed. To examine this apparent plateauing of the drug resistance phenotype following X-ray pretreatment, DXR-10 cells were instead treated with ten pulsed vincristine exposures. The resultant cell line, designated DXR-10/VCR-10, proved to be more resistant to vincristine, implying that the effect of further drug selection was additive to that of X-ray pretreatment. In addition, these cells showed resistance to doxorubicin and increased Pgp expression which was matched by a concomitant elevation in Pgp mRNA. These findings appear to confirm that Pgp expression is differentially regulated in tumour cells showing drug resistance after drug as opposed to X-ray selection. Images Figure 2 Figure 3 Figure 5 PMID:7908216

Novel potentiometric application for the determination of pantoprazole sodium and itopride hydrochloride in their pure and combined dosage form.

PubMed

Ragab, Mona T; Abd El-Rahman, Mohamed K; Ramadan, Nesrin K; El-Ragehy, Nariman A; El-Zeany, Badr A

2015-06-01

Three sensitive and selective polyvinyl chloride (PVC) matrix membrane electrodes were developed and investigated. Sensor I was developed using tetraheptylammonium bromide (THB) as an anion exchanger with 2-nitrophenyl octyl ether (2-NPOE) as a plasticizer for the determination of the anionic drug pantoprazole sodium sesquihydrate (PAN). To determine the cationic drug itopride hydrochloride (ITH), two electrodes (sensors II and III) were developed using potassium tetrakis(4-chlorophenyl) borate (KTCPB) as a cation exchanger with dioctyl phthalate (DOP) as a plasticizer. Selective molecular recognition components, 2-hydroxypropyl-β-cyclodextrin (2-HP βCD) and 4-tert-butylcalix[8]arene (tBC8), were used as ionophores to improve the selectivity of sensors II and III, respectively. The proposed sensors had a linear dynamic range of 1×10(-5) to 1×10(-2) mol L(-1) with Nernstian slopes of -54.83±0.451, 56.90±0.300, and 51.03±1.909 mV/decade for sensors I, II and III, respectively. The Nernstian slopes were also estimated over the pH ranges of 11-13, 3.5-8 and 4-7 for the three sensors, respectively. The proposed sensors displayed useful analytical characteristics for the determination of PAN and ITH in bulk powder, in laboratory prepared mixtures and in combined dosage forms with clear discrimination from several ions, sugars and some common drug excipients. The method was validated according to ICH guidelines. Statistical comparison between the results from the proposed method and the results from the reference methods showed no significant difference regarding accuracy and precision. Copyright © 2015 Elsevier B.V. All rights reserved.

Synthesis and biological evaluation of novel aromatic and heterocyclic bis-sulfonamide Schiff bases as carbonic anhydrase I, II, VII and IX inhibitors.

PubMed

Akocak, Suleyman; Lolak, Nabih; Nocentini, Alessio; Karakoc, Gulcin; Tufan, Anzel; Supuran, Claudiu T

2017-06-15

A series of sixteen novel aromatic and heterocyclic bis-sulfonamide Schiff bases were prepared by conjugation of well known aromatic and heterocyclic aminosulfonamide carbonic anhydrase (CA, EC 4.2.1.1) inhibitor pharmacophores with aromatic and heterocyclic bis-aldehydes. The obtained bis-sulfonamide Schiff bases were investigated as inhibitors of four selected human (h) CA isoforms, hCA I, hCA II, hCA VII and hCA IX. Most of the newly synthesized compounds showed a good inhibitory profile against isoforms hCA II and hCA IX, also showing moderate selectivity against hCA I and VII. Several efficient lead compounds were identified among this bis-sulfonamide Schiff bases with low nanomolar to sub-nanomolar activity against hCA II (K i s ranging between 0.4 and 861.1nM) and IX (K i s between 0.5 and 933.6nM). Since hCA II and hCA IX are important drug targets (antiglaucoma and anti-tumor agents), these isoform-selective inhibitors may be considered of interest for various biomedical applications. Copyright © 2017 Elsevier Ltd. All rights reserved.

Identification of FDA-approved oncology drugs with selective potency in high-risk childhood ependymoma.

PubMed

Donson, Andrew M; Amani, Vladimir; Warner, Elliot A; Griesinger, Andrea M; Witt, Davis A; Mulcahy Levy, Jean M; Hoffman, Lindsey M; Hankinson, Todd C; Handler, Michael H; Vibhakar, Rajeev; Dorris, Kathleen; Foreman, Nicholas K

2018-06-20

Children with ependymoma are cured in less than 50% of cases, with little improvement in outcome over the last several decades. Chemotherapy has not impacted survival in ependymoma, due in part to a lack of preclinical models that has precluded comprehensive drug testing. We recently developed two human ependymoma cell lines harboring high-risk phenotypes which provided us with an opportunity to execute translational studies. ependymoma and other pediatric brain tumor cell lines were subject to a large-scale comparative drug screen of ependymoma -approved oncology drugs for rapid clinical application. The results of this in vitro study were combined with in silico prediction of drug sensitivity to identify ependymoma -selective compounds, which were validated by dose curve and time course modelling. Mechanisms of ependymoma -selective antitumor effect were further investigated using transcriptome and proteome analyses. We identified three classes of oncology drugs that showed ependymoma -selective anti-tumor effect, namely (i) fluorinated pyrimidines (5-fluorouracil, carmofur and floxuridine), (ii) retinoids (bexarotene, tretinoin and isotretinoin), and (iii) a subset of small-molecule multi-receptor tyrosine kinase inhibitors (axitinib, imatinib and pazopanib). Axitinib's anti-tumor mechanism in ependymoma cell lines involved inhibition of PDGFR-alpha and PDGFR-beta and was associated with reduced mitosis-related gene expression and cellular senescence. The clinically available, ependymoma -selective oncology drugs identified by our study have the potential to critically inform design of upcoming clinical studies in ependymoma, in particular for those children with recurrent ependymoma who are in the greatest need of novel therapeutic approaches. Copyright ©2018, American Association for Cancer Research.

Antimalarial drug resistance: a review of the biology and strategies to delay emergence and spread.

PubMed

Klein, E Y

2013-04-01

The emergence of resistance to former first-line antimalarial drugs has been an unmitigated disaster. In recent years, artemisinin class drugs have become standard and they are considered an essential tool for helping to eradicate the disease. However, their ability to reduce morbidity and mortality and to slow transmission requires the maintenance of effectiveness. Recently, an artemisinin delayed-clearance phenotype was described. This is believed to be the precursor to resistance and threatens local elimination and global eradication plans. Understanding how resistance emerges and spreads is important for developing strategies to contain its spread. Resistance is the result of two processes: (i) drug selection of resistant parasites; and (ii) the spread of resistance. In this review, we examine the factors that lead to both drug selection and the spread of resistance. We then examine strategies for controlling the spread of resistance, pointing out the complexities and deficiencies in predicting how resistance will spread. Copyright © 2013 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.

Selective, retrieval-independent disruption of methamphetamine-associated memory by actin depolymerization.

PubMed

Young, Erica J; Aceti, Massimiliano; Griggs, Erica M; Fuchs, Rita A; Zigmond, Zachary; Rumbaugh, Gavin; Miller, Courtney A

2014-01-15

Memories associated with drugs of abuse, such as methamphetamine (METH), increase relapse vulnerability to substance use disorder. There is a growing consensus that memory is supported by structural and functional plasticity driven by F-actin polymerization in postsynaptic dendritic spines at excitatory synapses. However, the mechanisms responsible for the long-term maintenance of memories, after consolidation has occurred, are largely unknown. Conditioned place preference (n = 112) and context-induced reinstatement of self-administration (n = 19) were used to assess the role of F-actin polymerization and myosin II, a molecular motor that drives memory-promoting dendritic spine actin polymerization, in the maintenance of METH-associated memories and related structural plasticity. Memories formed through association with METH but not associations with foot shock or food reward were disrupted by a highly-specific actin cycling inhibitor when infused into the amygdala during the postconsolidation maintenance phase. This selective effect of depolymerization on METH-associated memory was immediate, persistent, and did not depend upon retrieval or strength of the association. Inhibition of non-muscle myosin II also resulted in a disruption of METH-associated memory. Thus, drug-associated memories seem to be actively maintained by a unique form of cycling F-actin driven by myosin II. This finding provides a potential therapeutic approach for the selective treatment of unwanted memories associated with psychiatric disorders that is both selective and does not rely on retrieval of the memory. The results further suggest that memory maintenance depends upon the preservation of polymerized actin. Copyright © 2014 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

New anticancer drug candidates sulfonamides as selective hCA IX or hCA XII inhibitors.

PubMed

Gul, Halise Inci; Yamali, Cem; Sakagami, Hiroshi; Angeli, Andrea; Leitans, Janis; Kazaks, Andris; Tars, Kaspars; Ozgun, Dilan Ozmen; Supuran, Claudiu T

2018-04-01

In this study, new 4-[3-(aryl)-5-substitutedphenyl-4,5-dihydro-1H-pyrazole-1-yl]benzensulfonamides (19-36) were synthesized and evaluated their cytotoxic/anticancer and CA inhibitory effects. According to results obtained, the compounds 34 (4-[5-(2,3,4-trimethoxyphenyl)-3-(thiophen-2-yl)-4,5-dihydro-1H-pyrazole-1-yl] benzensulfonamide, Potency-Selectivity Expression (PSE) = 141) and 36 (4-[5-(3,4,5-trimethoxyphenyl)-3-(thiophen-2-yl)-4,5-dihydro-1H-pyrazole-1-yl]benzensulfonamide, PSE = 54.5) were found the leader anticancer compounds with the highest PSE values. In CA inhibitory studies, the compounds 36 and 24 (4-[5-(3,4,5-trimethoxyphenyl)-3-(4-fluorophenyl)-4,5-dihydro-1H-pyrazole-1-yl]benzensulfonamide) were found the leader CA inhibitors depending on selectivity ratios. The compound 36 was a selective inhibitor of hCA XII isoenzyme (hCA I/hCA XII = 1250 and hCA II/hCA XII = 224) while the compound 24 was a selective inhibitor of hCA IX isoenzyme (hCA I/hCA IX = 161 and hCA II/hCA IX = 177). The compounds 24, 34, and 36 can be considered to develop new anticancer drug candidates. Copyright © 2018 Elsevier Inc. All rights reserved.

Imaging dynamic and selective low-complexity domain interactions that control gene transcription.

PubMed

Chong, Shasha; Dugast-Darzacq, Claire; Liu, Zhe; Dong, Peng; Dailey, Gina M; Cattoglio, Claudia; Heckert, Alec; Banala, Sambashiva; Lavis, Luke; Darzacq, Xavier; Tjian, Robert

2018-06-21

Many eukaryotic transcription factors (TFs) contain intrinsically disordered low-complexity domains (LCDs), but how they drive transactivation remains unclear. Here, live-cell single-molecule imaging reveals that TF-LCDs form local high-concentration interaction hubs at synthetic and endogenous genomic loci. TF-LCD hubs stabilize DNA binding, recruit RNA polymerase II (Pol II), and activate transcription. LCD-LCD interactions within hubs are highly dynamic, display selectivity with binding partners, and are differentially sensitive to disruption by hexanediols. Under physiological conditions, rapid and reversible LCD-LCD interactions occur between TFs and the Pol II machinery without detectable phase separation. Our findings reveal fundamental mechanisms underpinning transcriptional control and suggest a framework for developing single-molecule imaging screens for novel drugs targeting gene regulatory interactions implicated in disease. Copyright © 2018, American Association for the Advancement of Science.

Cytotoxicity and inhibitory properties against topoisomerase II of doxorubicin and its formamidine derivatives.

PubMed

Kik, Krzysztof; Studzian, Kazimierz; Wasowska-Łukawska, Małgorzata; Oszczapowicz, Irena; Szmigiero, Leszek

2009-01-01

This work was undertaken to compare cytotoxicity, DNA damaging properties and effect on DNA cleavage by topoisomerase II of the anthracycline drug doxorubicin (DOX) and its two derivatives with a formamidino group containing a cyclic amine moiety such as morpholine (DOXM) or hexamethyleneimine (DOXH). The tetrazolium dye colorimetric assay was used to determine the cytotoxic activity of anthracyclines toward L1210 leukemia cells. DNA damage was measured by alkaline elution technique. The effect of anthracyclines on DNA cleavage was studied in a cell-free system containing supercoiled pBR322 DNA and purified human topoisomerase II. The cytotoxicity data and the results of studies on the mechanism of DNA break formation by anthracyclines at the cellular level and in the cell-free system showed that the presence of the formamidino group in the doxorubicin molecule reduced its ability to stimulate DNA cleavage by DNA topoisomerase II. DNA topoisomerase II is not a primary cellular target for DOXM or DOXH. An advantageous feature of formamidinoanthracyclines is their mechanism of cytotoxic action which is not related to the inhibition of DNA topoisomerase II. Therefore this class of anthracyclines seems to be a good source for selection of an anticancer drug directed toward cancer cells with the developed multidrug resistance attributed to the presence of altered DNA topoisomerase II.

Rule of five in 2015 and beyond: Target and ligand structural limitations, ligand chemistry structure and drug discovery project decisions.

PubMed

Lipinski, Christopher A

2016-06-01

The rule of five (Ro5), based on physicochemical profiles of phase II drugs, is consistent with structural limitations in protein targets and the drug target ligands. Three of four parameters in Ro5 are fundamental to the structure of both target and drug binding sites. The chemical structure of the drug ligand depends on the ligand chemistry and design philosophy. Two extremes of chemical structure and design philosophy exist; ligands constructed in the medicinal chemistry synthesis laboratory without input from natural selection and natural product (NP) metabolites biosynthesized based on evolutionary selection. Exceptions to Ro5 are found mostly among NPs. Chemistry chameleon-like behavior of some NPs due to intra-molecular hydrogen bonding as exemplified by cyclosporine A is a strong contributor to NP Ro5 outliers. The fragment derived, drug Navitoclax is an example of the extensive expertise, resources, time and key decisions required for the rare discovery of a non-NP Ro5 outlier. Copyright © 2016 Elsevier B.V. All rights reserved.

Optimal dose selection accounting for patient subpopulations in a randomized Phase II trial to maximize the success probability of a subsequent Phase III trial.

PubMed

Takahashi, Fumihiro; Morita, Satoshi

2018-02-08

Phase II clinical trials are conducted to determine the optimal dose of the study drug for use in Phase III clinical trials while also balancing efficacy and safety. In conducting these trials, it may be important to consider subpopulations of patients grouped by background factors such as drug metabolism and kidney and liver function. Determining the optimal dose, as well as maximizing the effectiveness of the study drug by analyzing patient subpopulations, requires a complex decision-making process. In extreme cases, drug development has to be terminated due to inadequate efficacy or severe toxicity. Such a decision may be based on a particular subpopulation. We propose a Bayesian utility approach (BUART) to randomized Phase II clinical trials which uses a first-order bivariate normal dynamic linear model for efficacy and safety in order to determine the optimal dose and study population in a subsequent Phase III clinical trial. We carried out a simulation study under a wide range of clinical scenarios to evaluate the performance of the proposed method in comparison with a conventional method separately analyzing efficacy and safety in each patient population. The proposed method showed more favorable operating characteristics in determining the optimal population and dose.

Occult nodal metastasis in solid carcinomata

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

Moloy, P.J.; Nicolson, G.L.

1987-01-01

This book contains 23 selections. Some of the titles are: Rationale for radiotherapy in subclinical nodal disease; rationale of chemotherapy for nodal disease: The stabilization of topoisomerase II-DNA complexes as a mechanism of antineoplastic drug action; magnetic resonance imaging of malignant cervical adenopathy; and local and regional immune function in cancer patients.

Molecular recognition and regulation of human angiotensin-I converting enzyme (ACE) activity by natural inhibitory peptides

PubMed Central

Masuyer, Geoffrey; Schwager, Sylva L. U.; Sturrock, Edward D.; Isaac, R. Elwyn; Acharya, K. Ravi

2012-01-01

Angiotensin-I converting enzyme (ACE), a two-domain dipeptidylcarboxypeptidase, is a key regulator of blood pressure as a result of its critical role in the renin-angiotensin-aldosterone and kallikrein-kinin systems. Hence it is an important drug target in the treatment of cardiovascular diseases. ACE is primarily known for its ability to cleave angiotensin I (Ang I) to the vasoactive octapeptide angiotensin II (Ang II), but is also able to cleave a number of other substrates including the vasodilator bradykinin and N-acetyl-Ser-Asp-Lys-Pro (Ac-SDKP), a physiological modulator of hematopoiesis. For the first time we provide a detailed biochemical and structural basis for the domain selectivity of the natural peptide inhibitors of ACE, bradykinin potentiating peptide b and Ang II. Moreover, Ang II showed selective competitive inhibition of the carboxy-terminal domain of human somatic ACE providing evidence for a regulatory role in the human renin-angiotensin system (RAS). PMID:23056909

Synthesis of sulfadimethoxine based surfactants and their evaluation as antitumor agents.

PubMed

Khowdiary, Manal Mohmed; Mostafa, Nashwa S

2016-01-01

Synthesized CO (II) and Pt (II) of sulfadimethoxine. These compounds were tested for potential antitumor activity against two of human tumor cell lines, colon carcinoma cell line [Hct116], and breast carcinoma cell line MCF7. The structures of the resulting compounds have been investigated by elemental, FT-IR and H 1 NMR analyzes to insure the purity and confirmed the structures of them. The surface properties studies and octanol/water partition coefficients, Po/w were measured. The synthesized compounds exhibit biological activities with the lowest log Po/w and critical micelle concentration (CMC) values. In addition, in this article we provide an insight into this subject in order to increase the drug bioavailability. Inhibitory activity against colon carcinoma cells was detected for Pt and cobalt ion complex with IC50 = 4.5, 2.2 µg and against breast carcinoma cells IC50 = 18.2, 5.7 µg, respectively. The main goal of cancer therapy is to attain the maximum therapeutic damage of tumor cells in combination with a minimum concentration of the drug. This can be achieved in principle via selective antitumor preparations, the cytostatic effects of which would be restricted within tumor tissue. While 100% selectivity may be impractical, the achievement of reasonably high selectivity seems to be a feasible aim. Platinum and cobalt complex surfactants in our research affect tumor tissue at a very low concentration at values lower than their CMC values; this indicate that the sulfadimethoxine complexes merit further investigation as potential antitumor drugs.

Sequence-selective encapsulation and protection of long peptides by a self-assembled FeII8L6 cubic cage

NASA Astrophysics Data System (ADS)

Mosquera, Jesús; Szyszko, Bartosz; Ho, Sarah K. Y.; Nitschke, Jonathan R.

2017-03-01

Self-assembly offers a general strategy for the preparation of large, hollow high-symmetry structures. Although biological capsules, such as virus capsids, are capable of selectively recognizing complex cargoes, synthetic encapsulants have lacked the capability to specifically bind large and complex biomolecules. Here we describe a cubic host obtained from the self-assembly of FeII and a zinc-porphyrin-containing ligand. This cubic cage is flexible and compatible with aqueous media. Its selectivity of encapsulation is driven by the coordination of guest functional groups to the zinc porphyrins. This new host thus specifically encapsulates guests incorporating imidazole and thiazole moieties, including drugs and peptides. Once encapsulated, the reactivity of a peptide is dramatically altered: encapsulated peptides are protected from trypsin hydrolysis, whereas physicochemically similar peptides that do not bind are cleaved.

Two spectrophotometric methods for simultaneous determination of some antihyperlipidemic drugs

PubMed Central

Abdelwahab, Nada S.; El-Zeiny, Badr A.; Tohamy, Salwa I.

2012-01-01

Two simple, accurate, precise and economic spectrophotometric methods have been developed for simultaneous determination of Atorvastatin calcium (ATR) and Ezetimibe (EZ) in their bulk powder and pharmaceutical dosage form. Method (I) is based on dual wavelength analysis while method (II) is the mean centering of ratio spectra spectrophotometric (MCR) method. In method (I), two wavelengths were selected for each drug in such a way that the difference in absorbance was zero for the second drug. At wavelengths 226.6 and 244 nm EZ had equal absorbance values; therefore, these two wavelengths have been used to determine ATR; on a similar basis 228.6 and 262.8 nm were selected to determine EZ in their binary mixtures. In method II, the absorption spectra of both ATR and EZ with different concentrations were recorded over the range 200–350, divided by the spectrum of suitable divisor of both ATR and EZ and then the obtained ratio spectra were mean centered. The concentrations of active components were then determined from the calibration graphs obtained by measuring the amplitudes at 215–260 nm (peak to peak) for both ATR and EZ. Accuracy and precision of the developed methods have been tested; in addition recovery studies have been carried out in order to confirm their accuracy. On the other hand, selectivities of the methods were tested by application for determination of different synthetic mixtures containing different ratios of the studied drugs. The developed methods have been successfully used for determination of ATR and EZ in their combined dosage form and statistical comparison of the developed methods with the reported spectrophotometric one using F and Student's t-tests showed no significant difference regarding both accuracy and precision. PMID:29403754

Two spectrophotometric methods for simultaneous determination of some antihyperlipidemic drugs.

PubMed

Abdelwahab, Nada S; El-Zeiny, Badr A; Tohamy, Salwa I

2012-08-01

Two simple, accurate, precise and economic spectrophotometric methods have been developed for simultaneous determination of Atorvastatin calcium (ATR) and Ezetimibe (EZ) in their bulk powder and pharmaceutical dosage form. Method (I) is based on dual wavelength analysis while method (II) is the mean centering of ratio spectra spectrophotometric (MCR) method. In method (I), two wavelengths were selected for each drug in such a way that the difference in absorbance was zero for the second drug. At wavelengths 226.6 and 244 nm EZ had equal absorbance values; therefore, these two wavelengths have been used to determine ATR; on a similar basis 228.6 and 262.8 nm were selected to determine EZ in their binary mixtures. In method II, the absorption spectra of both ATR and EZ with different concentrations were recorded over the range 200-350, divided by the spectrum of suitable divisor of both ATR and EZ and then the obtained ratio spectra were mean centered. The concentrations of active components were then determined from the calibration graphs obtained by measuring the amplitudes at 215-260 nm (peak to peak) for both ATR and EZ. Accuracy and precision of the developed methods have been tested; in addition recovery studies have been carried out in order to confirm their accuracy. On the other hand, selectivities of the methods were tested by application for determination of different synthetic mixtures containing different ratios of the studied drugs. The developed methods have been successfully used for determination of ATR and EZ in their combined dosage form and statistical comparison of the developed methods with the reported spectrophotometric one using F and Student's t -tests showed no significant difference regarding both accuracy and precision.

Biocatalytic synthesis of 4-pregnen-20,21-diol-3-one, a selective inhibitor of human 5alpha-reductase type II.

PubMed

Hannemann, Frank; Bernhardt, Rita; Jose, Joachim

2007-10-01

Biocatalysis, the conversion of substrates into valuable products by the use of enzymes, has some striking advantages in comparison to standard organic chemistry for drug synthesis. By biocatalysis, substrates that contain several identical reactive groups at different positions can be converted with high regio-selectivity and enantio-selectivity. In this study, an E. coli isolate (E132) was identified which was able to convert the steroid desoxycorticosterone into the product 4-pregnen-20,21-diol-3-one in real terms. The product was purified from the cell culture supernatant by HPLC and its structure was demonstrated by mass spectrometry and NMR spectroscopy. It was tested on inhibition of human 5alpha-reductases type I and type II. At a concentration of 10 microM, inhibition was 49.0% for type I and 81.8% for type II, whereas there was no inhibition of human aromatase (CYP19) at 20 microM and human 17alpha-hydroxylase-C17,20-lyase (CYP17) at 2.5 microM detectable. The IC50 value of 4-pregnen-20,21-diol-3-one for human 5alpha-reductase type II was determined to be 1.56 microM.

Medulloblastoma in children and adolescents: a systematic review of contemporary phase I and II clinical trials and biology update.

PubMed

Bautista, Francisco; Fioravantti, Victoria; de Rojas, Teresa; Carceller, Fernando; Madero, Luis; Lassaletta, Alvaro; Moreno, Lucas

2017-11-01

Survival rates for patients with medulloblastoma have improved in the last decades but for those who relapse outcome is dismal and new approaches are needed. Emerging drugs have been tested in the last two decades within the context of phase I/II trials. In parallel, advances in genetic profiling have permitted to identify key molecular alterations for which new strategies are being developed. We performed a systematic review focused on the design and outcome of early-phase trials evaluating new agents in patients with relapsed medulloblastoma. PubMed, clinicaltrials.gov, and references from selected studies were screened to identify phase I/II studies with reported results between 2000 and 2015 including patients with medulloblastoma aged <18 years. A total of 718 studies were reviewed and 78 satisfied eligibility criteria. Of those, 69% were phase I; 31% phase II. Half evaluated conventional chemotherapeutics and 35% targeted agents. Overall, 662 patients with medulloblastoma/primitive neuroectodermal tumors were included. The study designs and the response assessments were heterogeneous, limiting the comparisons among trials and the correct identification of active drugs. Median (range) objective response rate (ORR) for patients with medulloblastoma in phase I/II studies was 0% (0-100) and 6.5% (0-50), respectively. Temozolomide containing regimens had a median ORR of 16.5% (0-100). Smoothened inhibitors trials had a median ORR of 8% (3-8). Novel drugs have shown limited activity against relapsed medulloblastoma. Temozolomide might serve as backbone for new combinations. Novel and more homogenous trial designs might facilitate the development of new drugs. © 2017 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Sucrose ester stabilized solid lipid nanoparticles and nanostructured lipid carriers. II. Evaluation of the imidazole antifungal drug-loaded nanoparticle dispersions and their gel formulations.

PubMed

Das, Surajit; Ng, Wai Kiong; Tan, Reginald B H

2014-03-14

This study focused on: (i) feasibility of the previously developed sucrose ester stabilized SLNs and NLCs to encapsulate different imidazole antifungal drugs and (ii) preparation and evaluation of topical gel formulations of those SLNs and NLCs. Three imidazole antifungal drugs; clotrimazole, ketoconazole and climbazole were selected for this study. The results suggested that size, size distribution and drug encapsulation efficiency depend on the drug molecule and type of nanoparticles (SLN/NLC). The drug release experiment always showed faster drug release from NLCs than SLNs when the same drug molecule was loaded in both nanoparticles. However, drug release rate from both SLNs and NLCs followed the order of climbazole > ketoconazole > clotrimazole. NLCs demonstrated better physicochemical stability than SLNs in the case of all drugs. The drug release rate from ketoconazole- and clotrimazole-loaded SLNs became faster after three months than a fresh formulation. There was no significant change in drug release rate from climbazole-loaded SLNs and all drug-loaded NLCs. Gel formulations of SLNs and NLCs were prepared using polycarbophil polymer. Continuous flow measurements demonstrated non-Newtonian flow with shear-thinning behavior and thixotropy. Oscillation measurements depicted viscoelasticity of the gel formulations. Similar to nanoparticle dispersion, drug release rate from SLN- and NLC-gel was in the order of climbazole > ketoconazole > clotrimazole. However, significantly slower drug release was noticed from all gel formulations than their nanoparticle counterparts. Unlike nanoparticle dispersions, no significant difference in drug release from gel formulations containing SLNs and NLCs was observed for each drug. This study concludes that gel formulation of imidazole drug-loaded SLNs and NLCs can be used for sustained/prolonged topical delivery of the drugs.

Chronopharmaceutical Drug Delivery Systems: Hurdles, Hype or Hope?⊗

PubMed Central

Youan, Bi-Botti C.

2010-01-01

The current advances in chronobiology and the knowledge gained from chronotherapy of selected diseases strongly suggest that “the one size fits all at all times” approach to drug delivery is no longer substantiated, at least for selected bioactive agents and disease therapy or prevention. Thus, there is a critical and urgent need for chronopharmaceutical research (e.g., design and evaluation of robust, spatially and temporally controlled drug delivery systems that would be clinically intended for chronotherapy by different routes of administration). This review provides a brief overview of current delivery system intended for chronotherapy. In theory, such an ideal “magic pill” preferably with affordable cost, would improve the safety, efficacy and patient compliance of old and new drugs. However, currently, there are three major hurdles for the successful transition of such system from laboratory to patient bedside. These include the challenges to identify adequate (i) rhythmic biomaterials and systems, (ii) rhythm engineering modeling, perhaps using system biology and (iii) regulatory guidance. PMID:20438781

Inhibitors of type II NADH:menaquinone oxidoreductase represent a class of antitubercular drugs

PubMed Central

Weinstein, Edward A.; Yano, Takahiro; Li, Lin-Sheng; Avarbock, David; Avarbock, Andrew; Helm, Douglas; McColm, Andrew A.; Duncan, Ken; Lonsdale, John T.; Rubin, Harvey

2005-01-01

Mycobacterium tuberculosis (Mtb) is an obligate aerobe that is capable of long-term persistence under conditions of low oxygen tension. Analysis of the Mtb genome predicts the existence of a branched aerobic respiratory chain terminating in a cytochrome bd system and a cytochrome aa3 system. Both chains can be initiated with type II NADH:menaquinone oxidoreductase. We present a detailed biochemical characterization of the aerobic respiratory chains from Mtb and show that phenothiazine analogs specifically inhibit NADH:menaquinone oxidoreductase activity. The emergence of drug-resistant strains of Mtb has prompted a search for antimycobacterial agents. Several phenothiazines analogs are highly tuberculocidal in vitro, suppress Mtb growth in a mouse model of acute infection, and represent lead compounds that may give rise to a class of selective antibiotics. PMID:15767566

Extending the scope of amantadine drug by incorporation of phenolic azo Schiff bases as potent selective inhibitors of carbonic anhydrase II, drug likeness and binding analysis.

PubMed

Channar, Pervaiz Ali; Saeed, Aamer; Shahzad, Danish; Larik, Fayaz Ali; Hassan, Mubashir; Raza, Hussain; Abbas, Qamar; Seo, Sung-Yum

2018-05-16

A series of Amantadine based azo Schiff base dyes 6a-6e have been synthesized and characterized by 1 H NMR and 13 C NMR and evaluated for their in vitro carbonic anhydrase II inhibition activity and antioxidant activity. All of the synthesized showed excellent carbonic inhibition. Compound 6b was found to be the most potent derivative in the series, the IC 50 of 6b was found to be 0.0849 ± 0.00245μM (standard Acetazolamide IC 50 =0.9975±0.049μM). The binding interactions of the most active analogs were confirmed through molecular docking studies. Docking studies showed 6b is interacting by making two hydrogen bonds w at His93 and Ser1 residues respectively. All compounds showed a good drug score and followed Lipinski's rule. In summary, our studies have shown that these amantadine derived phenolic azo Schiff base derivatives are a new class of carbonic anhydrase II inhibitors. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Phase I/II evaluation of RV1001, a novel PI3Kδ inhibitor, in spontaneous canine lymphoma.

PubMed

Gardner, Heather L; Rippy, Sarah B; Bear, Misty D; Cronin, Kim L; Heeb, Heather; Burr, Holly; Cannon, Claire M; Penmetsa, Kumar V; Viswanadha, Srikant; Vakkalanka, Swaroop; London, Cheryl A

2018-01-01

RV1001 is a novel, potent, and selective PI3Kδ inhibitor. The purpose of this study was to evaluate the safety and efficacy of RV1001 in canine Non-Hodgkin lymphoma (NHL). Inhibition of endogenous pAKT by RV1001 in primary canine NHL cells was determined by Western blotting. A phase I study of RV1001 was performed in 21 dogs with naïve and drug resistant T and B-cell NHL to assess safety, pharmacokinetic profile, and response to therapy. The objective response rate was 62% (complete response (CR) n = 3; partial response (PR) n = 10), and responses were observed in both naïve and chemotherapy-resistant B and T cell NHL. This study provided the recommended starting dose for a phase II, non-pivotal, exploratory, open label multi-centered clinical trial in 35 dogs with naïve and drug resistant T and B-cell NHL, to further define the efficacy and safety profile of RV1001. The objective response rate in the phase II study was 77% (CR n = 1; PR n = 26). Clinical toxicities were primarily hepatobiliary and gastrointestinal, and were responsive to dose modifications and/or temporary drug discontinuation. Hepatotoxicity was the primary dose limiting toxicity. RV1001 exhibits good oral bioavailability, an acceptable safety profile, and biologic activity with associated inhibition of pAKT in dogs with B and T cell NHL. Data from these studies can be leveraged to help inform the design of future studies involving isoform-selective PI3K inhibitors in humans.

Studies on Aspirin Crystals Generated by a Modified Vapor Diffusion Method.

PubMed

Mittal, Amit; Malhotra, Deepak; Jain, Preeti; Kalia, Anupama; Shunmugaperumal, Tamilvanan

2016-08-01

The objectives of the current investigation were (1) to study the influence of selected two different non-solvents (diethylether and dichloromethane) on the drug crystal formation of a model drug, aspirin (ASP-I) by the modified vapor diffusion method and (2) to characterize and compare the generated crystals (ASP-II and ASP-III) using different analytical techniques with that of unprocessed ASP-I. When compared to the classical vapor diffusion method which consumes about 15 days to generate drug crystals, the modified method needs only 12 h to get the same. Fourier transform-infrared spectroscopy (FT-IR) reveals that the internal structures of ASP-II and ASP-III crystals were identical when compared with ASP-I. Although the drug crystals showed a close similarity in X-ray diffraction patterns, the difference in the relative intensities of some of the diffraction peaks (especially at 2θ values of around 7.7 and 15.5) could be attributed to the crystal habit or crystal size modification. Similarly, the differential scanning calorimetry (DSC) study speculates that only the crystal habit modifications might occur but without involving any change in internal structure of the generated drug polymorphic form I. This is further substantiated from the scanning electron microscopy (SEM) pictures that indicated the formation of platy shape for the ASP-II crystals and needle shape for the ASP-III crystals. In addition, the observed slow dissolution of ASP crystals should indicate polymorph form I formation. Thus, the modified vapor diffusion method could routinely be used to screen and legally secure all possible forms of other drug entities too.

Polymeric hydrogels for novel contact lens-based ophthalmic drug delivery systems: a review.

PubMed

Xinming, Li; Yingde, Cui; Lloyd, Andrew W; Mikhalovsky, Sergey V; Sandeman, Susan R; Howel, Carol A; Liewen, Liao

2008-04-01

Only about 5% of drugs administrated by eye drops are bioavailable, and currently eye drops account for more than 90% of all ophthalmic formulations. The bioavailability of ophthalmic drugs can be improved by a soft contact lens-based ophthalmic drug delivery system. Several polymeric hydrogels have been investigated for soft contact lens-based ophthalmic drug delivery systems: (i) polymeric hydrogels for conventional contact lens to absorb and release ophthalmic drugs; (ii) polymeric hydrogels for piggyback contact lens combining with a drug plate or drug solution; (iii) surface-modified polymeric hydrogels to immobilize drugs on the surface of contact lenses; (iv) polymeric hydrogels for inclusion of drugs in a colloidal structure dispersed in the lens; (v) ion ligand-containing polymeric hydrogels; (vi) molecularly imprinted polymeric hydrogels which provide the contact lens with a high affinity and selectivity for a given drug. Polymeric hydrogels for these contact lens-based ophthalmic drug delivery systems, their advantages and drawbacks are critically analyzed in this review.

Engineering human T cells for resistance to methotrexate and mycophenolate mofetil as an in vivo cell selection strategy.

PubMed

Jonnalagadda, Mahesh; Brown, Christine E; Chang, Wen-Chung; Ostberg, Julie R; Forman, Stephen J; Jensen, Michael C

2013-01-01

Gene transfer and drug selection systems that enforce ongoing transgene expression in vitro and in vivo which are compatible with human pharmaceutical drugs are currently underdeveloped. Here, we report on the utility of incorporating human enzyme muteins that confer resistance to the lymphotoxic/immunosuppressive drugs methotrexate (MTX) and mycophenolate mofetil (MMF) in a multicistronic lentiviral vector for in vivo T lymphocyte selection. We found that co-expression of human dihydrofolate reductase (DHFR(FS); L22F, F31S) and inosine monophosphate dehydrogenase II (IMPDH2(IY); T333I, S351Y) conferred T cell resistance to the cytocidal and anti-proliferative effects of these drugs at concentrations that can be achieved clinically (up to 0.1 µM MTX and 1.0 µM MPA). Furthermore, using a immunodeficient mouse model that supports the engraftment of central memory derived human T cells, in vivo selection studies demonstrate that huEGFRt(+)DHFR(FS+)IMPDH2(IY+) T cells could be enriched following adoptive transfer either by systemic administration of MTX alone (4.4 -fold), MMF alone (2.9-fold), or combined MTX and MMF (4.9-fold). These findings demonstrate the utility of both DHFR(FS)/MTX and IMPDH2(IY)/MMF for in vivo selection of lentivirally transduced human T cells. Vectors incorporating these muteins in combination with other therapeutic transgenes may facilitate the selective engraftment of therapeutically active cells in recipients.

42 CFR 417.155 - How the HMO option must be included in the health benefits plan.

Code of Federal Regulations, 2011 CFR

2011-10-01

... HMO or of transfer from HMO to non-HMO coverage, or exclusions, or limitations based on health status... this selection, lose their eligibility for free-standing dental, optical, or prescription drug benefits... option.) - (ii) The non-HMO option provides free-standing coverage for optical services (such as...

Inhibition of human TDP2 by deazaflavins | Center for Cancer Research

Cancer.gov

Tyrosyl-DNA phosphodiesterase 2 repairs irreversible topoisomerase II-mediated cleavage complexes generated by anticancer topoisomerase-targeted drugs and processes replication intermediates for picornaviruses (VPg unlinkase) and hepatitis B virus. There is currently no TDP2 inhibitor in clinical development. Here, we report a series of deazaflavin derivatives that selectively

Dipeptides as effective prodrugs of the unnatural amino acid (+)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY354740), a selective group II metabotropic glutamate receptor agonist.

PubMed

Bueno, Ana Belén; Collado, Iván; de Dios, Alfonso; Domínguez, Carmen; Martín, José Alfredo; Martín, Luisa M; Martínez-Grau, María Angeles; Montero, Carlos; Pedregal, Concepción; Catlow, John; Coffey, D Scott; Clay, Michael P; Dantzig, Anne H; Lindstrom, Terry; Monn, James A; Jiang, Haiyan; Schoepp, Darryle D; Stratford, Robert E; Tabas, Linda B; Tizzano, Joseph P; Wright, Rebecca A; Herin, Marc F

2005-08-11

(+)-2-Aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (1), also known as LY354740, is a highly potent and selective agonist for group II metabotropic glutamate receptors (mGlu receptors 2 and 3) tested in clinical trials. It has been shown to block anxiety in the fear-potentiated startle model. Its relatively low bioavailability in different animal species drove the need for an effective prodrug form that would produce a therapeutic response at lower doses for the treatment of anxiety disorders. We have investigated the increase of intestinal absorption of this compound by targeting the human peptide transporter hPepT1 for active transport of di- and tripeptides derived from 1. We have found that oral administration of an N dipeptide derivative of 1 (12a) in rats shows up to an 8-fold increase in drug absorption and a 300-fold increase in potency in the fear-potentiated startle model in rats when compared with the parent drug 1.

Medication and monitoring in palliative sedation therapy: a systematic review and quality assessment of published guidelines.

PubMed

Schildmann, Eva Katharina; Schildmann, Jan; Kiesewetter, Isabel

2015-04-01

Palliative sedation therapy (PST) is increasingly used in patients at the end of life. However, consensus about medications and monitoring is lacking. To assess published PST guidelines with regard to quality and recommendations on drugs and monitoring. We searched CINAHL, the Cochrane Library, Embase, PsycINFO, PubMed, and references of included articles until July 2014. Search terms included "palliative sedation" or "sedation" and "guideline" or "policy" or "framework." Guideline selection was based on English or German publications that included a PST guideline. Two investigators independently assessed the quality of the guidelines according to the Appraisal of Guidelines for Research and Evaluation II instrument (AGREE II) and extracted information on drug selection and monitoring. Nine guidelines were eligible. Eight guidelines received high quality scores for the domain "scope and purpose" (median 69%, range 28-83%), whereas in the other domains the guidelines' quality differed considerably. The majority of guidelines suggest midazolam as drug of first choice. Recommendations on dosage and alternatives vary. The guidelines' recommendations regarding monitoring of PST show wide variation in the number and details of outcome parameters and methods of assessment. The published guidelines on PST vary considerably regarding their quality and content on drugs and monitoring. Given the need for clear guidance regarding PST in patients at the end of life, this comparative analysis may serve as a starting point for further improvement. Copyright © 2015 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.

Investigation of the effect of solubility increase at the main absorption site on bioavailability of BCS class II drug (risperidone) using liquisolid technique.

PubMed

Khames, Ahmed

2017-11-01

BCS class II drugs usually suffer inadequate bioavailability as dissolution step is the absorption rate limiting step. In this work, the effect of solubility increase at the main absorption site for these drugs was investigated using risperidone as a drug model. Liquisolid technique was applied to prepare risperidone per-oral tablets of high dissolution rate at intestinal pH (6.8) using versatile nonionic surfactants of high solubilizing ability [Transcutol HP, Labrasol and Labrasol/Labrafil (1:1) mixture] as liquid vehicles at different drug concentrations (10-30%) and fixed (R). The prepared liquisolid tablets were fully evaluated and the dissolution rate at pH 6.8 was investigated. The formulae that showed significantly different release rate were selected and subjected to mathematical modeling using DE 25 , MDT and similarity factor (f2). Depending on mathematical modeling results, formula of higher dissolution rate was subjected to solid state characterization using differential scanning calorimetric (DSC), infrared spectroscopy (IR) and X-ray diffraction (XRD). Finally, the drug bioavailability was studied in comparison to conventional tablets in rabbits. Results showed that liquisolid tablet prepared using Labrasol/Labrafil (1:1) mixture as liquid vehicle containing 10% risperidone is a compatible formula with law drug crystallinity and higher dissolution rate (100% in 25 min). The drug bioavailability was significantly increased in comparison to the conventional tablets (1441.711 μg h/mL and 137.518 μg/mL in comparison to 321.011 μg h/mL and 38.673 μg/mL for AUC and Cp max , respectively). This led to the conclusion that liquisolid technique was efficiently improved drug solubility and solubility increase of BCS class II drugs at their main absorption site significantly increases their bioavailability.

Binding ability of impromidine, a potent H2 agonist of histamine

NASA Astrophysics Data System (ADS)

Anouar, A.; Lhadi, E.; Decock, P.; Kozlowskyinst4, H.

1999-09-01

Impromidine (fig.1) is a potent and selective histamine H2 receptor agonist and its structure comprises a strongly basic guanidine group containing two different imidazole-containing side chains. The present work deals with the study of coordination equilibria between impromidine and Cu(II) and Ni(II) in aqueous solution at 25 circC. Potentiometric, UV-Visible and EPR studies on Cu(II) complexes with impromidine have shown that this anti-ulcerogenic drug is a very potent chelating agent. This drug is found to be a very effective ligand for Ni(II) ions also. The effective coordination of impromidine to metal ions may have significant biological implications. L'impromidine est un agoniste H2 de l'histamine, sa structure possède un groupement guanidinique de forte basicité et dont l'environne ment des deux groupements imidazoliques est différent. Le présent travail consiste en l'étude de la coordination de l'impromidine avec le Cu(II) et le Ni(II) en milieu aqueux à 25 circC. La potentiométrie, LíUV-Visible et la RPE montrent que le cuivre se coordine très fortement avec l'impromidine. Nous avons trouvé que ce médicament se coordine aussi fortement avec le nickel(II). La coordination de l'impromidine avec les métaux pourrait avoir des applications importantes en médecine.

Topoisomerase II Inhibitors and Poisons, and the Influence of Cell Cycle Checkpoints.

PubMed

D Arcy, Nicholas; Gabrielli, Brian

2017-01-01

Interactions between the decatenation checkpoint and Topoisomerase II (TopoII) are vital for maintaining integrity of the genome. Agents that target this enzyme have been in clinical use in cancer therapy for over 30 years with great success. The types of compounds that have been developed to target TopoII are broadly divided into poisons and catalytic inhibitors. The TopoII poisons are in clinical use as anti-cancer therapies, although in common to most chemotherapeutic agents, they display considerable normal tissue toxicity. Inhibition of the TopoIIb isoform has been implicated in this cytotoxicity. Response to TopoII active agents is determined by several factors, but cell cycle checkpoints play a large role in sensitivity and resistance. The G2/M phase checkpoints are of particular importance in considering the effectiveness of these drugs and are reviewed in this article. Functionality of the ATM dependent decatenation checkpoint may represent a new avenue for selective cancer therapy. Here we review the function of TopoII, the anti-cancer mechanisms and limitations of current catalytic inhibitors and poisons, and their influence on cell cycle checkpoints. We will also assess potential new mechanisms for targeting this enzyme to limit normal tissue toxicity, and how the cell cycle checkpoint triggered by these drugs may provide an alternative and possibly better target for novel therapies. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

The 'wise list'- a comprehensive concept to select, communicate and achieve adherence to recommendations of essential drugs in ambulatory care in Stockholm.

PubMed

Gustafsson, Lars L; Wettermark, Björn; Godman, Brian; Andersén-Karlsson, Eva; Bergman, Ulf; Hasselström, Jan; Hensjö, Lars-Olof; Hjemdahl, Paul; Jägre, Ingrid; Julander, Margaretha; Ringertz, Bo; Schmidt, Daniel; Sjöberg, Susan; Sjöqvist, Folke; Stiller, Carl-Olav; Törnqvist, Elisabeth; Tryselius, Rolf; Vitols, Sigurd; von Bahr, Christer

2011-04-01

The aim was to present and evaluate the impact of a comprehensive strategy over 10 years to select, communicate and achieve adherence to essential drug recommendations (EDR) in ambulatory care in a metropolitan healthcare region. EDRs were issued and launched as a 'Wise List' by the regional Drug and Therapeutics Committee in Stockholm. This study presents the concept by: (i) documenting the process for selecting, communicating and monitoring the impact of the 'Wise List'; (ii) analysing the variation in the number of drug substances recommended between 2000 and 2010; (iii) assessing the attitudes to the 'Wise List' among prescribers and the public; (iv) evaluating the adherence to recommendations between 2003 and 2009. The 'Wise List' consistently contained 200 drug substances for treating common diseases. The drugs were selected based on their efficacy, safety, suitability and cost-effectiveness. The 'Wise List' was known among one-third of a surveyed sample of the public in 2002 after initial marketing campaigns. All surveyed prescribers knew about the concept and 81% found the recommendations trustworthy in 2005. Adherence to recommendations increased from 69% in 1999 to 77% in 2009. In primary care, adherence increased from 83% to 87% from 2003 to 2009. The coefficient of variation (CV%) decreased from 6.1% to 3.8% for 156 healthcare centres between these years. The acceptance of the 'Wise List' in terms of trust among physicians and among the public and increased adherence may be explained by clear criteria for drug recommendations, a comprehensive communication strategy, electronic access to recommendations, continuous medical education and involvement of professional networks and patients.

Characterization of Selective Exosite-Binding Inhibitors of Matrix Metalloproteinase 13 That Prevent Articular Cartilage Degradation in Vitro

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

Spicer, Timothy P.; Jiang, Jianwen; Taylor, Alexander B.

Matrix metalloproteinase 13 (MMP-13) has been shown to be the main collagenase responsible for degradation of articular cartilage during osteoarthritis and therefore represents a target for drug development. Here, as a result of high-throughput screening and structure$-$activity relationship studies, we identified a novel, highly selective class of MMP-13 inhibitors (compounds 1 (Q), 2 (Q1), and 3 (Q2)). Mechanistic characterization revealed a noncompetitive nature of these inhibitors with binding constants in the low micromolar range. Crystallographic analyses revealed two binding modes for compound 2 in the MMP-13 S 1' subsite and in an S 1/S 2* subsite. Type II collagen- andmore » cartilage-protective effects exhibited by compounds 1, 2, and 3 suggested that these compounds might be efficacious in future in vivo studies. Lastly, these compounds were also highly selective when tested against a panel of 30 proteases, which, in combination with a good CYP inhibition profile, suggested low off-target toxicity and drug$-$drug interactions in humans.« less

Characterization of Selective Exosite-Binding Inhibitors of Matrix Metalloproteinase 13 That Prevent Articular Cartilage Degradation in Vitro

DOE PAGES

Spicer, Timothy P.; Jiang, Jianwen; Taylor, Alexander B.; ...

2014-10-20

Matrix metalloproteinase 13 (MMP-13) has been shown to be the main collagenase responsible for degradation of articular cartilage during osteoarthritis and therefore represents a target for drug development. Here, as a result of high-throughput screening and structure$-$activity relationship studies, we identified a novel, highly selective class of MMP-13 inhibitors (compounds 1 (Q), 2 (Q1), and 3 (Q2)). Mechanistic characterization revealed a noncompetitive nature of these inhibitors with binding constants in the low micromolar range. Crystallographic analyses revealed two binding modes for compound 2 in the MMP-13 S 1' subsite and in an S 1/S 2* subsite. Type II collagen- andmore » cartilage-protective effects exhibited by compounds 1, 2, and 3 suggested that these compounds might be efficacious in future in vivo studies. Lastly, these compounds were also highly selective when tested against a panel of 30 proteases, which, in combination with a good CYP inhibition profile, suggested low off-target toxicity and drug$-$drug interactions in humans.« less

Improving the quality of randomized controlled trials in Chinese herbal medicine, part II: control group design.

PubMed

Bian, Zhao-Xiang; Moher, David; Dagenais, Simon; Li, You-Ping; Liu, Liang; Wu, Tai-Xiang; Miao, Jiang-Xia

2006-03-01

To discuss the types of control groups in randomized controlled trials (RCTs) of Chinese herbal medicine (CHM), and to provide suggestions for improving the design of control group in future clinical studies in this therapeutic area. A search of the Cochrane Library was conducted in July 2005 to identify RCTs of CHM, and 66 RCTs with CHM for type 2 diabetes mellitus were obtained as the basis for further analysis. Of 66 RCTs with CHM for type 2 diabetes mellitus, 61 (92.4%) trials had both a treatment group and a control group. Twenty-seven (40.9%) RCTs compared CHM plus conventional drug vs conventional drug, 24 (36.4%) compared CHM vs conventional drug, 5 (7.6%) compared CHM vs placebo, 3 (4.5%) compared CHM plus conventional drug vs conventional drug plus placebo, 3 (4.5%) compared CHM plus conventional drug vs other CHM, 1 (1.5%) compared CHM vs no treatment, 1 (1.5%) compared CHM plus placebo vs conventional drug plus placebo, 1 (1.5%) compared CHM vs CHM plus conventional drug vs conventional drug vs placebo, and 1 (1.5%) compared CHM vs conventional drug vs CHM plus conventional drug. A variety of control groups were used in RCTs of CHM for type 2 diabetes mellitus, including placebo, active, and no treatment control groups. Justification for selecting particular types of control groups were not provided in the trials reviewed in this study. Different control groups may be appropriate according to the study objectives, and several factors should be considered prior to selecting control groups in future RCTs of CHM. (1) Investigators of CHM who design clinical trials should understand the rationale for selecting different types of control groups; (2) Control groups for RCTs should be selected according to study objectives; (3) Active control groups should select interventions for comparisons that have the strongest evidence of efficacy and prescribe them as recommended; (4) Placebo control groups should select a placebo that mimics the physical characteristics of test intervention as closely as possible and is completely inert; (5) No treatment control groups should only be used when withholding treatment is ethical and objectives outcomes will not be subject to bias due to absent blinding; (6) Crossover control groups may be appropriate in chronic and stable conditions.

42 CFR 417.155 - How the HMO option must be included in the health benefits plan.

Code of Federal Regulations, 2012 CFR

2012-10-01

... enrollment in the HMO or of transfer from HMO to non-HMO coverage, or exclusions, or limitations based on..., because of this selection, lose their eligibility for free-standing dental, optical, or prescription drug... option.) - (ii) The non-HMO option provides free-standing coverage for optical services (such as...

42 CFR 417.155 - How the HMO option must be included in the health benefits plan.

Code of Federal Regulations, 2013 CFR

2013-10-01

... enrollment in the HMO or of transfer from HMO to non-HMO coverage, or exclusions, or limitations based on..., because of this selection, lose their eligibility for free-standing dental, optical, or prescription drug... option.) - (ii) The non-HMO option provides free-standing coverage for optical services (such as...

42 CFR 417.155 - How the HMO option must be included in the health benefits plan.

Code of Federal Regulations, 2014 CFR

2014-10-01

... enrollment in the HMO or of transfer from HMO to non-HMO coverage, or exclusions, or limitations based on..., because of this selection, lose their eligibility for free-standing dental, optical, or prescription drug... option.) - (ii) The non-HMO option provides free-standing coverage for optical services (such as...

Anxiety Sensitivity and Psychological Vulnerability

DTIC Science & Technology

1999-01-01

Fibiger, 1979), drugs that effectively treat panic such as selective serotonin reuptake inhibitors do not directly affect noradrenergic receptors (den...specific gene related to anxiety that affects the brain s use of the neurotransmitter 5-hydroxytryptamine ( serotonin ). Evidence indicated that a...ii The author hereby certifies that the use of any copyrighted material in the dissertation entitled: Anxiety Sensitivity and Psychological

21 CFR 352.52 - Labeling of sunscreen drug products.

Code of Federal Regulations, 2011 CFR

2011-04-01

... protective clothing, and using sunscreens may reduce the risks of skin aging, skin cancer, and other harmful... “[bullet] for skin that sunburns minimally”. (ii) For products that provide an SPF of 12 to under 30... “[bullet] for skin that sunburns easily”. (iii) For products that provide an SPF of 30 or above. Select one...

21 CFR 352.52 - Labeling of sunscreen drug products.

Code of Federal Regulations, 2010 CFR

2010-04-01

... protective clothing, and using sunscreens may reduce the risks of skin aging, skin cancer, and other harmful... “[bullet] for skin that sunburns minimally”. (ii) For products that provide an SPF of 12 to under 30... “[bullet] for skin that sunburns easily”. (iii) For products that provide an SPF of 30 or above. Select one...

Applicability of bioanalysis of multiple analytes in drug discovery and development: review of select case studies including assay development considerations.

PubMed

Srinivas, Nuggehally R

2006-05-01

The development of sound bioanalytical method(s) is of paramount importance during the process of drug discovery and development culminating in a marketing approval. Although the bioanalytical procedure(s) originally developed during the discovery stage may not necessarily be fit to support the drug development scenario, they may be suitably modified and validated, as deemed necessary. Several reviews have appeared over the years describing analytical approaches including various techniques, detection systems, automation tools that are available for an effective separation, enhanced selectivity and sensitivity for quantitation of many analytes. The intention of this review is to cover various key areas where analytical method development becomes necessary during different stages of drug discovery research and development process. The key areas covered in this article with relevant case studies include: (a) simultaneous assay for parent compound and metabolites that are purported to display pharmacological activity; (b) bioanalytical procedures for determination of multiple drugs in combating a disease; (c) analytical measurement of chirality aspects in the pharmacokinetics, metabolism and biotransformation investigations; (d) drug monitoring for therapeutic benefits and/or occupational hazard; (e) analysis of drugs from complex and/or less frequently used matrices; (f) analytical determination during in vitro experiments (metabolism and permeability related) and in situ intestinal perfusion experiments; (g) determination of a major metabolite as a surrogate for the parent molecule; (h) analytical approaches for universal determination of CYP450 probe substrates and metabolites; (i) analytical applicability to prodrug evaluations-simultaneous determination of prodrug, parent and metabolites; (j) quantitative determination of parent compound and/or phase II metabolite(s) via direct or indirect approaches; (k) applicability in analysis of multiple compounds in select disease areas and/or in clinically important drug-drug interaction studies. A tabular representation of select examples of analysis is provided covering areas of separation conditions, validation aspects and applicable conclusion. A limited discussion is provided on relevant aspects of the need for developing bioanalytical procedures for speedy drug discovery and development. Additionally, some key elements such as internal standard selection, likely issues of mass detection, matrix effect, chiral aspects etc. are provided for consideration during method development.

Tyrosyl-DNA phosphodiesterase inhibitors: Progress and potential.

PubMed

Laev, Sergey S; Salakhutdinov, Nariman F; Lavrik, Olga I

2016-11-01

DNA topoisomerases are essential during transcription and replication. The therapeutic mechanism of action of topoisomerase inhibitors is enzyme poisoning rather than catalytic inhibition. Tyrosyl-DNA phosphodiesterases 1 or 2 were found as DNA repair enzymes hydrolyzing the covalent bond between the tyrosyl residue of topoisomerases I or II and the 3'- or 5'-phosphate groups in DNA, respectively. Tyrosyl-DNA phosphodiesterase 1 is a key enzyme in DNA repair machinery and a promising target for antitumor and neurodegenerative therapy. Inhibitors of tyrosyl-DNA phosphodiesterase 1 could act synergistically with topoisomerase I inhibitors and thereby potentiate the effects of topoisomerase I poisons. Tyrosyl-DNA phosphodiesterase 2 is an enzyme that specifically repairs DNA damages induced by topoisomerase II poisons and causes resistance to these drugs. Selective inhibition of tyrosyl-DNA phosphodiesterase 2 may be a novel approach to overcome intrinsic or acquired resistance to topoisomerase II-targeted drug therapy. Thus, agents that inhibit tyrosyl-DNA phosphodiesterases 1 and 2 have many applications in biochemical and physiological research and they have the potential to become anticancer and antiviral drugs. The structures, mechanism of action and therapeutic rationale of tyrosyl-DNA phosphodiesterase inhibitors and their development for combinations with topoisomerase inhibitors and DNA damaging agents are discussed. Copyright © 2016 Elsevier Ltd. All rights reserved.

[Missile-Type Tumor-Targeting Polymer Drug, P-THP, Seeks Tumors via Three Different Steps Based on the EPR Effect].

PubMed

Maeda, Hiroshi; Fang, Jun; Ulbrich, Karel; Etrych, Tomáš; Nakamura, Hideaki

2016-05-01

The enhanced permeability and retention (EPR) effect, a tumor-targeting principle of nanomedicine, serves as a standard for tumor-targeted anticancer drug design. There are 3 key issues in ideal EPR-based antitumor drug design: i) stability in blood circulation; ii) tumor-selective accumulation (EPR effect) and efficient release of the active anticancer moiety in tumor tissues; and iii) the active uptake of the active drug into tumor cells. Using these principles, we developed N-(2- hydroxypropyl)methacrylamide (HPMA) copolymer-conjugated pirarubicin (P-THP), which uses hydrazone bond linkage; it was shown to exhibit prolonged circulation time, thereby resulting in good tumor-selective accumulation. More importantly, the hydrazone bond ensured selective and rapid release of the active drug, pirarubicin (THP), in acidic tumor environments. Further, compared to other anthracycline anticancer drugs (eg, doxorubicin), THP demonstrated more rapid intracellular uptake. Consequently, P-THP showed remarkable antitumor effect with minimal side effects. In a clinical pilot study of a stage IV prostate cancer patient with multiple metastases in the lung and bone, P-THP (50-75 mg administered once every 2-3 weeks) was shown to clear the metastatic nodules in the lung almost completely after 3 treatments where 50-70 mg THP equivalent each was administerd per 70 kg body wt, and bone metastasis disappeared after 6 months. There was no recurrence after 2 years. The patient also retained an excellent quality of life during the treatment without any apparent side effects. Thus, we propose the clinical development of P-THP as an EPR-based tumor-targeted anticancer drug.

Importance of Control Groups When Delineating Antibiotic Use as Risk Factors for Carbapenem-Resistance, Extreme-Drug and Pan-Drug Resistance in Acinetobacter baumannii and Pseudomonas aeruginosa: A Systematic Review and Meta-Analysis.

PubMed

Lim, Cheryl Li Ling; Chua, Alvin Qijia; Teo, Jocelyn Qi Min; Cai, Yiying; Lee, Winnie; Kwa, Andrea Lay-Hoon

2018-06-02

Carbapenem-resistant (CR), extreme-drug-resistant (XDR) & pan-drug-resistant (PDR) AB and PA (AB-PA) pose a huge clinical threat. This study reviews the impact of control groups on association of antecedent antibiotic use & acquisition of CR/XDR/PDR AB-PA. Studies investigating the role of antibiotics as risk factor for CR/XDR/PDR AB-PA acquisition in adult hospitalized patients from 1950 to 2016 were identified with databases. These were divided into 2 groups: antibiotic-resistant versus antibiotic-sensitive pathogens (Group I); versus no infection (Group II). A random effects model was performed. Eighty-five studies (46 AB, 38 PA, 1 both) with 22,396 patients were included. CR, XDR & PDR was investigated in 60, 20 and 2 studies respectively. Prior antibiotic exposure was associated with significant acquisition of CR/XDR/PDR AB-PA in both Groups I and II (p <0.05). Antibiotic classes implicated in both groups include aminoglycosides, carbapenems, glycopeptides and penicillins. Cephalosporin use was not associated with resistance in either group. Fluoroquinolones exposure was only associated with resistance in Group I but not Group II. Control groups play an important role in determining magnitudes of risk estimates for risk factor studies, hence careful selection is necessary. Antibiotic exposure increases acquisition of highly-resistant AB-PA, thus appropriate antibiotic use is imperative. Copyright © 2018. Published by Elsevier Ltd.

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.

Reactions to Graphic Health Warnings in the United States

ERIC Educational Resources Information Center

Nonnemaker, James M.; Choiniere, Conrad J.; Farrelly, Matthew C.; Kamyab, Kian; Davis, Kevin C.

2015-01-01

This study reports consumer reactions to the graphic health warnings selected by the Food and Drug Administration to be placed on cigarette packs in the United States. We recruited three sets of respondents for an experimental study from a national opt-in e-mail list sample: (i) current smokers aged 25 or older, (ii) young adult smokers aged 18-24…

Computation-based virtual screening for designing novel antimalarial drugs by targeting falcipain-III: a structure-based drug designing approach.

PubMed

Kesharwani, Rajesh Kumar; Singh, Durg Vijay; Misra, Krishna

2013-01-01

Cysteine proteases (falcipains), a papain-family of enzymes of Plasmodium falciparum, are responsible for haemoglobin degradation and thus necessary for its survival during asexual life cycle phase inside the human red blood cells while remaining non-functional for the human body. Therefore, these can act as potential targets for designing antimalarial drugs. The P. falciparum cysteine proteases, falcipain-II and falcipain- III are the enzymes which initiate the haemoglobin degradation, therefore, have been selected as targets. In the present study, we have designed new leupeptin analogues and subjected to virtual screening using Glide at the active site cavity of falcipain-II and falcipain-III to select the best docked analogues on the basis of Glide score and also compare with the result of AutoDock. The proposed analogues can be synthesized and tested in vivo as future potent antimalarial drugs. Protein falcipain-II and falcipain-III together with bounds inhibitors epoxysuccinate E64 (E64) and leupeptin respectively were retrieved from protein data bank (PDB) and latter leupeptin was used as lead molecule to design new analogues by using Ligbuilder software and refined the molecules on the basis of Lipinski rule of five and fitness score parameters. All the designed leupeptin analogues were screened via docking simulation at the active site cavity of falcipain-II and falcipain-III by using Glide software and AutoDock. The 104 new leupeptin-based antimalarial ligands were designed using structure-based drug designing approach with the help of Ligbuilder and subjected for virtual screening via docking simulation method against falcipain-II and falcipain-III receptor proteins. The Glide docking results suggest that the ligands namely result_037 shows good binding and other two, result_044 and result_042 show nearly similar binding than naturally occurring PDB bound ligand E64 against falcipain-II and in case of falcipain-III, 15 designed leupeptin analogues having better binding affinity compared to the PDB bound inhibitor of falcipain-III. The docking simulation results of falcipain-III with designed leupeptin analogues using Glide compared with AutoDock and find 80% similarity as better binder than leupeptin. These results further highlight new leupeptin analogues as promising future inhibitors for chemotherapeutic prevention of malaria. The result of Glide for falcipain-III has been compared with the result of AutoDock and finds very less differences in their order of binding affinity. Although there are no extra hydrogen bonds, however, equal number of hydrogen bonds with variable strength as compared to leupeptin along with the enhanced hydrophobic and electrostatic interactions in case of analogues supports our study that it holds the ligand molecules strongly within the receptor. The comparative e-pharmacophoric study also suggests and supports our predictions regarding the minimum features required in ligand molecule to behave as falcipain- III inhibitors and is also helpful in screening the large database as future antimalarial inhibitors.

Inflammatory Signaling by NOD-RIPK2 Is Inhibited by Clinically Relevant Type II Kinase Inhibitors

PubMed Central

Canning, Peter; Ruan, Qui; Schwerd, Tobias; Hrdinka, Matous; Maki, Jenny L.; Saleh, Danish; Suebsuwong, Chalada; Ray, Soumya; Brennan, Paul E.; Cuny, Gregory D.; Uhlig, Holm H.; Gyrd-Hansen, Mads; Degterev, Alexei; Bullock, Alex N.

2015-01-01

Summary RIPK2 mediates pro-inflammatory signaling from the bacterial sensors NOD1 and NOD2, and is an emerging therapeutic target in autoimmune and inflammatory diseases. We observed that cellular RIPK2 can be potently inhibited by type II inhibitors that displace the kinase activation segment, whereas ATP-competitive type I inhibition was only poorly effective. The most potent RIPK2 inhibitors were the US Food and Drug Administration-approved drugs ponatinib and regorafenib. Their mechanism of action was independent of NOD2 interaction and involved loss of downstream kinase activation as evidenced by lack of RIPK2 autophosphorylation. Notably, these molecules also blocked RIPK2 ubiquitination and, consequently, inflammatory nuclear factor κB signaling. In monocytes, the inhibitors selectively blocked NOD-dependent tumor necrosis factor production without affecting lipopolysaccharide-dependent pathways. We also determined the first crystal structure of RIPK2 bound to ponatinib, and identified an allosteric site for inhibitor development. These results highlight the potential for type II inhibitors to treat indications of RIPK2 activation as well as inflammation-associated cancers. PMID:26320862

Environmental risk assessment of medicinal products for human use according to European Commission recommendations.

PubMed

Huschek, Gerd; Hansen, Peter D; Maurer, Hans H; Krengel, Dietmar; Kayser, Anja

2004-06-01

Presented here, based on new recommendations of the European Commission, is an environmental risk assessment (ERA) of a selected group of pharmaceuticals for Phase I, environmental exposure assessment, and Phase II Tier A, initial environmental fate and effect analysis. This pharmaceutical group is composed of the 111 highest-selling human drug substances that have annual sales in Germany of more than 5,000 kg. The data required for this ERA came from analyzing: (1) sales annually (in kg or IU) of the 2671 active pharmaceutical drug substances (2001) on the German market in all medicinal products sold by pharmacies (with and without prescriptions) and used in hospitals in 1996-2001; (2) the use pattern of drug substances as categorized according to Anatomical Therapeutic Chemical (ATC) classification indexes ATC3 and ATC7; (3) data for excretion, toxicity, and metabolites of the 111 selected human drug substances; (4) the physicochemical properties of these substances; and (5) the degradability of selected drug substances in sewage treatment plants (STPs) by using a validated and accredited liquid chromatography-electrospray ionization tandem mass spectrometry method. A correction factor for the pharmaceutical therapeutic (PT) activity of metabolites, the PT(Index) (excretion rate/100) for drug substances and PT active metabolites was established to refine the predicted environmental concentration (PEC(SURFACEWATER)). A refinement of the PEC(SURFACEWATER) was carried out with the market penetration factor of the human drug substances in Germany. In addition, for effect analysis the predicted no-effects concentration (PNEC) was calculated using assessment factors. The estimated PEC results were validated with the exposure results of effluents of the STPs. All results on ERA of drug substances have been documented in a Microsoft Access 2000 database. Copyright 2004 Wiley Periodicals, Inc.

Optimising Drug Solubilisation in Amorphous Polymer Dispersions: Rational Selection of Hot-melt Extrusion Processing Parameters.

PubMed

Li, Shu; Tian, Yiwei; Jones, David S; Andrews, Gavin P

2016-02-01

The aim of this article was to construct a T-ϕ phase diagram for a model drug (FD) and amorphous polymer (Eudragit® EPO) and to use this information to understand the impact of how temperature-composition coordinates influenced the final properties of the extrudate. Defining process boundaries and understanding drug solubility in polymeric carriers is of utmost importance and will help in the successful manufacture of new delivery platforms for BCS class II drugs. Physically mixed felodipine (FD)-Eudragit(®) EPO (EPO) binary mixtures with pre-determined weight fractions were analysed using DSC to measure the endset of melting and glass transition temperature. Extrudates of 10 wt% FD-EPO were processed using temperatures (110°C, 126°C, 140°C and 150°C) selected from the temperature-composition (T-ϕ) phase diagrams and processing screw speed of 20, 100 and 200rpm. Extrudates were characterised using powder X-ray diffraction (PXRD), optical, polarised light and Raman microscopy. To ensure formation of a binary amorphous drug dispersion (ADD) at a specific composition, HME processing temperatures should at least be equal to, or exceed, the corresponding temperature value on the liquid-solid curve in a F-H T-ϕ phase diagram. If extruded between the spinodal and liquid-solid curve, the lack of thermodynamic forces to attain complete drug amorphisation may be compensated for through the use of an increased screw speed. Constructing F-H T-ϕ phase diagrams are valuable not only in the understanding drug-polymer miscibility behaviour but also in rationalising the selection of important processing parameters for HME to ensure miscibility of drug and polymer.

Multiply Intercalator-Substituted Cu(II) Cyclen Complexes as DNA Condensers and DNA/RNA Synthesis Inhibitors.

PubMed

Hormann, Jan; Malina, Jaroslav; Lemke, Oliver; Hülsey, Max J; Wedepohl, Stefanie; Potthoff, Jan; Schmidt, Claudia; Ott, Ingo; Keller, Bettina G; Brabec, Viktor; Kulak, Nora

2018-05-07

Many drugs that are applied in anticancer therapy such as the anthracycline doxorubicin contain DNA-intercalating 9,10-anthraquinone (AQ) moieties. When Cu(II) cyclen complexes were functionalized with up to three (2-anthraquinonyl)methyl substituents, they efficiently inhibited DNA and RNA synthesis resulting in high cytotoxicity (selective for cancer cells) accompanied by DNA condensation/aggregation phenomena. Molecular modeling suggests an unusual bisintercalation mode with only one base pair between the two AQ moieties and the metal complex as a linker. A regioisomer, in which the AQ moieties point in directions unfavorable for such an interaction, had a much weaker biological activity. The ligands alone and corresponding Zn(II) complexes (used as redox inert control compounds) also exhibited lower activity.

Prediction of adverse drug reactions using decision tree modeling.

PubMed

Hammann, F; Gutmann, H; Vogt, N; Helma, C; Drewe, J

2010-07-01

Drug safety is of great importance to public health. The detrimental effects of drugs not only limit their application but also cause suffering in individual patients and evoke distrust of pharmacotherapy. For the purpose of identifying drugs that could be suspected of causing adverse reactions, we present a structure-activity relationship analysis of adverse drug reactions (ADRs) in the central nervous system (CNS), liver, and kidney, and also of allergic reactions, for a broad variety of drugs (n = 507) from the Swiss drug registry. Using decision tree induction, a machine learning method, we determined the chemical, physical, and structural properties of compounds that predispose them to causing ADRs. The models had high predictive accuracies (78.9-90.2%) for allergic, renal, CNS, and hepatic ADRs. We show the feasibility of predicting complex end-organ effects using simple models that involve no expensive computations and that can be used (i) in the selection of the compound during the drug discovery stage, (ii) to understand how drugs interact with the target organ systems, and (iii) for generating alerts in postmarketing drug surveillance and pharmacovigilance.

Lorcaserin: drug profile and illustrative model of the regulatory challenges of weight-loss drug development.

PubMed

Bays, Harold E

2011-03-01

Lorcaserin is a selective 5-hydroxytryptamine receptor 2c agonist developed as a weight-loss drug. Phase II and III clinical trials support lorcaserin as not only reducing adiposity (i.e., fat mass), but also as improving the metabolic diseases commonly associated with adiposopathy (i.e., fat dysfunction). At the time of this writing, regulatory processes continue towards evaluating lorcaserin as a potentially marketed weight-loss and weight-maintenance agent. Some of the challenges facing lorcaserin are similar to the difficulties encountered by all investigational weight-loss therapeutic agents, which include evolving paths towards approval. While important for clinicians to understand approval hurdles for all therapeutics, it is especially critical for researchers and developers to grasp the unique regulatory complexities of anti-obesity agents. This article profiles lorcaserin as an illustrative example of general drug development regulatory processes, and specifically details the unique challenge of weight-loss drug development.

Delayed photolysis of liposomes: a strategy for the precision timing of bolus drug release using ex-vivo photochemical sensitization

NASA Astrophysics Data System (ADS)

Kozikowski, Raymond T.; Sorg, Brian S.

2012-03-01

Chemotherapy is a standard treatment for metastatic cancer. However drug toxicity limits the dosage that can safely be used, thus reducing treatment efficacy. Drug carrier particles, like liposomes, can help reduce toxicity by shielding normal tissue from drug and selectively depositing drug in tumors. Over years of development, liposomes have been optimized to avoid uptake by the Reticuloendothelial System (RES) as well as effectively retain their drug content during circulation. As a result, liposomes release drug passively, by slow leakage, but this uncontrolled drug release can limit treatment efficacy as it can be difficult to achieve therapeutic concentrations of drug at tumor sites even with tumor-specific accumulation of the carriers. Lipid membranes can be photochemically lysed by both Type I (photosensitizer-substrate) and Type II (photosensitizer-oxygen) reactions. It has been demonstrated in red blood cells (RBCs) in vitro that these photolysis reactions can occur in two distinct steps: a light-initiated reaction followed by a thermally-initiated reaction. These separable activation steps allow for the delay of photohemolysis in a controlled manner using the irradiation energy, temperature and photosensitizer concentration. In this work we have translated this technique from RBCs to liposomal nanoparticles. To that end, we present in vitro data demonstrating this delayed bolus release from liposomes, as well as the ability to control the timing of this event. Further, we demonstrate for the first time the improved delivery of bioavailable cargo selectively to target sites in vivo.

XPO1 Inhibition Using Selinexor Synergizes With Chemotherapy in Acute Myeloid Leukemia (AML) by Targeting DNA Repair and Restoring Topoisomerase IIα to the Nucleus

PubMed Central

Ranganathan, Parvathi; Kashyap, Trinayan; Yu, Xueyan; Meng, Xiaomei; Lai, Tzung-Huei; McNeil, Betina; Bhatnagar, Bhavana; Shacham, Sharon; Kauffman, Michael; Dorrance, Adrienne M.; Blum, William; Sampath, Deepa; Landesman, Yosef; Garzon, Ramiro

2016-01-01

Purpose Selinexor, a selective inhibitor of XPO1, is currently being tested as single agent in clinical trials in acute myeloid leukemia (AML). However, considering the molecular complexity of AML, it is unlikely that AML can be cured with monotherapy. Therefore we asked whether adding already established effective drugs such as Topoisomerase (Topo) II inhibitors to selinexor will enhance its anti-leukemic effects in AML. Experimental Design The efficacy of combinatorial drug treatment using Topo II inhibitors (idarubicin, daunorubicin, mitoxantrone, etoposide) and selinexor was evaluated in established cellular and animal models of AML. Results Concomitant treatment with selinexor and Topo II inhibitors resulted in therapeutic synergy in AML cell lines and patient samples. Using a xenograft MV4-11 AML mouse model, we show that treatment with selinexor and idarubicin significantly prolongs survival of leukemic mice compared to each single therapy. Conclusions Aberrant nuclear export and cytoplasmic localization of Topo IIα has been identified as one of the mechanisms leading to drug resistance in cancer. Here, we show that in a subset of AML patients that express cytoplasmic Topo IIα, selinexor treatment results in nuclear retention of Topo IIα protein, resulting in increased sensitivity to idarubicin. Selinexor treatment of AML cells resulted in a c-MYC dependent reduction of DNA damage repair genes (Rad51 and Chk1) mRNA and protein expression, and subsequent inhibition of homologous recombination repair and increased sensitivity to Topo II inhibitors. The preclinical data reported here support further clinical studies using selinexor and Topo II inhibitors in combination to treat AML. PMID:27358488

High-performance liquid chromatography–tandem mass spectrometry in the identification and determination of phase I and phase II drug metabolites

PubMed Central

Kolářová, L.; Nobilis, M.

2008-01-01

Applications of tandem mass spectrometry (MS/MS) techniques coupled with high-performance liquid chromatography (HPLC) in the identification and determination of phase I and phase II drug metabolites are reviewed with an emphasis on recent papers published predominantly within the last 6 years (2002–2007) reporting the employment of atmospheric pressure ionization techniques as the most promising approach for a sensitive detection, positive identification and quantitation of metabolites in complex biological matrices. This review is devoted to in vitro and in vivo drug biotransformation in humans and animals. The first step preceding an HPLC-MS bioanalysis consists in the choice of suitable sample preparation procedures (biomatrix sampling, homogenization, internal standard addition, deproteination, centrifugation, extraction). The subsequent step is the right optimization of chromatographic conditions providing the required separation selectivity, analysis time and also good compatibility with the MS detection. This is usually not accessible without the employment of the parent drug and synthesized or isolated chemical standards of expected phase I and sometimes also phase II metabolites. The incorporation of additional detectors (photodiode-array UV, fluorescence, polarimetric and others) between the HPLC and MS instruments can result in valuable analytical information supplementing MS results. The relation among the structural changes caused by metabolic reactions and corresponding shifts in the retention behavior in reversed-phase systems is discussed as supporting information for identification of the metabolite. The first and basic step in the interpretation of mass spectra is always the molecular weight (MW) determination based on the presence of protonated molecules [M+H]+ and sometimes adducts with ammonium or alkali-metal ions, observed in the positive-ion full-scan mass spectra. The MW determination can be confirmed by the [M-H]- ion for metabolites providing a signal in negative-ion mass spectra. MS/MS is a worthy tool for further structural characterization because of the occurrence of characteristic fragment ions, either MSn analysis for studying the fragmentation patterns using trap-based analyzers or high mass accuracy measurements for elemental composition determination using time of flight based or Fourier transform mass analyzers. The correlation between typical functional groups found in phase I and phase II drug metabolites and corresponding neutral losses is generalized and illustrated for selected examples. The choice of a suitable ionization technique and polarity mode in relation to the metabolite structure is discussed as well. PMID:18345532

The second Lilly Prize Lecture, University of Newcastle, July 1977. beta-Adrenergic receptor blockade in hypertension, past, present and future.

PubMed Central

Prichard, B N

1978-01-01

All beta-adrenoceptor blocking drugs that have been described share the common property of being competitive inhibitors. They differ in their associated properties, the presence or absence of cardioselectivity, membrane stabilizing activity, and partial agonist activity. Recently some beta-adrenoceptor blocking drugs have been reported which also possess alpha-adrenoceptor blocking activity. The associated properties have been used as a basis for classifying beta-adrenoceptor blocking drugs (Fitzgerald, 1969, 1972). The presence or absence of cardioselectivity is most useful for dividing beta-adrenoceptor blocking drugs. The non-selective drugs (Division I) can be further divided according to the presence or absence of intrinsic sympathomimetic activity (ISA) and membrane stabilizing activity (Fitzgerald's groups I-IV). Group I possess both membrane activity and ISA, e.g. alprenolol, oxprenolol, group II just membrane action, e.g. propanolol, group III ISA but no membrane action, e.g. pindolol. Fitzgerald placed pindolol in group I but should be placed in group III as it possesses a high degree of beta-adrenoceptor blocking potency in relation to its membrane activity (Prichard, 1974). Finally drugs in group IV have neither ISA nor membrane action, e.g. sotalol, timolol. The cardioselective drugs (Division II) can be similarly sub-divided into groups I-IV according to the presence or absence of ISA or membrane action (Fitzgerald grouped all these together as group V). Lastly there are new beta-adrenergic receptor blocking drugs which in addition have alpha- adrenergic receptor blocking properties (Division III). PMID:26370

Mutation Supply and Relative Fitness Shape the Genotypes of Ciprofloxacin-Resistant Escherichia coli.

PubMed

Huseby, Douglas L; Pietsch, Franziska; Brandis, Gerrit; Garoff, Linnéa; Tegehall, Angelica; Hughes, Diarmaid

2017-05-01

Ciprofloxacin is an important antibacterial drug targeting Type II topoisomerases, highly active against Gram-negatives including Escherichia coli. The evolution of resistance to ciprofloxacin in E. coli always requires multiple genetic changes, usually including mutations affecting two different drug target genes, gyrA and parC. Resistant mutants selected in vitro or in vivo can have many different mutations in target genes and efflux regulator genes that contribute to resistance. Among resistant clinical isolates the genotype, gyrA S83L D87N, parC S80I is significantly overrepresented suggesting that it has a selective advantage. However, the evolutionary or functional significance of this high frequency resistance genotype is not fully understood. By combining experimental data and mathematical modeling, we addressed the reasons for the predominance of this specific genotype. The experimental data were used to model trajectories of mutational resistance evolution under different conditions of drug exposure and population bottlenecks. We identified the order in which specific mutations are selected in the clinical genotype, showed that the high frequency genotype could be selected over a range of drug selective pressures, and was strongly influenced by the relative fitness of alternative mutations and factors affecting mutation supply. Our data map for the first time the fitness landscape that constrains the evolutionary trajectories taken during the development of clinical resistance to ciprofloxacin and explain the predominance of the most frequently selected genotype. This study provides strong support for the use of in vitro competition assays as a tool to trace evolutionary trajectories, not only in the antibiotic resistance field. © The Author 2017. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

Molecular dynamics approach to probe PKCβII-ligand interactions and influence of crystal water molecules on these interactions.

PubMed

Grewal, Baljinder K; Bhat, Jyotsna; Sobhia, Masilamani Elizabeth

2015-01-01

PKCβII is a potential target for therapeutic intervention against pandemic diabetic complications. Present study probes the molecular interactions of PKCβII with its clinically important ligands, viz. ruboxistaurin, enzastaurin and co-crystallized ligand, 2-methyl-1H-indol-3-yl-BIM-1. The essentials of PKCβII-ligand interaction, crystal water-induced alterations in these interactions and key interacting flexible residues are analyzed. Computational methodologies, viz. molecular docking and molecular simulation coupled with molecular mechanics-Poisson-Boltzmann surface area and generalized born surface area (MM-PB[GB]SA) are employed. The structural changes in the presence and absence of crystal water molecules in PKCβII ATP binding site residues, and its interaction with bound ligand, are identified. Difference in interaction of selective and nonselective ligand with ATP binding site residues of PKCβII is reported. The study showed that the nonbonding interactions contribute significantly in PKCβII-ligand binding and presence of crystal water molecules affects the interactions. The findings of present work may integrate the new aspects in the drug design process of PKCβII inhibitors.

Fluorine-Directed Glycosylation Enables the Stereocontrolled Synthesis of Selective SGLT2 Inhibitors for Type II Diabetes.

PubMed

Sadurní, Anna; Kehr, Gerald; Ahlqvist, Marie; Wernevik, Johan; Sjögren, Helena Peilot; Kankkonen, Cecilia; Knerr, Laurent; Gilmour, Ryan

2018-02-26

Inhibition of the sodium-glucose co-transporters (SGLT1 and SGLT2) is a validated strategy to address the increasing prevalence of type II diabetes mellitus. However, achieving selective inhibition of human SGLT1 or SGLT2 remains challenging. Orally available small molecule drugs based on the d-glucose core of the natural product Gliflozin have proven to be clinically effective in this regard, effectively impeding glucose reabsorption. Herein, we disclose the influence of molecular editing with fluorine at the C2 position of the pyranose ring of Phlorizin analogues Remogliflozin Etabonate and Dapagliflozin (Farxiga ® ) to concurrently direct β-selective glycosylation, as is required for biological efficacy, and enhance aspects of the physicochemical profile. Given the abundance of glycosylated pharmaceuticals in diabetes therapy that contain a β-configured d-glucose nucleus, it is envisaged that this strategy may prove to be expansive. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Discovery of core-structurally novel PTP1B inhibitors with specific selectivity containing oxindole-fused spirotetrahydrofurochroman by one-pot reaction.

PubMed

Dong, Suzhen; Lei, Yubing; Jia, Shikun; Gao, Lixin; Li, Jia; Zhu, Tong; Liu, Shunying; Hu, Wenhao

2017-02-15

Protein tyrosine phosphatase 1B (PTP1B) has been proposed to be an ideal target for treatment of type II diabetes and obesity. However, no druggable PTP1B inhibitor has been established and there is still an urgent demand for the development of structurally novel PTPIB inhibitor. Herein, we reported core-structurally novel PTP1B inhibitors with low micromole-ranged inhibitory activity by one-pot reaction from simple starting materials. Further studies demonstrated some of these active compounds had a specific selectivity over other PTPs. The structure and activity relationship was also described. The best active and selective compound 5e inhibited PTP1B activity with an IC 50 of 4.53μM. Molecular docking analysis further demonstrated that compound 5e bound to the active pocket of PTP1B. The results might provide some insights for further development of new drugs for type II diabetes and obesity. Copyright © 2016 Elsevier Ltd. All rights reserved.

[Prolonged-release drug formulations for parenteral administration. Part II. Microspheres and implants for injection].

PubMed

Płaczek, Margin; Jacyna, Julia; Sznitowska, Małgorzata

2014-01-01

Microspheres and implants are injectable drug forms, which by special design and selection of appropriate excipients, provide for a long time constant release rate of an active substance in the body. Development of both would not be possible without advances in polymer technology and invention of safe and biocompatible polymers such as: polyesters, vinyl acetate derivatives or silicones. Polymeric matrices provide retardation of drug release--for some implants up to a few years. In addition, this paper presents examples of all commercially available medicinal products containing microspheres and implants, currently registered in Poland, together with their characteristics: composition, time course and frequency of administration. Comments are also enclosed on frequently occurring inconsistent terminology in pharmaceutical forms.

Design and validation of an immunoaffinity LC-MS/MS assay for the quantification of a collagen type II neoepitope peptide in human urine: application as a biomarker of osteoarthritis.

PubMed

Nemirovskiy, Olga; Li, Wenlin Wendy; Szekely-Klepser, Gabriella

2010-01-01

Biomarkers play an increasingly important role for drug efficacy and safety evaluation in all stages of drug development. It is especially important to develop and validate sensitive and selective biomarkers for diseases where the onset of the disease is very slow and/or the disease progression is hard to follow, i.e., osteoarthritis (OA). The degradation of Type II collagen has been associated with the disease state of OA. Matrix metalloproteinases (MMPs) are enzymes that catalyze the degradation of collagen and therefore pursued as potential targets for the treatment of OA. Peptide biomarkers of MMP activity related to type II collagen degradation were identified and the presence of these peptides in MMP digests of human articular cartilage (HAC) explants and human urine were confirmed. An immunoaffinity LC/MS/MS assay for the quantification of the most abundant urinary type II collagen neoepitope (uTIINE) peptide, a 45-mer with 5 HO-proline residues was developed and clinically validated. The assay has subsequently been applied to analyze human urine samples from clinical studies. We have shown that the assay is able to differentiate between symptomatic OA and normal subjects, indicating that uTIINE can be used as potential biomarker for OA. This chapter discusses the assay procedure and provides information on the validation experiments used to evaluate the accuracy, precision, and selectivity data with attention to the specific challenges related to the quantification of endogenous protein/peptide biomarker analytes. The generalized approach can be used as a follow-up to studies whereby proteomics-based urinary biomarkers are identified and an assay needs to be developed. Considerations for the validation of such an assay are described.

Postsynaptic and presynaptic group II metabotropic glutamate receptor activation reduces neuronal excitability in rat midline paraventricular thalamic nucleus.

PubMed

Hermes, M L H J; Renaud, L P

2011-03-01

Drugs that interact with group II metabotropic glutamate receptors (mGluRs) are presently being evaluated for a role in the treatment of anxiety disorders and symptoms of schizophrenia. Their mechanism of action is believed to involve a reduction in excitatory neurotransmission in limbic and forebrain regions commonly associated with these mental disorders. In rodents, the glutamatergic neurons in the midline paraventricular thalamic nucleus (PVT) provide excitatory inputs to the limbic system and forebrain. PVT also displays a high density of group II mGluRs, predominantly the metabotropic glutamate 2 receptor (mGluR2). Because the role of group II mGluRs in regulating cellular and synaptic excitability in this location has yet to be determined, we used whole-cell patch-clamp recording and acute rat brain slice preparations to evaluate PVT neuron responses to a selective group II mGluR agonist, (1R,4R,5S,6R)-4-amino-2-oxabicyclo[3.1.0]hexane-4,6-dicarboxylic acid (LY 379268). LY 379268 consistently induced membrane hyperpolarization and suppressed firing by postsynaptic receptor-mediated activation of a barium-sensitive background K(+) conductance. This effect could be blocked by (2S)-2-amino-2-[(1S,2S)-2-carboxycycloprop-1-yl]-3-(xanth-9-yl)propanoic acid (LY 341495), a selective group II mGluR antagonist. In addition, LY 379268 acted at presynaptic receptors to reduce ionotropic glutamate receptor-mediated excitatory synaptic transmission. An mGluR2-positive allosteric modulator, 2,2,2-trifluoro-N-[4-(2-methoxyphenoxy)phenyl]-N-(3-pyridinylmethyl)ethanesulfonamide hydrochloride (LY 487379), resulted in leftward shifts of the LY 379268 dose-response curve for both postsynaptic and presynaptic actions. The data demonstrate that activation of postsynaptic and presynaptic group II (presumably mGluR2) mGluRs reduces neuronal excitability in midline thalamus, an action that may contribute to the effectiveness of mGluR2-activating drugs in rodent models of anxiety and psychosis.

Identification of Direct Activator of Adenosine Monophosphate-Activated Protein Kinase (AMPK) by Structure-Based Virtual Screening and Molecular Docking Approach.

PubMed

Huang, Tonghui; Sun, Jie; Zhou, Shanshan; Gao, Jian; Liu, Yi

2017-06-30

Adenosine monophosphate-activated protein kinase (AMPK) plays a critical role in the regulation of energy metabolism and has been targeted for drug development of therapeutic intervention in Type II diabetes and related diseases. Recently, there has been renewed interest in the development of direct β1-selective AMPK activators to treat patients with diabetic nephropathy. To investigate the details of AMPK domain structure, sequence alignment and structural comparison were used to identify the key amino acids involved in the interaction with activators and the structure difference between β1 and β2 subunits. Additionally, a series of potential β1-selective AMPK activators were identified by virtual screening using molecular docking. The retrieved hits were filtered on the basis of Lipinski's rule of five and drug-likeness. Finally, 12 novel compounds with diverse scaffolds were obtained as potential starting points for the design of direct β1-selective AMPK activators.

Synthesis of novel 4-functionalized 1,5-diaryl-1,2,3-triazoles containing benzenesulfonamide moiety as carbonic anhydrase I, II, IV and IX inhibitors.

PubMed

Vats, Lalit; Sharma, Vikas; Angeli, Andrea; Kumar, Rajiv; Supuran, Claudiu T; Sharma, Pawan K

2018-04-25

The design, synthesis and biological evaluation of a library of 1,2,3-triazole carboxylates incorporating carboxylic acid, hydroxymethyl, carboxylic acid hydrazide, carboxamide and benzenesulfonamide moieties is disclosed. All the novel compounds were investigated for their inhibition potential against carbonic anhydrase (CA, EC 4.2.1.1) human (h) isoforms hCA I, II, IV and IX, well established drug targets. The cytosolic isoform hCA I was inhibited with K i 's ranging between 53.2 nM and 7.616 μM whereas the glaucoma associated cytosolic isoform hCA II was inhibited with K i 's in the range 21.8 nM-0.807 μM. The membrane bound isoform hCA IV, involved in glaucoma and retinitis pigmentosa among others, was effectively inhibited by some of these compounds with K i  < 60 nM, better than the reference drug acetazolamide (AAZ). The tumor associated isoform hCA IX, a recently validated antitumor/antimetastatic drug target, was also effectively inhibited by some of the new sulfonamides, which possess thus the potential to be used as tools for exploring in more details the selective inhibition of hCAs involved in various pathologies. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Mechanisms of Acquired Drug Resistance to the HDAC6 Selective Inhibitor Ricolinostat Reveals Rational Drug-Drug Combination with Ibrutinib.

PubMed

Amengual, Jennifer E; Prabhu, Sathyen A; Lombardo, Maximilian; Zullo, Kelly; Johannet, Paul M; Gonzalez, Yulissa; Scotto, Luigi; Serrano, Xavier Jirau; Wei, Ying; Duong, Jimmy; Nandakumar, Renu; Cremers, Serge; Verma, Akanksha; Elemento, Olivier; O'Connor, Owen A

2017-06-15

Purpose: Pan-class I/II histone deacetylase (HDAC) inhibitors are effective treatments for select lymphomas. Isoform-selective HDAC inhibitors are emerging as potentially more targeted agents. ACY-1215 (ricolinostat) is a first-in-class selective HDAC6 inhibitor. To better understand the discrete function of HDAC6 and its role in lymphoma, we developed a lymphoma cell line resistant to ACY-1215. Experimental Design: The diffuse large B-cell lymphoma cell line OCI-Ly10 was exposed to increasing concentrations of ACY-1215 over an extended period of time, leading to the development of a resistant cell line. Gene expression profiling (GEP) was performed to investigate differentially expressed genes. Combination studies of ACY-1215 and ibrutinib were performed in cell lines, primary human lymphoma tissue, and a xenograft mouse model. Results: Systematic incremental increases in drug exposure led to the development of distinct resistant cell lines with IC 50 values 10- to 20-fold greater than that for parental lines. GEP revealed upregulation of MAPK10, HELIOS, HDAC9, and FYN, as well as downregulation of SH3BP5 and LCK. Gene-set enrichment analysis (GSEA) revealed modulation of the BTK pathway. Ibrutinib was found to be synergistic with ACY-1215 in cell lines as well as in 3 primary patient samples of lymphoma. In vivo confirmation of antitumor synergy was demonstrated with a xenograft of DLBCL. Conclusions: The development of this ACY-1215-resistant cell line has provided valuable insights into the mechanistic role of HDAC6 in lymphoma and offered a novel method to identify rational synergistic drug combinations. Translation of these findings to the clinic is underway. Clin Cancer Res; 23(12); 3084-96. ©2016 AACR . ©2016 American Association for Cancer Research.

A look at treatment strategies for relapsed multiple myeloma.

PubMed

Cetani, Giusy; Boccadoro, Mario; Oliva, Stefania

2018-05-16

Multiple myeloma treatment considerably improved during the past decade, thanks to novel effective drugs, a better understanding of myeloma biology and clonal heterogeneity, and an improved management of toxicities. The choice of regimen at relapse is usually based on prior response, toxicities, age and comorbidities of relapsed patients. Areas covered: A review was performed of the most recent and effective therapeutic strategies for the relapsed myeloma setting, by documenting the latest clinical evidence from phase II and III clinical trials. Of note, new drugs, such as carfilzomib, ixazomib, pomalidomide, daratumumab and elotuzumab, alone or in combinations in doublet or triplet regimens, have greatly increased the treatment armamentarium against myeloma. Expert Commentary: Impressive results have been obtained with new drugs in relapsed patients. Besides number of prior therapies and previous response, other factors play a crucial role in the selection of therapy. Re-challenge with previous drugs can be adopted if previous responses lasted at least 6 months and therapy had induced low toxicity. Patients' risk status can further help to appropriately select therapy at relapse, and clinical trials will allow physicians to use newer targeted therapies and immune-therapies, thus delaying palliative approaches to later relapse stages.

Investing in Our Nation's Youth. National Youth Anti-Drug Media Campaign: Phase II (Final Report).

ERIC Educational Resources Information Center

Office of National Drug Control Policy, Washington, DC.

This publication presents the findings from an evaluation of Phase II of the National Youth Anti-Drug Media Campaign. The number one goal of the campaign was to educate youth to reject illegal drugs. This report evaluates Phase II and focuses on the effect of paid television advertising on awareness of anti-drug messages among youth, teens, and…

Rational Clinical Experiment: Assessing Prior Probability and Its Impact on the Success of Phase II Clinical Trials

PubMed Central

Halperin, Daniel M.; Lee, J. Jack; Dagohoy, Cecile Gonzales; Yao, James C.

2015-01-01

Purpose Despite a robust clinical trial enterprise and encouraging phase II results, the vast minority of oncologic drugs in development receive regulatory approval. In addition, clinicians occasionally make therapeutic decisions based on phase II data. Therefore, clinicians, investigators, and regulatory agencies require improved understanding of the implications of positive phase II studies. We hypothesized that prior probability of eventual drug approval was significantly different across GI cancers, with substantial ramifications for the predictive value of phase II studies. Methods We conducted a systematic search of phase II studies conducted between 1999 and 2004 and compared studies against US Food and Drug Administration and National Cancer Institute databases of approved indications for drugs tested in those studies. Results In all, 317 phase II trials were identified and followed for a median of 12.5 years. Following completion of phase III studies, eventual new drug application approval rates varied from 0% (zero of 45) in pancreatic adenocarcinoma to 34.8% (24 of 69) for colon adenocarcinoma. The proportion of drugs eventually approved was correlated with the disease under study (P < .001). The median type I error for all published trials was 0.05, and the median type II error was 0.1, with minimal variation. By using the observed median type I error for each disease, phase II studies have positive predictive values ranging from less than 1% to 90%, depending on primary site of the cancer. Conclusion Phase II trials in different GI malignancies have distinct prior probabilities of drug approval, yielding quantitatively and qualitatively different predictive values with similar statistical designs. Incorporation of prior probability into trial design may allow for more effective design and interpretation of phase II studies. PMID:26261263

Rheological Characterization of Molten Polymer-Drug Dispersions as a Predictive Tool for Pharmaceutical Hot-Melt Extrusion Processability.

PubMed

Van Renterghem, Jeroen; Vervaet, Chris; De Beer, Thomas

2017-11-01

The aim of this study was to investigate (i) the influence of drug solid-state (crystalline or dissolved in the polymer matrix) on the melt viscosity and (ii) the influence of the drug concentration, temperature and shear rate on polymer crystallization using rheological tests. Poly (ethylene oxide) (PEO) (100.000 g/mol) and physical mixtures (PM) containing 10-20-30-40% (w/w) ketoprofen or 10% (w/w) theophylline in PEO were rheologically characterized. Rheological tests were performed (frequency and temperature sweeps in oscillatory shear as well as shear-induced crystallization experiments) to obtain a thorough understanding of the flow behaviour and crystallization of PEO-drug dispersions. Theophylline did not dissolve in PEO as the complex viscosity (η*) of the drug-polymer mixture increased as compared to that of neat PEO. In contrast, ketoprofen dissolved in PEO and acted as a plasticizer, decreasing η*. Acting as a nucleating agent, theophylline induced the crystallization of PEO upon cooling from the melt. On the other hand, ketoprofen inhibited crystallization upon cooling. Moreover, higher concentrations of ketoprofen in the drug-polymer mixture increasingly inhibited polymer crystallization. However, shear-induced crystallization was observed for all tested mixtures containing ketoprofen. The obtained rheological results are relevant for understanding and predicting HME processability (e.g., barrel temperature selection) and downstream processing such as injection moulding (e.g., mold temperature selection).

The life sciences mass spectrometry research unit.

PubMed

Hopfgartner, Gérard; Varesio, Emmanuel

2012-01-01

The Life Sciences Mass Spectrometry (LSMS) research unit focuses on the development of novel analytical workflows based on innovative mass spectrometric and software tools for the analysis of low molecular weight compounds, peptides and proteins in complex biological matrices. The present article summarizes some of the recent work of the unit: i) the application of matrix-assisted laser desorption/ionization (MALDI) for mass spectrometry imaging (MSI) of drug of abuse in hair, ii) the use of high resolution mass spectrometry for simultaneous qualitative/quantitative analysis in drug metabolism and metabolomics, and iii) the absolute quantitation of proteins by mass spectrometry using the selected reaction monitoring mode.

Novel metals and metal complexes as platforms for cancer therapy.

PubMed

Frezza, Michael; Hindo, Sarmad; Chen, Di; Davenport, Andrew; Schmitt, Sara; Tomco, Dajena; Dou, Q Ping

2010-06-01

Metals are essential cellular components selected by nature to function in several indispensable biochemical processes for living organisms. Metals are endowed with unique characteristics that include redox activity, variable coordination modes, and reactivity towards organic substrates. Due to their reactivity, metals are tightly regulated under normal conditions and aberrant metal ion concentrations are associated with various pathological disorders, including cancer. For these reasons, coordination complexes, either as drugs or prodrugs, become very attractive probes as potential anticancer agents. The use of metals and their salts for medicinal purposes, from iatrochemistry to modern day, has been present throughout human history. The discovery of cisplatin, cis-[Pt(II) (NH(3))(2)Cl(2)], was a defining moment which triggered the interest in platinum(II)- and other metal-containing complexes as potential novel anticancer drugs. Other interests in this field address concerns for uptake, toxicity, and resistance to metallodrugs. This review article highlights selected metals that have gained considerable interest in both the development and the treatment of cancer. For example, copper is enriched in various human cancer tissues and is a co-factor essential for tumor angiogenesis processes. However the use of copper-binding ligands to target tumor copper could provide a novel strategy for cancer selective treatment. The use of nonessential metals as probes to target molecular pathways as anticancer agents is also emphasized. Finally, based on the interface between molecular biology and bioinorganic chemistry the design of coordination complexes for cancer treatment is reviewed and design strategies and mechanisms of action are discussed.

Characterization and Expression of Drug Resistance Genes in MDROs Originating from Combat Wound Infections

DTIC Science & Technology

2016-09-01

and virulence mechanism contributing to their success as pathogens in the wound environment. A novel bioinformatics pipeline was used to incorporate...enable mapping of these features onto the genomes of the 25 selected MDROs. Preliminary investigations of IS element content showed considerable...23 Appendices (Supporting Data)……………………………………………………. 25 Appendix I. Publication ……………………………………………………….. 25 Appendix II. Select A

Sodium alginate as a potential carrier in solid dispersion formulations to enhance dissolution rate and apparent water solubility of BCS II drugs.

PubMed

Borba, Paola Aline Amarante; Pinotti, Marihá; de Campos, Carlos Eduardo Maduro; Pezzini, Bianca Ramos; Stulzer, Hellen Karine

2016-02-10

The solid dispersion technique is the most effective method for improving the dissolution rate of poorly water-soluble drugs, however it depends on a suitable carrier selection. The work explored the use of the biopolymer sodium alginate (SA) as a potential carrier in solid dispersions (SD). The data demonstrated that SA was able to improve the biopharmaceutical properties of the BCS II drug telmisartan (TEL) of low solubility even using relative small drug:polymer ratio. A solid state grinding process was used to prepare the solid dispersions (SD) during 45 min. The SD were prepared in different proportions of drug and carrier of 1:1, 1:3, 1:5, 1:7 and 1:9 (mass/mass). DSC, XRPD, FTIR and Raman confirmed the presence of molecular interactions between TEL and the carrier. FTIR supports the presence of hydrogen bonds between TEL and the carrier. SD_1:5, SD_1:7 and SD_1:9 enhanced the dissolution rate of the drug releasing more than 80% of the drug in just 30 min (83%, 84% and 87%). The the t-test results demonstrated equal dissolution efficiency values for SD_1:7 and Micardis(®), however the similarity (f2) and difference (f1) fit factors showed that the SD and Micardis(®) are statistically different. The physical stability studies demonstrated that SD using sodium alginate as a carrier remained unchanged during the period of 90 days at room temperature, showing that the sodium alginate acts as a good anti plasticizer agent, preventing the drug recrystallization. Copyright © 2015 Elsevier Ltd. All rights reserved.

The Neurocircuitry of Impaired Insight in Drug Addiction

PubMed Central

Goldstein, Rita Z.; Craig, A. D. (Bud); Bechara, Antoine; Garavan, Hugh; Childress, Anna Rose; Paulus, Martin P.; Volkow, Nora D.

2010-01-01

More than 80% of addicted individuals fail to seek treatment, which might reflect impairments in recognition of severity of disorder. Considered by some as intentional deception, such `denial' might instead reflect dysfunction of brain networks subserving insight and selfawareness. Here we review the scant literature on insight in addiction and integrate this perspective with the role of: (i) the insula in interoception, self-awareness and drug craving; (ii) the anterior cingulate in behavioral monitoring and response selection (relevant to disadvantageous choices in addiction); (iii) the dorsal striatum in automatic habit formation; and (iv) drug related stimuli that predict emotional behavior in addicted individuals, even without conscious awareness. We discuss implications for clinical treatment including the design of interventions to improve insight into illness severity in addiction. PMID:19716751

Inflammatory Signaling by NOD-RIPK2 Is Inhibited by Clinically Relevant Type II Kinase Inhibitors.

PubMed

Canning, Peter; Ruan, Qui; Schwerd, Tobias; Hrdinka, Matous; Maki, Jenny L; Saleh, Danish; Suebsuwong, Chalada; Ray, Soumya; Brennan, Paul E; Cuny, Gregory D; Uhlig, Holm H; Gyrd-Hansen, Mads; Degterev, Alexei; Bullock, Alex N

2015-09-17

RIPK2 mediates pro-inflammatory signaling from the bacterial sensors NOD1 and NOD2, and is an emerging therapeutic target in autoimmune and inflammatory diseases. We observed that cellular RIPK2 can be potently inhibited by type II inhibitors that displace the kinase activation segment, whereas ATP-competitive type I inhibition was only poorly effective. The most potent RIPK2 inhibitors were the US Food and Drug Administration-approved drugs ponatinib and regorafenib. Their mechanism of action was independent of NOD2 interaction and involved loss of downstream kinase activation as evidenced by lack of RIPK2 autophosphorylation. Notably, these molecules also blocked RIPK2 ubiquitination and, consequently, inflammatory nuclear factor κB signaling. In monocytes, the inhibitors selectively blocked NOD-dependent tumor necrosis factor production without affecting lipopolysaccharide-dependent pathways. We also determined the first crystal structure of RIPK2 bound to ponatinib, and identified an allosteric site for inhibitor development. These results highlight the potential for type II inhibitors to treat indications of RIPK2 activation as well as inflammation-associated cancers. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

77 FR 60124 - Draft Guidance for Industry on Initial Completeness Assessments for Type II Active Pharmaceutical...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-10-02

... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2012-D-1010] Draft Guidance for Industry on Initial Completeness Assessments for Type II Active Pharmaceutical... certain drug master files, namely, Type II active pharmaceutical ingredient (API) drug master files (DMFs...

Selective activation of heparin cofactor II by a sulfated polysaccharide isolated from the leaves of Artemisia princeps.

PubMed

Hayakawa, Y; Hayashi, T; Hayashi, T; Niiya, K; Sakuragawa, N

1995-10-01

While checking anticoagulant activities in crude fractions from Wakan-Yakus (traditional herbal drugs), we detected antithrombin activity in the polysaccharide fraction of the leaves of Artemisia princeps Pamp. A sulfated polysaccharide purified from the crude fractions by ion-exchange chromatography on DEAE-cellulose and gel filtration on Sepharose 6B potentiated the heparin cofactor II (HC II)-dependent antithrombin activity but not the antithrombin activity of antithrombin III (AT III). The polysaccharide enhanced the HC II-thrombin reaction more than 6000-fold. The apparent second-order rate constant of thrombin inhibition by HC II increased from 3.8 x 10(4) (in the absence of the polysaccharide) to 2.5 x 10(8) M-1 min-1 in the presence of 25-125 micrograms/ml of the polysaccharide. In human plasma, the polysaccharide accelerated the formation of thrombin-HC II complex. The stimulating effect on HC II-dependent antithrombin activity was almost totally abolished by treatment with chondroitinase AC I, heparinase or heparitinase, while chondroitinase ABC or chondroitinase AC II had little or no effect. These results suggest that the polysaccharide is a glycosaminoglycan-like material with properties that are quite distinct from heparin or dermatan sulfate.

Naphthalocyanine-complexes as potential photosensitizers for PDT of tumors

NASA Astrophysics Data System (ADS)

Shopova, Maria; Woehrle, Dieter; Mantareva, Vanya; Mueller, Silke

1999-07-01

In the present paper information about the synthesis and results on the pharmacokinetic and experimental photodynamic therapy (PDT) of naphthalocyanines are given. The photodynamic activity of differently substituted zinc(II)- and silicon(IV)-naphthalocyanines using liposomes or Cremophor EL as drug-delivery systems is shown on different tumor models. For the evaluation of the phototherapeutic effect different assessment criteria were used, including light and electron microscope observations. The main conclusions which can be arrived at on the basis of our findings are the following: silicon(IV)-naphthalocyanine seems to be not a very effective tumor sensitizer, especially in the treatment o pigmented melanoma, while zinc(II)-naphthalocyanines appear to be very promising for PDT of tumors. Their selective targeting and slow clearance from tumor tissue, fast clearance from skin and pronounced phototherapeutic effect on different tumor models and especially at melanotic tumors, even after application of low drug doses, make this group of photosensitizers very attractive for successful PDT of cancer.

Celecoxib enhances the anti-inflammatory effects of farnesylthiosalicylic acid on T cells independent of prostaglandin E(2) production.

PubMed

Mor, Adam; Aizman, Elizabeta; Kloog, Yoel

2012-10-01

Celecoxib (Celebrex(®)), a non-steroidal anti-inflammatory drug and selective cyclooxygenase-2 inhibitor, is widely used to treat arthritis and other inflammatory disorders. Awareness of its anti-proliferative properties has prompted another indication for its use, in preventing colon polyps in high-risk populations. Farnesylthiosalicylic acid (FTS; Salirasib(®)), designed to inhibit oncogenic Ras and currently under evaluation in phase I/II and II clinical trials, was recently shown by our group to exert anti-inflammatory effects on both lymphocytes and mast cells. Here we examined whether celecoxib combined with FTS would enhance this anti-inflammatory activity. While each drug separately inhibited Ras activation in these cells, their combination yielded more marked inhibition as well as further inhibition of ERK phosphorylation, lymphocyte adhesion, and interleukin-2 secretion. The inhibitory effects, moreover, were independent of prostaglandin E(2) secretion. These data point to the promising potential of combined treatment with celecoxib and FTS for inflammatory disorders involving lymphocytes.

Dual-tail arylsulfone-based benzenesulfonamides differently match the hydrophobic and hydrophilic halves of human carbonic anhydrases active sites: Selective inhibitors for the tumor-associated hCA IX isoform.

PubMed

Ibrahim, Hany S; Allam, Heba Abdelrasheed; Mahmoud, Walaa R; Bonardi, Alessandro; Nocentini, Alessio; Gratteri, Paola; Ibrahim, Eslam S; Abdel-Aziz, Hatem A; Supuran, Claudiu T

2018-05-25

The synthesis and characterization of two new sets of arylsulfonehydrazone benzenesulfonamides (4a-4i with phenyl tail and 4j-4q with tolyl tail) are reported. The compounds were designed according to a dual-tails approach to modulate the interactions of the ligands portions at the outer rim of both hydrophobic and hydrophilic active site halves of human isoforms of carbonic anhydrase (CA, EC 4.2.1.1). The synthesized sulfonamides were evaluated in vitro for their inhibitory activity against the following human (h) isoforms, hCA I, II, IV and IX. With the latter being a validated anticancer drug target and a marker of tumor hypoxia, attractive results arose from the Compounds' inhibitory screening in terms of potency and selectivity. Indeed, whereas the first subset of compounds 4a-4i exhibited great efficacy in inhibiting both the ubiquitous, off-target hCA II (K I s 9.5-172.0 nM) and hCA IX (K I s 7.5-131.5 nM), the second subset of tolyl-bearing derivatives 4j-4q were shown to possess a selective hCA IX inhibitory action over isoforms I, II and IV. The most selective compounds 4l and 4n were further screened for their in vitro cytotoxic activity against MCF-7 and MDA-MB-231 cancer cell lines under hypoxic conditions. The selective IX/II inhibitory trend of 4j-4q compared to those of compounds 4a-4i was unveiled by docking studies. Further exploration of these molecules could be useful for the development of novel antitumor agents with a selective CA inhibitory mechanism. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Pharmacological traits of delta opioid receptors: pitfalls or opportunities?

PubMed Central

van Rijn, Richard M.; DeFriel, Julia N.; Whistler, Jennifer L.

2013-01-01

Delta opioid receptors (DORs) have been considered as a potential target to relieve pain as well as treat depression and anxiety disorders, and are known to modulate other physiological responses, including ethanol and food consumption. A small number of DOR selective drugs are in clinical trials, but no DOR selective drugs have been approved by the Federal Drug Administration and some candidates have failed in phase II clinical trials, highlighting current difficulties producing effective delta opioid based therapies. Recent studies have provided new insights into the pharmacology of the DOR, which is often complex and at times paradoxical. This review will discuss the existing literature focusing on four aspects: 1) Two DOR subtypes have been postulated based on differences in pharmacological effects of existing DOR-selective ligands 2) DORs are expressed ubiquitously throughout the body and central nervous system and are, thus, positioned to play a role in a multitude of diseases. 3) DOR expression is often dynamic, with many reports of increased expression during exposure to chronic stimuli, such as stress, inflammation, neuropathy, morphine, or changes in endogenous opioid tone. 4) A large structural variety in DOR ligands implies potential different mechanisms of activating the receptor. These combined features of DOR pharmacology illustrate the potential benefit of designing tailored or biased DOR ligands. PMID:23649885

Human transport protein carrier for controlled photoactivation of antitumor prodrug and real-time intracellular tumor imaging.

PubMed

Li, Xi; Mu, Jing; Liu, Fang; Tan, Eddy Wei Ping; Khezri, Bahareh; Webster, Richard D; Yeow, Edwin Kok Lee; Xing, Bengang

2015-05-20

Current anticancer chemotherapy often suffers from poor tumor selectivity and serious drug resistance. Proper vectors for targeted delivery and controlled drug release play crucial roles in improving the therapeutic selectivity to tumor areas and also overcoming the resistance of cancer cells. In this work, we developed a novel human serum albumin (HSA) protein-based nanocarrier system, which combines the photoactivatable Pt(IV) antitumor prodrug for realizing the controlled release and fluorescent light-up probe for evaluations of drug action and efficacy. The constructed Pt(IV)-probe@HSA platform can be locally activated by light irradiation to release the active Pt species, which results in enhanced cell death at both drug-sensitive A2780 and cisplatin-resistant A2780cis cell lines when compared to the free prodrug molecules. Simultaneously, the cytotoxicity caused by light controlled drug release would further lead to the cellular apoptosis and trigger the activation of caspases 3, one crucial protease enzyme in apoptotic process, which could cleave the recognition peptide moiety (DEVD) with a flanking fluorescent resonance energy transfer (FRET) pair containing near-infrared (NIR) fluorophore Cy5 and quencher Qsy21 on the HSA nanocarrier surface. The turn-on fluorescence in response to caspase-3 could be assessed by fluorescence microscopy and flow cytometry analysis. Our results supported the hypothesis that such a unique design may present a successful platform for multiple roles: (i) a biocompatible protein-based nanocarrier for drug delivery, (ii) the controlled drug release with strengthened therapeutic effects, (iii) real-time monitoring of antitumor drug efficacy at the earlier stage.

21 CFR 1301.33 - Application for bulk manufacture of Schedule I and II substances.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 9 2013-04-01 2013-04-01 false Application for bulk manufacture of Schedule I and II substances. 1301.33 Section 1301.33 Food and Drugs DRUG ENFORCEMENT ADMINISTRATION, DEPARTMENT OF... manufacture of Schedule I and II substances. (a) In the case of an application for registration or...

Synthesis, biological assessment and molecular modeling of new multipotent MAO and cholinesterase inhibitors as potential drugs for the treatment of Alzheimer's disease.

PubMed

Samadi, Abdelouahid; Chioua, Mourad; Bolea, Irene; de Los Ríos, Cristóbal; Iriepa, Isabel; Moraleda, Ignacio; Bastida, Agatha; Esteban, Gerard; Unzeta, Mercedes; Gálvez, Enrique; Marco-Contelles, José

2011-09-01

The synthesis, biological evaluation and molecular modeling of new multipotent inhibitors of type I and type II, able to simultaneously inhibit monoamine oxidases (MAO) as well as acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), is described. Compounds of type I were prepared by sequential reaction of 2,6-dichloro-4-phenylpyridine-3,5-dicarbonitrile (14) [or 2,6-dichloropyridine-3,5-dicarbonitrile (15)] with prop-2-yn-1-amine (or N-methylprop-2-yn-1-amine) and 2-(1-benzyl-piperidin-4-yl)alkylamines 22-25. Compounds of type II were prepared by Friedländer type reaction of 6-amino-5-formyl-2-(methyl(prop-2-yn-1-yl)amino)nicotinonitriles 32 and 33 with 4-(1-benzylpiperidin-4-yl)butan-2-one (31). The biological evaluation of molecules 1-11 showed that most of these compounds are potent, in the nanomolar range, and selective AChEI, with moderate and equipotent selectivity for MAO-A and MAO-B inhibition. Kinetic studies of compound 8 proved that this is a EeAChE mixed type inhibitor (IC(50) = 16 ± 2; Ki = 12 ± 3 nM). Molecular modeling investigation on compound 8 confirmed its dual AChE inhibitory profile, binding simultaneously at the catalytic active site (CAS) and at the peripheric anionic site (PAS). In overall, compound 11, as a potent and selective dual AChEI, showing a moderate and selective MAO-A inhibitory profile, can be considered as an attractive multipotent drug for further development on two key pharmacological targets playing key roles in the therapy of Alzheimer's disease. Copyright © 2011 Elsevier Masson SAS. All rights reserved.

Targeted theranostic platinum(IV) prodrug with a built-in aggregation-induced emission light-up apoptosis sensor for noninvasive early evaluation of its therapeutic responses in situ.

PubMed

Yuan, Youyong; Kwok, Ryan T K; Tang, Ben Zhong; Liu, Bin

2014-02-12

Targeted drug delivery to tumor cells with minimized side effects and real-time in situ monitoring of drug efficacy is highly desirable for personalized medicine. In this work, we report the synthesis and biological evaluation of a chemotherapeutic Pt(IV) prodrug whose two axial positions are functionalized with a cyclic arginine-glycine-aspartic acid (cRGD) tripeptide for targeting integrin αvβ3 overexpressed cancer cells and an apoptosis sensor which is composed of tetraphenylsilole (TPS) fluorophore with aggregation-induced emission (AIE) characteristics and a caspase-3 enzyme specific Asp-Glu-Val-Asp (DEVD) peptide. The targeted Pt(IV) prodrug can selectively bind to αvβ3 integrin overexpressed cancer cells to facilitate cellular uptake. In addition, the Pt(IV) prodrug can be reduced to active Pt(II) drug in cells and release the apoptosis sensor TPS-DEVD simultaneously. The reduced Pt(II) drug can induce the cell apoptosis and activate caspase-3 enzyme to cleave the DEVD peptide sequence. Due to free rotation of the phenylene rings, TPS-DEVD is nonemissive in aqueous media. The specific cleavage of DEVD by caspase-3 generates the hydrophobic TPS residue, which tends to aggregate, resulting in restriction of intramolecular rotations of the phenyl rings and ultimately leading to fluorescence enhancement. Such noninvasive and real-time imaging of drug-induced apoptosis in situ can be used as an indicator for early evaluation of the therapeutic responses of a specific anticancer drug.

A Structural Equation Modeling of the Relationships between Depression, Drug Abuse and Social Support with Suicidal Ideation among Soldiers in Iran in 2015.

PubMed

Nosratabadi, Mehdi; Halvaiepour, Zohreh

2016-01-01

Military service is a crucial period in the lives of young people and during this period soldier facing with multiple psychosocial problems. The present study aimed to explore structural analysis of the relationships between depression, drug abuse, social support and the risk of suicidal ideation among Military Medical University soldiers in Iran. In the present correlational research, a sample of 176 soldiers, from three units, was selected using randomly stratified sampling. Data were collected through the Social Support Questionnaire (SSQ), the Beck Depression Inventory-II (BDI-II), the Beck Scale for Suicide Ideation (BSS) and the Possibility of Drug Abuse Scale (LDAS). Structural equation modeling was used to test the fit of the model, identify direct and indirect effects of the psychosocial correlates. Data were analyzed using the SPSS and AMOS software (Verson22). out of the whole subjects, 28.4% had suicidal ideation and 65.3% had degrees of depression (mild to severe). A significant reverse relationship was observed between social support and suicidal ideation (p<0.05). The strongest relationship was detected between drug abuse and suicidal ideation. The final structural model indicated that 74% of the variance in suicidal ideation was explained by the three examined variables of depression, social support and drug abuse. The overall results showed that the risk of suicidal ideation, depression and drug abuse are relatively significant in Military Medical University soldiers requiring taking serious actions by the authorities and other relevant organizations in order to improve the psychosocial health status of these soldiers.

Insight into the Development of Dissolution Media for BCS Class II Drugs: A Review from Quality Control and Prediction of In Vivo Performance Perspectives.

PubMed

Wu, Chunnuan; Liu, Yan; He, Zhonggui; Sun, Jin

2016-01-01

To assess in vivo behavior through in vitro method, the dissolution test is mostly used, both for quality control (QC) and for development purpose. In view of the fact that a dissolution test can hardly achieve two goals at the same time, the design of dissolution testing generally varies along with the development stage of drug products and therefore the selection of dissolution media may change with the goals of the dissolution test. To serve the QC purpose, a dissolution medium is designed to provide a sink condition; for development purpose, the dissolution medium is required to simulate the physiological conditions in the gastrointestinal tract as far as possible. In this review, we intended to provide an initial introduction to the various dissolution media applied for QC and formulation development purposes for poorly water soluble drugs. We focused on these methods like addition of cosolvents, surfactants and utilization of biphasic media, applied to provide sink conditions which are difficult to be achieved by simple aqueous buffers for lipophilic drugs, and introduced the development of physiologically relevant media for human and animals like dog and rat with respect to the choice of buffers, bile salts, lipids and so on. In addition, we further discussed the influence of biorelevant dissolution media on the modification of drug Biopharmaceutical Classification System (BCS) classification, especially for BCS class II drugs with low solubility and high permeability, the solubility of which is relatively sensitive to the presence of bile salts and lipids.

Anti-proliferative activities on HeLa cancer cell line of Thai medicinal plant recipes selected from MANOSROI II database.

PubMed

Manosroi, Jiradej; Boonpisuttinant, Korawinwich; Manosroi, Worapaka; Manosroi, Aranya

2012-07-13

The Thai/Lanna medicinal plant recipe database "MANOSROI II" contained the medicinal plant recipes of all regions in Thailand for the treatment of various diseases including anti-cancer medicinal plant recipes. To investigate anti-proliferative activity on HeLa cell lines of medicinal plant recipes selected from the Thai/Lanna medicinal plant recipe database "MANOSROI II". The forty aqueous extracts of Thai/Lanna medicinal plant recipes selected from the Thai/Lanna medicinal plant recipe database "MANOSROI II" were investigated for anti-proliferative activity on HeLa cell line by SRB assay. The apoptosis induction by caspase-3 activity and MMP-2 inhibition activity by zymography on HeLa cell line of the three selected aqueous extracts, which gave the highest anti-proliferative activity were determined. Phytochemicals and anti-oxidative activities including free radical scavenging activity, inhibition of lipid peroxidation and metal chelating inhibition activities were also investigated. Sixty percentages of the medicinal plant recipes selected from "MANOSROI II" database showed anti-proliferative activity on HeLa cell line. The recipes of N031(Albizia chinensis (Osbeck) Merr, Cassia fistula L., and Dargea volubilis Benth.ex Hook. etc.), N039 (Nymphoides indica L., Peltophorum pterocarpum (DC.), and Polyalthia debilis Finet et Gagnep etc.) and N040 (Nymphoides indica L. Kuntze, Sida rhombifolia L., and Xylinbaria minutiflora Pierre. etc.) gave higher anti-proliferative activity than the standard anti-cancer drug, cisplatin of 1.25, 1.29 and 30.18 times, respectively. The positive relationship between the anti-proliferative activity and the MMP-2 inhibition activity and metal chelating inhibition activity was observed, but no relationship between the anti-proliferative activity and apoptosis induction, free radical scavenging activity and lipid peroxidation inhibition activity. Phytochemicals found in these extracts were alkaloids, flavonoids, tannins and xanthones, but not anthraquinones and carotenoids. The recipe N040 exhibited the highest anti-proliferative and MMP-2 inhibition on HeLa cancer cell line at 30 and threefolds of cisplatin, respectively (p<0.05), while recipe N031 gave the highest caspase-3 activity (1.29-folds over the control) (p<0.05). This study has demonstrated that recipe N040 selected from MANOSROI II database appeared to be a good candidate with high potential for the further development as an anti-cancer agent. Crown Copyright © 2012. Published by Elsevier Ireland Ltd. All rights reserved.

[Dexrazoxane (ICRF-187)--a cardioprotectant and modulator of action of some anticancer drugs].

PubMed

Kik, Krzysztof; Szmigiero, Leszek

2006-01-01

The nthracycline antibiotics are among the most widely used and effective anticancer drugs. The therapeutic efficacy of this class of drugs is limited by cumulative cardiac toxicity. Dexrazoxane is the only clinically approved cardioprotective agent used in anthracycline-containing anticancer therapy. Its cardioprotective action allows the use of a much higher cumulative dose of anthracyclines and improvement in the effectiveness of treatment. Anthracyclines form complexes with iron ions, which are very active in the production of reactive oxygen species responsible for the lipid peroxidation of mitochondrial and endoplasmatic reticulum membranes. This process seems to be the major cause of anthracycline-induced cardiotoxicity. Dexrazoxane exerts its protective effects by rapid and complete binding of ferric and ferrous ions, even by displacing the metal ions from complexes with anthracyclines. Besides its cardioprotective effect, dexrazoxane also exhibits anticancer properties. Like other derivatives of bisdioxopiperazine, dexrazoxane is a catalytic inhibitor of eukaryotic DNA topoisomerase II, the key enzyme controlling DNA topology and contributing to the replication and transcription processes. Dexrazoxane is able to lock topoisomerase II at the stage of the enzyme reaction cycle where the enzyme forms a closed clamp around the DNA. This phenomenon seems to be the main reason for the generation of DNA double-strand breaks by dexrazoxane as well as its cytotoxicity against quickly proliferating cancer cells. Other effects of its topoisomerase II catalytic inhibition is the induction of cell differentiation and apoptosis. Dexrazoxane may be used not only as a cardioprotective agent, but also as a modulator of action of some anticancer drugs by enhancing their selectivity or by delaying the development of multidrug resistance.

A proteomic approach to identifying new drug targets (potentiating topoisomerase II poisons).

PubMed

Jenkins, J R

2008-10-01

Topoisomerase II poisons are an established part of best clinical practice for the treatment of a number of solid tumours and haematological malignancies. However, toxicity and resistance to chemotherapeutic drugs often complicate the treatment. Furthermore, topoisomerase II poisons can also induce sister chromatid exchange, chromosomal recombination and chromosome aberrations and are associated with a significant risk of secondary leukaemia. It would therefore be of great clinical benefit if the efficacy of topoisomerase II inhibitors could be enhanced without the increased toxic side effects. It is proposed that clinical agents targeting topoisomerase II can be enhanced by inhibiting proteins that modulate topoisomerase II. The aim is to identify proteins, that by the nature of their interaction with topoisomerase II, represent putative drug targets.

Selecting promising treatments in randomized Phase II cancer trials with an active control.

PubMed

Cheung, Ying Kuen

2009-01-01

The primary objective of Phase II cancer trials is to evaluate the potential efficacy of a new regimen in terms of its antitumor activity in a given type of cancer. Due to advances in oncology therapeutics and heterogeneity in the patient population, such evaluation can be interpreted objectively only in the presence of a prospective control group of an active standard treatment. This paper deals with the design problem of Phase II selection trials in which several experimental regimens are compared to an active control, with an objective to identify an experimental arm that is more effective than the control or to declare futility if no such treatment exists. Conducting a multi-arm randomized selection trial is a useful strategy to prioritize experimental treatments for further testing when many candidates are available, but the sample size required in such a trial with an active control could raise feasibility concerns. In this study, we extend the sequential probability ratio test for normal observations to the multi-arm selection setting. The proposed methods, allowing frequent interim monitoring, offer high likelihood of early trial termination, and as such enhance enrollment feasibility. The termination and selection criteria have closed form solutions and are easy to compute with respect to any given set of error constraints. The proposed methods are applied to design a selection trial in which combinations of sorafenib and erlotinib are compared to a control group in patients with non-small-cell lung cancer using a continuous endpoint of change in tumor size. The operating characteristics of the proposed methods are compared to that of a single-stage design via simulations: The sample size requirement is reduced substantially and is feasible at an early stage of drug development.

21 CFR 314.440 - Addresses for applications and abbreviated applications.

Code of Federal Regulations, 2010 CFR

2010-04-01

...-600), Center for Drug Evaluation and Research, Food and Drug Administration, Metro Park North II, 7500... Evaluation and Research, Food and Drug Administration, Attn: [insert name of person], Metro Park North II... 21 Food and Drugs 5 2010-04-01 2010-04-01 false Addresses for applications and abbreviated...

76 FR 43690 - Guidance for Industry and Food and Drug Administration Staff; Class II Special Controls Guidance...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-07-21

... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2007-D-0149] (Formerly 2007D-0309) Guidance for Industry and Food and Drug Administration Staff; Class II Special Controls Guidance Document: Electrocardiograph Electrodes; Availability AGENCY: Food and Drug...

Drug development: from concept to marketing!

PubMed

Tamimi, Nihad A M; Ellis, Peter

2009-01-01

Drug development is an expensive, long and high-risk business taking 10-15 years and is associated with a high attrition rate. It is driven by medical need, disease prevalence and the likelihood of success. Drug candidate selection is an iterative process between chemistry and biology, refining the molecular properties until a compound suitable for advancing to man is found. Typically, about one in a thousand synthesised compounds is ever selected for progression to the clinic. Prior to administration to humans, the pharmacology and biochemistry of the drug is established using an extensive range of in vitro and in vivo test procedures. It is also a regulatory requirement that the drug is administered to animals to assess its safety. Later-stage animal testing is also required to assess carcinogenicity and effects on the reproductive system. Clinical phases of drug development include phase I in healthy volunteers to assess primarily pharmacokinetics, safety and toleration, phase II in a cohort of patients with the target disease to establish efficacy and dose-response relationship and large-scale phase III studies to confirm safety and efficacy. Experience tells us that approximately only 1 in 10 drugs that start the clinical phase will make it to the market. Each drug must demonstrate safety and efficacy in the intended patient population and its benefits must outweigh its risks before it will be approved by the regulatory agencies. Strict regulatory standards govern the conduct of pre-clinical and clinical trials as well as the manufacturing of pharmaceutical products. The assessment of the new medicinal product's safety continues beyond the initial drug approval through post-marketing monitoring of adverse events. Copyright 2009 S. Karger AG, Basel.

Praziquantel for Schistosomiasis: Single-Drug Metabolism Revisited, Mode of Action, and Resistance.

PubMed

Vale, Nuno; Gouveia, Maria João; Rinaldi, Gabriel; Brindley, Paul J; Gärtner, Fátima; Correia da Costa, José M

2017-05-01

Schistosomiasis, a major neglected tropical disease, affects more than 250 million people worldwide. Treatment of schistosomiasis has relied on the anthelmintic drug praziquantel (PZQ) for more than a generation. PZQ is the drug of choice for the treatment of schistosomiasis; it is effective against all major forms of schistosomiasis, although it is less active against juvenile than mature parasites. A pyrazino-isoquinoline derivative, PZQ is not considered to be toxic and generally causes few or transient, mild side effects. Increasingly, mass drug administration targeting populations in sub-Saharan Africa where schistosomiasis is endemic has led to the appearance of reduced efficacy of PZQ, which portends the selection of drug-resistant forms of these pathogens. The synthesis of improved derivatives of PZQ is attracting attention, e.g., in the (i) synthesis of drug analogues, (ii) rational design of pharmacophores, and (iii) discovery of new compounds from large-scale screening programs. This article reviews reports from the 1970s to the present on the metabolism and mechanism of action of PZQ and its derivatives against schistosomes. Copyright © 2017 American Society for Microbiology.

Effects of landiolol, an ultra-short-acting beta1-selective blocker, on electrical storm refractory to class III antiarrhythmic drugs.

PubMed

Miwa, Yosuke; Ikeda, Takanori; Mera, Hisaaki; Miyakoshi, Mutsumi; Hoshida, Kyoko; Yanagisawa, Ryoji; Ishiguro, Haruhisa; Tsukada, Takehiro; Abe, Atsuko; Yusu, Satoru; Yoshino, Hideaki

2010-05-01

Occasionally it is difficult to inhibit electrical storm (ES) with standard pharmacological treatment. In the present study the effect of landiolol, an ultra-short-acting beta(1)-selective blocker, on ES refractory to class III antiarrhythmic drugs was evaluated. The study group comprised 42 consecutive patients who developed ES for which intravenous class III antiarrhythmic drugs, such as amiodarone and nifekalant, were ineffective. Landiolol was administered intravenously with an initial dose of 2.5 microg x kg(-1) x min(-1), which was doubled if it was ineffective, up to a maximum dose of 80 microg x kg(-1) x min(-1). Landiolol inhibited ES in 33 patients (79%) at a mean dose of 7.5+/-12.2 microg x kg(-1) x min(-1). All patients in whom landiolol was ineffective died of arrhythmia. Of the 33 patients in whom landiolol was effective, 25 survived and were discharged (60% of all patients). Landiolol significantly decreased heart rate (P<0.0001), but did not affect blood pressure. Landiolol was not discontinued for adverse effects in any of the responders. Age, APACHE II score, and pH of arterial blood gas differed significantly between the responders and nonresponders. Landiolol is useful as a life-saving drug for class III antiarrhythmic drug-resistant ES. The main mechanism of ES refractory to class III antiarrhythmic drugs could be abnormal automaticity but not reentry.

Development of optimized self-nano-emulsifying drug delivery systems (SNEDDS) of carvedilol with enhanced bioavailability potential.

PubMed

Singh, Bhupinder; Khurana, Lalit; Bandyopadhyay, Shantanu; Kapil, Rishi; Katare, O O P

2011-11-01

Carvedilol, a widely prescribed cardiovascular drug for hypertension and congestive heart failure, exhibits low and variable bioavailability owing to poor absorption and extensive hepatic first-pass metabolism. The current research work, therefore, entails formulation development of liquid self-nano-emulsifying drug delivery systems (SNEDDS) to enhance the bioavailability of carvedilol by facilitating its transport via lymphatic circulation. The formulation constituents, i.e. lipids, surfactants, and co-surfactants, were selected on the basis of solubility studies. Pseudo-ternary phase diagrams were constructed to embark upon the selection of blend of lipidic (i.e. Capmul PG8) and hydrophilic components (i.e. Cremophor EL as surfactant and Transcutol HP as co-surfactant) for efficient and robust formulation of SNEDDS. The SNEDDS, systematically optimized employing a central composite design (CCD), were evaluated for various response variables viz drug release parameters, emulsification time, emulsion droplet size, and mean dissolution time. In vitro drug release studies depicted that the release from SNEDDS systems followed a non-Fickian kinetic behavior. The TEM imaging of the optimized formulation affirmed the uniform shape and nano size of the system. Accelerated studies of the optimized formulation indicated high stability of the formulation for 6 months. The in situ perfusion studies carried out in wistar rats construed several fold augmentation in the permeability and absorption potential of the optimized formulation vis-à-vis marketed formulation. Thus, the present studies ratified the potential of SNEDDS in augmenting the oral bioavailability of BCS class II drugs.

INTEGRATING HEALTH TECHNOLOGY ASSESSMENT PRINCIPLES IN FORMULARY MANAGEMENT.

PubMed

Teng, Monica; Khoo, Ai Leng; Zhao, Ying Jiao; Lin, Liang; Lim, Boon Peng

2016-01-01

Effective formulary management in healthcare institutions safeguards rational drug use and optimizes health outcomes. We implemented a formulary management program integrating the principles of health technology assessment (HTA) to improve the safe, appropriate, and cost-effective use of medicine in Singapore. A 3-year formulary management program was initiated in 2011 in five public healthcare institutions. This program was managed by a project team comprising HTA researchers. The project team worked with institutional pharmacy and therapeutics (P&T) committees to: (i) develop tools for formulary drug review and decision making; (ii) enhance the HTA knowledge and skills of formulary pharmacists and members of P&T committees; (iii) devise a prioritization framework to overcome resource constraints and time pressure; and (iv) conceptualize and implement a framework to review existing formulary. Tools that facilitate drug request submission, drug review, and decision making were developed for formulary drug inclusion. A systematic framework to review existing formulary was also developed and tested in selected institutions. A competency development plan was rolled out over 2 years to enhance formulary pharmacists' proficiency in systematic literature search and review, meta-analysis, and pharmacoeconomic evaluation. The plan comprised training workshops and on-the-job knowledge transfer between the project team and institutional formulary pharmacists through collaborating on selected drug reviews. A resource guide that consolidated the tools and templates was published to encourage the adoption of best practices in formulary management. Based on the concepts of HTA, we implemented an evidence-based approach to optimize formulary management.

The University of Kansas High-Throughput Screening Laboratory. Part II: enabling collaborative drug-discovery partnerships through cutting-edge screening technology.

PubMed

McDonald, Peter R; Roy, Anuradha; Chaguturu, Rathnam

2011-07-01

The University of Kansas High-Throughput Screening (KU HTS) core is a state-of-the-art drug-discovery facility with an entrepreneurial open-service policy, which provides centralized resources supporting public- and private-sector research initiatives. The KU HTS core was established in 2002 at the University of Kansas with support from an NIH grant and the state of Kansas. It collaborates with investigators from national and international academic, nonprofit and pharmaceutical organizations in executing HTS-ready assay development and screening of chemical libraries for target validation, probe selection, hit identification and lead optimization. This is part two of a contribution from the KU HTS laboratory.

Drug carrier systems for solubility enhancement of BCS class II drugs: a critical review.

PubMed

Kumar, Sumit; Bhargava, Deepak; Thakkar, Arti; Arora, Saahil

2013-01-01

Poor aqueous solubility impedes a drug's bioavailability and challenges its pharmaceutical development. Pharmaceutical development of drugs with poor water solubility requires the establishment of a suitable formulation layout among various techniques. Various approaches have been investigated extensively to improve the aqueous solubility and poor dissolution rate of BCS class II and IV drugs. In this literature review, novel formulation options, particularly for class II drugs designed for applications such as micronization, self-emulsification, cyclodextrin complexation, co-crystallisation, super critical fluid technology, solubilisation by change in pH, salt formation, co-solvents, melt granulation, and solid dispersion, liposomal/niosomal formulations, are discussed in detail to introduce biopharmaceutical challenges and recent approaches to facilitate more efficient drug formulation and development.

Progression of Ebola Therapeutics During the 2014-2015 Outbreak.

PubMed

Mendoza, Emelissa J; Qiu, Xiangguo; Kobinger, Gary P

2016-02-01

The recent Ebola virus (EBOV) outbreak in West Africa was the deadliest EBOV epidemic in history, highlighting the need for a safe and efficacious treatment against EBOV disease (EVD). In the absence of an approved treatment, experimental drugs were utilized under compassionate grounds hoping to diminish EVD-associated morbidity and mortality. As more data were collected from safety studies, Phase II/III clinical trials were introduced in Guinea, Sierra Leone, and Liberia to test promising candidates, including small-molecule drugs, RNA-based treatments, and antibody-based therapies. In this review, we summarize the use of, and preliminary observations from, current clinical trials with EVD therapeutics, shedding light on experimental drug selection, emergency clinical evaluation, and the impact these factors may have on future infectious disease outbreaks. Crown Copyright © 2015. Published by Elsevier Ltd. All rights reserved.

Extracellular proteases as targets for drug development

PubMed Central

Cudic, Mare

2015-01-01

Proteases constitute one of the primary targets in drug discovery. In the present review, we focus on extracellular proteases (ECPs) because of their differential expression in many pathophysiological processes, including cancer, cardiovascular conditions, and inflammatory, pulmonary, and periodontal diseases. Many new ECP inhibitors are currently under clinical investigation and a significant increase in new therapies based on protease inhibition can be expected in the coming years. In addition to directly blocking the activity of a targeted protease, one can take advantage of differential expression in disease states to selectively deliver therapeutic or imaging agents. Recent studies in targeted drug development for the metalloproteases (matrix metalloproteinases, adamalysins, pappalysins, neprilysin, angiotensin-converting enzyme, metallocarboxypeptidases, and glutamate carboxypeptidase II), serine proteases (elastase, coagulation factors, tissue/urokinase plasminogen activator system, kallikreins, tryptase, dipeptidyl peptidase IV), cysteine proteases (cathepsin B), and renin system are discussed herein. PMID:19689354

Homology modeling, binding site identification and docking study of human angiotensin II type I (Ang II-AT1) receptor.

PubMed

Vyas, Vivek K; Ghate, Manjunath; Patel, Kinjal; Qureshi, Gulamnizami; Shah, Surmil

2015-08-01

Ang II-AT1 receptors play an important role in mediating virtually all of the physiological actions of Ang II. Several drugs (SARTANs) are available, which can block the AT1 receptor effectively and lower the blood pressure in the patients with hypertension. Currently, there is no experimental Ang II-AT1 structure available; therefore, in this study we modeled Ang II-AT1 receptor structure using homology modeling followed by identification and characterization of binding sites and thereby assessing druggability of the receptor. Homology models were constructed using MODELLER and I-TASSER server, refined and validated using PROCHECK in which 96.9% of 318 residues were present in the favoured regions of the Ramachandran plots. Various Ang II-AT1 receptor antagonist drugs are available in the market as antihypertensive drug, so we have performed docking study with the binding site prediction algorithms to predict different binding pockets on the modeled proteins. The identification of 3D structures and binding sites for various known drugs will guide us for the structure-based drug design of novel compounds as Ang II-AT1 receptor antagonists for the treatment of hypertension. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

A microhydrodynamic rationale for selection of bead size in preparation of drug nanosuspensions via wet stirred media milling.

PubMed

Li, Meng; Alvarez, Paulina; Bilgili, Ecevit

2017-05-30

Although wet stirred media milling has proven to be a robust process for producing nanoparticle suspensions of poorly water-soluble drugs and thereby enhancing their bioavailability, selection of bead size has been largely empirical, lacking fundamental rationale. This study aims to establish such rationale by investigating the impact of bead size at various stirrer speeds on the drug breakage kinetics via a microhydrodynamic model. To this end, stable suspensions of griseofulvin, a model BCS Class II drug, were prepared using hydroxypropyl cellulose and sodium dodecyl sulfate. The suspensions were milled at four different stirrer speeds (1000-4000rpm) using various sizes (50-1500μm) of zirconia beads. Laser diffraction, SEM, and XRPD were used for characterization. Our results suggest that there is an optimal bead size that achieves fastest breakage at each stirrer speed and that it shifts to a smaller size at higher speed. Calculated microhydrodynamic parameters reveal two counteracting effects of bead size: more bead-bead collisions with less energy/force upon a decrease in bead size. The optimal bead size exhibits a negative power-law correlation with either specific energy consumption or the microhydrodynamic parameters. Overall, this study rationalizes the use of smaller beads for more energetic wet media milling. Copyright © 2017 Elsevier B.V. All rights reserved.

77 FR 16123 - Draft Guidance for Industry and Food and Drug Administration Staff; Class II Special Controls...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-03-19

...; Class II Special Controls Guidance Document: Nucleic Acid-Based In Vitro Diagnostic Devices for the... Guidance for Industry and Food and Drug Administration Staff; Class II Special Controls Guidance Document... II Special Controls Guidance Document: Nucleic Acid-Based In Vitro Diagnostic Devices for the...

77 FR 37058 - Draft Guidance for Industry and Food and Drug Administration Staff; Class II Special Controls...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-06-20

...] Draft Guidance for Industry and Food and Drug Administration Staff; Class II Special Controls Guidance... availability of the draft guidance entitled ``Class II Special Controls Guidance Document: Implanted Blood... blood access devices may comply with the requirement of special controls for class II devices. This...

Novel Metals and Metal Complexes as Platforms for Cancer Therapy

PubMed Central

Frezza, Michael; Hindo, Sarmad; Chen, Di; Davenport, Andrew; Schmitt, Sara; Tomco, Dajena; Dou, Q. Ping

2013-01-01

Metals are essential cellular components selected by nature to function in several indispensable biochemical processes for living organisms. Metals are endowed with unique characteristics that include redox activity, variable coordination modes, and reactivity towards organic substrates. Due to their reactivity, metals are tightly regulated under normal conditions and aberrant metal ion concentrations are associated with various pathological disorders, including cancer. For these reasons, coordination complexes, either as drugs or prodrugs, become very attractive probes as potential anticancer agents. The use of metals and their salts for medicinal purposes, from iatrochemistry to modern day, has been present throughout human history. The discovery of cisplatin, cis-[PtII(NH3)2Cl2], was a defining moment which triggered the interest in platinum(II)- and other metal-containing complexes as potential novel anticancer drugs. Other interests in this field address concerns for uptake, toxicity, and resistance to metallodrugs. This review article highlights selected metals that have gained considerable interest in both the development and the treatment of cancer. For example, copper is enriched in various human cancer tissues and is a co-factor essential for tumor angiogenesis processes. However the use of copper-binding ligands to target tumor copper could provide a novel strategy for cancer selective treatment. The use of nonessential metals as probes to target molecular pathways as anticancer agents is also emphasized. Finally, based on the interface between molecular biology and bioinorganic chemistry the design of coordination complexes for cancer treatment is reviewed and design strategies and mechanisms of action are discussed. PMID:20337575

In vitro DNA binding, pBR322 plasmid cleavage and molecular modeling study of chiral benzothiazole Schiff-base-valine Cu(II) and Zn(II) complexes to evaluate their enantiomeric biological disposition for molecular target DNA

NASA Astrophysics Data System (ADS)

Alizadeh, Rahman; Afzal, Mohd; Arjmand, Farukh

2014-10-01

Bicyclic heterocyclic compounds viz. benzothiazoles are key components of deoxyribonucleic acid (DNA) molecules and participate directly in the encoding of genetic information. Benzothiazoles, therefore, represent a potent and selective class of antitumor compounds. The design and synthesis of chiral antitumor chemotherapeutic agents of Cu(II) and Zn(II), L- and -D benzothiazole Schiff base-valine complexes 1a &b and 2a &b, respectively were carried out and thoroughly characterized by spectroscopic and analytical techniques. Interaction of 1a and b and 2a and b with CT DNA by employing UV-vis, florescence, circular dichroic methods and cleavage studies of 1a with pBR322 plasmid, molecular docking were done in order to demonstrate their enantiomeric disposition toward the molecular drug target DNA. Interestingly, these studies unambiguously demonstrated the greater potency of L-enantiomer in comparison to D-enantiomer.

77 FR 14403 - Guidance for Industry and Food and Drug Administration Staff; Class II Special Controls Guidance...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-03-09

... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2012-D-0167] Guidance for Industry and Food and Drug Administration Staff; Class II Special Controls Guidance Document: Norovirus Serological Reagents; Availability AGENCY: Food and Drug Administration, HHS. ACTION: Notice...

In vitro inhibition of African swine fever virus-topoisomerase II disrupts viral replication.

PubMed

Freitas, Ferdinando B; Frouco, Gonçalo; Martins, Carlos; Leitão, Alexandre; Ferreira, Fernando

2016-10-01

African swine fever virus (ASFV) is the etiological agent of a highly-contagious and fatal disease of domestic pigs, leading to serious socio-economic impact in affected countries. To date, neither a vaccine nor a selective anti-viral drug are available for prevention or treatment of African swine fever (ASF), emphasizing the need for more detailed studies at the role of ASFV proteins involved in viral DNA replication and transcription. Notably, ASFV encodes for a functional type II topoisomerase (ASFV-Topo II) and we recently showed that several fluoroquinolones (bacterial DNA topoisomerase inhibitors) fully abrogate ASFV replication in vitro. Here, we report that ASFV-Topo II gene is actively transcribed throughout infection, with transcripts being detected as early as 2 hpi and reaching a maximum peak concentration around 16 hpi, when viral DNA synthesis, transcription and translation are more active. siRNA knockdown experiments showed that ASFV-Topo II plays a critical role in viral DNA replication and gene expression, with transfected cells presenting lower viral transcripts (up to 89% decrease) and reduced cytopathic effect (-66%) when compared to the control group. Further, a significant decrease in the number of both infected cells (75.5%) and viral factories per cell and in virus yields (up to 99.7%, 2.5 log) was found only in cells transfected with siRNA targeting ASFV-Topo II. We also demonstrate that a short exposure to enrofloxacin during the late phase of infection (from 15 to 1 hpi) induces fragmentation of viral genomes, whereas no viral genomes were detected when enrofloxacin was added from the early phase of infection (from 2 to 16 hpi), suggesting that fluoroquinolones are ASFV-Topo II poisons. Altogether, our results demonstrate that ASFV-Topo II enzyme has an essential role during viral genome replication and transcription, emphasizing the idea that this enzyme can be a potential target for drug and vaccine development against ASF. Copyright © 2016 Elsevier B.V. All rights reserved.

Improved Tumor-Specific Drug Accumulation by Polymer Therapeutics with pH-Sensitive Drug Release Overcomes Chemotherapy Resistance.

PubMed

Heinrich, Anne-Kathrin; Lucas, Henrike; Schindler, Lucie; Chytil, Petr; Etrych, Tomáš; Mäder, Karsten; Mueller, Thomas

2016-05-01

The success of chemotherapy is limited by poor selectivity of active drugs combined with occurrence of tumor resistance. New star-like structured N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer-based drug delivery systems containing doxorubicin attached via a pH-sensitive hydrazone bond were designed and investigated for their ability to overcome chemotherapy resistance. These conjugates combine two strategies to achieve a high drug concentration selectively at the tumor site: (I) high accumulation by passive tumor targeting based on enhanced permeability and retention effect and (II) pH-sensitive site-specific drug release due to an acidic tumor microenvironment. Mice bearing doxorubicin-resistant xenograft tumors were treated with doxorubicin, PBS, poly HPMA (pHPMA) precursor or pHPMA-doxorubicin conjugate at different equivalent doses of 5 mg/kg bodyweight doxorubicin up to a 7-fold total dose using different treatment schedules. Intratumoral drug accumulation was analyzed by fluorescence imaging utilizing intrinsic fluorescence of doxorubicin. Free doxorubicin induced significant toxicity but hardly any tumor-inhibiting effects. Administering at least a 3-fold dose of pHPMA-doxorubicin conjugate was necessary to induce a transient response, whereas doses of about 5- to 6-fold induced strong regressions. Tumors completely disappeared in some cases. The onset of response was differential delayed depending on the tumor model, which could be ascribed to distinct characteristics of the microenvironment. Further fluorescence imaging-based analyses regarding underlying mechanisms of the delayed response revealed a related switch to a more supporting intratumoral microenvironment for effective drug release. In conclusion, the current study demonstrates that the concept of tumor site-restricted high-dose chemotherapy is able to overcome therapy resistance. Mol Cancer Ther; 15(5); 998-1007. ©2016 AACR. ©2016 American Association for Cancer Research.

Activation of PKC isoform beta(I) at the blood-brain barrier rapidly decreases P-glycoprotein activity and enhances drug delivery to the brain.

PubMed

Rigor, Robert R; Hawkins, Brian T; Miller, David S

2010-07-01

P-glycoprotein is an ATP (adenosine triphosphate)-driven drug efflux transporter that is highly expressed at the blood-brain barrier (BBB) and is a major obstacle to the pharmacotherapy of central nervous system diseases, including brain tumors, neuro-AIDS, and epilepsy. Previous studies have shown that P-glycoprotein transport activity in rat brain capillaries is rapidly reduced by the proinflammatory cytokine, tumor necrosis factor-alpha (TNF-alpha) acting through protein kinase C (PKC)-dependent signaling. In this study, we used isolated rat brain capillaries to show that the TNF-alpha-induced reduction of P-glycoprotein activity was prevented by a PKCbeta(I/II) inhibitor, LY333531, and mimicked by a PKCbeta(I/II) activator, 12-deoxyphorbol-13-phenylacetate-20-acetate (dPPA). Western blotting of brain capillary extracts with phospho-specific antibodies showed that dPPA activated PKCbeta(I), but not PKCbeta(II). Moreover, in intact rats, intracarotid infusion of dPPA potently increased brain accumulation of the P-glycoprotein substrate, [(3)H]-verapamil without compromising tight junction integrity. Thus, PKCbeta(I) activation selectively reduced P-glycoprotein activity both in vitro and in vivo. Targeting PKCbeta(I) at the BBB may prove to be an effective strategy for enhancing the delivery of small molecule therapeutics to the brain.

Update on the urotensinergic system: new trends in receptor localization, activation, and drug design

PubMed Central

Chatenet, David; Nguyen, Thi-Tuyet M.; Létourneau, Myriam; Fournier, Alain

2012-01-01

The urotensinergic system plays central roles in the physiological regulation of major mammalian organ systems, including the cardiovascular system. As a matter of fact, this system has been linked to numerous pathophysiological states including atherosclerosis, heart failure, hypertension, diabetes as well as psychological, and neurological disorders. The delineation of the (patho)physiological roles of the urotensinergic system has been hampered by the absence of potent and selective antagonists for the urotensin II-receptor (UT). Thus, a more precise definition of the molecular functioning of the urotensinergic system, in normal conditions as well as in a pathological state is still critically needed. The recent discovery of nuclear UT within cardiomyocytes has highlighted the cellular complexity of this system and suggested that UT-associated biological responses are not only initiated at the cell surface but may result from the integration of extracellular and intracellular signaling pathways. Thus, such nuclear-localized receptors, regulating distinct signaling pathways, may represent new therapeutic targets. With the recent observation that urotensin II (UII) and urotensin II-related peptide (URP) exert different biological effects and the postulate that they could also have distinct pathophysiological roles in hypertension, it appears crucial to reassess the recognition process involving UII and URP with UT, and to push forward the development of new analogs of the UT system aimed at discriminating UII- and URP-mediated biological activities. The recent development of such compounds, i.e. urocontrin A and rUII(1–7), is certainly useful to decipher the specific roles of UII and URP in vitro and in vivo. Altogether, these studies, which provide important information regarding the pharmacology of the urotensinergic system and the conformational requirements for binding and activation, will ultimately lead to the development of potent and selective drugs. PMID:23293631

Combined angiotensin receptor/neprilysin inhibitors: a review of the new paradigm in the management of chronic heart failure.

PubMed

Macdonald, Peter S

2015-10-01

The aims of this article were to review the rationale behind the development of combined angiotensin receptor/neprilysin inhibitors (ARNIs) for the management of chronic heart failure (HF) and to review the major clinical trials of LCZ696, the first drug in this class, that have been conducted to date. A selected review was undertaken of publications examining the preclinical and clinical studies of drugs aimed at enhancing the activity of the endogenous natriuretic peptide system and their combination with inhibitors of the renin-angiotensin-aldosterone system, initially angiotensin-converting enzyme inhibitors (ACEIs) and more recently angiotensin II type 1 receptor blockers. Selective neprilysin inhibitors are unlikely to be of benefit and may be associated with adverse effects when used in isolation in HF. Combining NIs with ACEIs is unsafe because of an unacceptably high prevalence of angioedema, which may be mediated by elevated levels of endogenous bradykinin. Combining a neprilysin inhibitor with an angiotensin II type 1 receptor blockers avoids the risk for angioedema. The ARNI LCZ696 was associated with greater reductions both mortality and morbidity compared with those with enalapril in a large-scale, Phase III clinical trial in patients with HF with reduced ejection fraction. Findings from a Phase II clinical trial suggested that LCZ696 may also be beneficial in HF with preserved ejection fraction, and a Phase III clinical trial of LCZ696 used for this indication is under way. ARNIs have been described as a "game changer" by cardiologists. Based on findings from clinical trials conducted to date, there is an expectation that they will replace ACEIs as a building block of the pharmacologic treatment of chronic HF. Copyright © 2015 Elsevier HS Journals, Inc. All rights reserved.

Crystal Structure-Based Selective Targeting of the Pyridoxal 5′-Phosphate Dependent Enzyme Kynurenine Aminotransferase II for Cognitive Enhancement†

PubMed Central

Rossi, Franca; Valentina, Casazza; Garavaglia, Silvia; Sathyasaikumar, Korrapati V.; Schwarcz, Robert; Kojima, Shin-ichi; Okuwaki, Keisuke; Ono, Shin-ichiro; Kajii, Yasushi; Rizzi, Menico

2014-01-01

Fluctuations in the brain levels of the neuromodulator kynurenic acid may control cognitive processes and play a causative role in several catastrophic brain diseases. Elimination of the pyridoxal 5′-phosphate dependent enzyme kynurenine aminotransferase II reduces cerebral kynurenic acid synthesis and has procognitive effects. The present description of the crystal structure of human kynurenine aminotransferase II in complex with its potent and specific primary amine-bearing fluoroquinolone inhibitor (S)-(−)-9-(4-aminopiperazin-1-yl)-8-fluoro-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3a-azaphenalene-5-carboxylic acid (BFF-122) should facilitate the structure-based development of cognition-enhancing drugs. From a medicinal chemistry perspective our results demonstrate that the issue of inhibitor specificity for highly conserved PLP-dependent enzymes could be successfully addressed. PMID:20684605

Availability of and access to orphan drugs: an international comparison of pharmaceutical treatments for pulmonary arterial hypertension, Fabry disease, hereditary angioedema and chronic myeloid leukaemia.

PubMed

Blankart, Carl Rudolf; Stargardt, Tom; Schreyögg, Jonas

2011-01-01

Market authorization does not guarantee patient access to any given drug. This is particularly true for costly orphan drugs because access depends primarily on co-payments, reimbursement policies and prices. The objective of this article is to identify differences in the availability of orphan drugs and in patient access to them in 11 pharmaceutical markets: Australia, Canada, England, France, Germany, Hungary, the Netherlands, Poland, Slovakia, Switzerland and the US. Four rare diseases were selected for analysis: pulmonary arterial hypertension (PAH), Fabry disease (FD), hereditary angioedema (HAE) and chronic myeloid leukaemia (CML). Indicators for availability were defined as (i) the indications for which orphan drugs had been authorized in the treatment of these diseases; (ii) the application date; and (iii) the date upon which these drugs received market authorization in each country. Indicators of patient access were defined as (i) the outcomes of technology appraisals; (ii) the extent of coverage provided by healthcare payers; and (iii) the price of the drugs in each country. For PAH we analysed bosentan, iloprost, sildenafil, treprostinil (intravenous and inhaled) as well as sitaxentan and ambrisentan; for FD we analysed agalsidase alfa and agalsidase beta; for HAE we analysed icatibant, ecallantide and two complement C1s inhibitors; for CML we analysed imatinib, dasatinib and nilotinib. Most drugs included in this study had received market authorization in all countries, but the range of indications for which they had been authorized differed by country. The broadest range of indications was found in Australia, and the largest variations in indications were found for PAH drugs. Authorization process speed (the time between application and market authorization) was fastest in the US, with an average of 362 days, followed by the EU (394 days). The highest prices for the included drugs were found in Germany and the US, and the lowest in Canada, Australia and England. Although the prices of all of the included drugs were high compared with those of most non-orphan drugs, most of the insurance plans in our country sample provided coverage for authorized drugs after a certain threshold. Availability of and access to orphan drugs play a key role in determining whether patients will receive adequate and efficient treatment. Although the present study showed some variations between countries in selected indicators of availability and access to orphan drugs, virtually all of the drugs in question were available and accessible in our sample. However, substantial co-payments in the US and Canada represent important barriers to patient access, especially in the case of expensive treatments such as those analysed in this study. Market exclusivity is a strong instrument for fostering orphan drug development and drug availability. However, despite the positive effect of this instrument, the conditions under which market exclusivity is granted should be reconsidered in cases where the costs of developing an orphan drug have already been amortized through the use of the drug's active ingredient for the treatment of a common indication.

Hydrodynamics-induced variability in the USP apparatus II dissolution test.

PubMed

Baxter, Jennifer L; Kukura, Joseph; Muzzio, Fernando J

2005-03-23

The USP tablet dissolution test is an analytical tool used for the verification of drug release processes and formulation selection within the pharmaceutical industry. Given the strong impact of this test, it is surprising that operating conditions and testing devices have been selected empirically. In fact, the flow phenomena in the USP test have received little attention in the past. An examination of the hydrodynamics in the USP apparatus II shows that the device is highly vulnerable to mixing problems that can affect testing performance and consistency. Experimental and computational techniques reveal that the flow field within the device is not uniform, and dissolution results can vary dramatically with the position of the tablet within the vessel. Specifically, computations predict sharp variations in the shear along the bottom of the vessel where the tablet is most likely to settle. Experiments in which the tablet location was carefully controlled reveal that the variation of shear within the testing device can affect the measured dissolution rate.

21 CFR 522.1010 - Furosemide.

Code of Federal Regulations, 2014 CFR

2014-04-01

... horses intended for human consumption. (ii) Amount. 0.5 mg/lb body weight once or twice daily... Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS...) body weight once or twice daily, intramuscularly or intravenously. (ii) Indications for use. For the...

Target-Independent Prediction of Drug Synergies Using Only Drug Lipophilicity

PubMed Central

2015-01-01

Physicochemical properties of compounds have been instrumental in selecting lead compounds with increased drug-likeness. However, the relationship between physicochemical properties of constituent drugs and the tendency to exhibit drug interaction has not been systematically studied. We assembled physicochemical descriptors for a set of antifungal compounds (“drugs”) previously examined for interaction. Analyzing the relationship between molecular weight, lipophilicity, H-bond donor, and H-bond acceptor values for drugs and their propensity to show pairwise antifungal drug synergy, we found that combinations of two lipophilic drugs had a greater tendency to show drug synergy. We developed a more refined decision tree model that successfully predicted drug synergy in stringent cross-validation tests based on only lipophilicity of drugs. Our predictions achieved a precision of 63% and allowed successful prediction for 58% of synergistic drug pairs, suggesting that this phenomenon can extend our understanding for a substantial fraction of synergistic drug interactions. We also generated and analyzed a large-scale synergistic human toxicity network, in which we observed that combinations of lipophilic compounds show a tendency for increased toxicity. Thus, lipophilicity, a simple and easily determined molecular descriptor, is a powerful predictor of drug synergy. It is well established that lipophilic compounds (i) are promiscuous, having many targets in the cell, and (ii) often penetrate into the cell via the cellular membrane by passive diffusion. We discuss the positive relationship between drug lipophilicity and drug synergy in the context of potential drug synergy mechanisms. PMID:25026390

A comparative study of efficacy of Tugaksheeree [Curcuma angustifolia Roxb. and Maranta arundinacea Linn.] in management of Amlapitta

PubMed Central

Rajashekhara, N.; Sharma, P. P.

2010-01-01

Amlapitta is a disease caused by increase of Amla Guna of Pitta. Starch obtained from the rhizomes of two plants viz., Curcuma angustifolia Roxb. (Fam. Zingiberaceae) and Maranta arundinacea Linn. (Fam. Marantaceae) are used as Tugaksheeree. In the present clinical study, the efficacy of Tugaksheeree was studied on 67 patients of Amlapitta. A 0 total of 84 patients suffering from Amlapitta were selected from the O.P.D. and I.P.D. sections in the department of Dravyaguna, I.P.G.T. and R.A., Hospital, Jamnagar, and were randomly divided into two groups. Thirty four patients completed the treatment course in Group I, and 33 patients completed the treatment course in Group II. The efficacy of drug Tugaksheeree was studied through internal administration of the starches of C. angustifolia Roxb. (Fam. Zingiberaceae) in Group I and M. arundinacea Linn. (Fam. Marantaceae) in Group II with the dose of 4 g TID with water for 30 days. Both the drugs were found highly effective in treating Amlapitta. They significantly relieved the cardinal symptoms viz., Avipaka, Tikta-amlodgara, Daha, Shoola, Chhardi and the associated symptoms viz., Aruchi, Gaurava, Udaradhmana, Antrakujana, Vit bheda, Shiroruja, Angasada, and Trit. Statistically significant increase in body weight was noticed in both the groups. This may be because the drugs corrected the Agni and acted as Brihmana and Dhatupushtikara. Both the drugs did not produce any side effects. Therefore, both these drugs (C. angustifolia Roxb. and M. arundinacea Linn.) can be used as substitutes for each other. PMID:22048544

A comparative study of efficacy of Tugaksheeree [Curcuma angustifolia Roxb. and Maranta arundinacea Linn.] in management of Amlapitta.

PubMed

Rajashekhara, N; Sharma, P P

2010-10-01

Amlapitta is a disease caused by increase of Amla Guna of Pitta. Starch obtained from the rhizomes of two plants viz., Curcuma angustifolia Roxb. (Fam. Zingiberaceae) and Maranta arundinacea Linn. (Fam. Marantaceae) are used as Tugaksheeree. In the present clinical study, the efficacy of Tugaksheeree was studied on 67 patients of Amlapitta. A 0 total of 84 patients suffering from Amlapitta were selected from the O.P.D. and I.P.D. sections in the department of Dravyaguna, I.P.G.T. and R.A., Hospital, Jamnagar, and were randomly divided into two groups. Thirty four patients completed the treatment course in Group I, and 33 patients completed the treatment course in Group II. The efficacy of drug Tugaksheeree was studied through internal administration of the starches of C. angustifolia Roxb. (Fam. Zingiberaceae) in Group I and M. arundinacea Linn. (Fam. Marantaceae) in Group II with the dose of 4 g TID with water for 30 days. Both the drugs were found highly effective in treating Amlapitta. They significantly relieved the cardinal symptoms viz., Avipaka, Tikta-amlodgara, Daha, Shoola, Chhardi and the associated symptoms viz., Aruchi, Gaurava, Udaradhmana, Antrakujana, Vit bheda, Shiroruja, Angasada, and Trit. Statistically significant increase in body weight was noticed in both the groups. This may be because the drugs corrected the Agni and acted as Brihmana and Dhatupushtikara. Both the drugs did not produce any side effects. Therefore, both these drugs (C. angustifolia Roxb. and M. arundinacea Linn.) can be used as substitutes for each other.

United Nations Office on Drugs and Crime International Network of Drug Dependence Treatment and Rehabilitation Resource Centres: Treatnet.

PubMed

Tomás-Rosselló, Juana; Rawson, Richard A; Zarza, Maria J; Bellows, Anne; Busse, Anja; Saenz, Elizabeth; Freese, Thomas; Shawkey, Mansour; Carise, Deni; Ali, Robert; Ling, Walter

2010-10-01

Key to the dissemination of evidence-based addiction treatments is the exchange of experiences and mutual support among treatment practitioners, as well as the availability of accurate addiction training materials and effective trainers. To address the shortage of such resources, the United Nations Office on Drugs and Crime (UNODC) created Treatnet, a network of 20 drug dependence treatment resource centers around the world. Treatnet's primary goal is to promote the use of effective addiction treatment practices. Phase I of this project included (1) selecting and establishing a network of geographically distributed centers; (2) conducting a capacity-building program consisting of a training needs assessment, development of training packages, and the training of 2 trainers per center in 1 content area each; and (3) creating good-practice documents. Data on the training activities conducted by the trainers during their first 6 months in the field are presented. Plans for Phase II of the Treatnet project are also discussed.

Differential Regulation of CYP3A4 and CYP3A5 and Its Implication in Drug Discovery

PubMed Central

Lolodi, Ogheneochukome; Wang, Yue-Ming; Wright, William C.; Chen, Taosheng

2017-01-01

Cancer cells use several mechanisms to resist the cytotoxic effects of drugs, resulting in tumor progression and invasion. One such mechanism capitalizes on the body’s natural defense against xenobiotics by increasing the rate of xenobiotic efflux and metabolic inactivation. Xenobiotic metabolism typically involves conversion of parent molecules to more soluble and easily excreted derivatives in reactions catalyzed by Phase I and Phase II drug metabolizing enzymes. Recent reports indicate that components of the xenobiotic response system are upregulated in some diseases, including many cancers. Such components include the pregnane X receptor (PXR) and the cytochrome P450 (CYP) 3A4 and 3A5 enzymes. The CYP3A enzymes are a subset of the numerous enzymes that are transcriptionally activated following the interaction of PXR and many ligands. Intense research is ongoing to understand the functional ramifications of aberrant expression of these components in diseased states with the goal of designing novel drugs that can selectively target them. PMID:28558634

Current approaches to prevent NSAID-induced gastropathy – COX selectivity and beyond

PubMed Central

Becker, Jan C; Domschke, Wolfram; Pohle, Thorsten

2004-01-01

Gastrointestinal (GI) toxicity associated with nonsteroidal anti-inflammatory drugs (NSAIDs) is still an important medical and socio-economic problem – despite recent pharmaceutical advances. To prevent NSAID-induced gastropathy, three strategies are followed in clinical routine: (i) coprescription of a gastroprotective drug, (ii) use of selective COX-2 inhibitors, and (iii) eradication of Helicobacter pylori. Proton pump inhibitors are the comedication of choice as they effectively reduce gastrointestinal adverse events of NSAIDs and are safe even in long-term use. Co-medication with vitamin C has only been little studied in the prevention of NSAID-induced gastropathy. Apart from scavenging free radicals it is able to induce haeme-oxgenase 1 in gastric cells, a protective enzyme with antioxidant and vasodilative properties. Final results of the celecoxib outcome study (CLASS study) attenuated the initial enthusiasm about the GI safety of selective COX-2 inhibitors, especially in patients concomitantly taking aspirin for cardiovascular prophylaxis. Helicobacter pylori increases the risk for ulcers particularly in NSAID-naive patients and therefore eradication is recommended prior to long-term NSAID therapy at least in patients at high risk. New classes of COX-inhibitors are currently evaluated in clinical studies with very promising results: NSAIDs combined with a nitric oxide releasing moiety (NO-NSAID) and dual inhibitors of COX and 5-LOX. These drugs offer extended anti-inflammatory potency while sparing gastric mucosa. PMID:15563357

21 CFR 522.1010 - Furosemide.

Code of Federal Regulations, 2012 CFR

2012-04-01

... Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS...) body weight once or twice daily, intramuscularly or intravenously. (ii) Indications for use. For the... horses intended for food. (ii) Amount. 0.5 mg/lb body weight once or twice daily, intramuscularly or...

21 CFR 522.1010 - Furosemide.

Code of Federal Regulations, 2013 CFR

2013-04-01

... Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS...) body weight once or twice daily, intramuscularly or intravenously. (ii) Indications for use. For the... horses intended for food. (ii) Amount. 0.5 mg/lb body weight once or twice daily, intramuscularly or...

76 FR 30969 - Importer of Controlled Substances; Notice of Registration

Federal Register 2010, 2011, 2012, 2013, 2014

2011-05-27

... DEPARTMENT OF JUSTICE Drug Enforcement Administration Importer of Controlled Substances; Notice of... renewal to the Drug Enforcement Administration (DEA) to be registered as an importer of the following basic classes of controlled substances: Drug Schedule Phenylacetone (8501) II Coca Leaves (9040) II...

78 FR 12104 - Manufacturer of Controlled Substances; Notice of Registration; Cedarburg Pharmaceuticals, Inc.

Federal Register 2010, 2011, 2012, 2013, 2014

2013-02-21

... DEPARTMENT OF JUSTICE Drug Enforcement Administration Manufacturer of Controlled Substances... Badger Circle, Grafton, Wisconsin 53024, made application by renewal to the Drug Enforcement... substances: Drug Schedule 4-Anilino-N-phenethyl-4-piperidine ANPP) II (8333). Fentanyl (9801) II The company...

Sortase A Inhibitors: Recent Advances and Future Perspectives.

PubMed

Cascioferro, Stella; Raffa, Demetrio; Maggio, Benedetta; Raimondi, Maria Valeria; Schillaci, Domenico; Daidone, Giuseppe

2015-12-10

Here, we describe the most promising small synthetic organic compounds that act as potent Sortase A inhibitors and cater the potential to be developed as antivirulence drugs. Sortase A is a polypeptide of 206 amino acids, which catalyzes two sequential reactions: (i) thioesterification and (ii) transpeptidation. Sortase A is involved in the process of bacterial adhesion by anchoring LPXTG-containing proteins to lipid II. Sortase A inhibitors do not affect bacterial growth, but they restrain the virulence of pathogenic bacterial strains, thereby preventing infections caused by Staphylococcus aureus or other Gram-positive bacteria. The efficacy of the most promising inhibitors needs to be comprehensively evaluated in in vivo models of infection, in order to select compounds eligible for the treatment of bacterial infections in humans.

Drug Discovery Targeting Bromodomain-Containing Protein 4

PubMed Central

2017-01-01

BRD4, the most extensively studied member of the BET family, is an epigenetic regulator that localizes to DNA via binding to acetylated histones and controls the expression of therapeutically important gene regulatory networks through the recruitment of transcription factors to form mediator complexes, phosphorylating RNA polymerase II, and by its intrinsic histone acetyltransferase activity. Disrupting the protein–protein interactions between BRD4 and acetyl-lysine has been shown to effectively block cell proliferation in cancer, cytokine production in acute inflammation, and so forth. To date, significant efforts have been devoted to the development of BRD4 inhibitors, and consequently, a dozen have progressed to human clinical trials. Herein, we summarize the advances in drug discovery and development of BRD4 inhibitors by focusing on their chemotypes, in vitro and in vivo activity, selectivity, relevant mechanisms of action, and therapeutic potential. Opportunities and challenges to achieve selective and efficacious BRD4 inhibitors as a viable therapeutic strategy for human diseases are also highlighted. PMID:28195723

Safinamide: first global approval.

PubMed

Deeks, Emma D

2015-04-01

Safinamide (Xadago(®)) is an oral α-aminoamide derivative developed by Newron for the treatment of Parkinson's disease (PD). The drug has both dopaminergic properties (highly selective and reversible inhibition of monoamine oxidase-B) and non-dopaminergic properties (selective sodium channel blockade and calcium channel modulation, with consequent inhibition of excessive glutamate release). Safinamide is approved in the EU, Iceland, Lichtenstein and Norway, as an add-on therapy to stable-dose levodopa, alone or in combination with other PD therapies in mid- to late-stage fluctuating PD patients; regulatory submissions have also been filed in the USA and Switzerland for its use in this indication. Additional submissions have been made in the USA, Iceland, Lichtenstein, Norway and Switzerland for early-stage PD. Safinamide has also undergone phase II investigation in PD patients with drug-induced dyskinesia (France, Germany, Austria, Canada and South Africa) or cognitive impairment (USA and Spain). This article summarizes the milestones in the development of safinamide leading to its first approval for PD.

Hybrid Drug Delivery Patches Based on Spherical Cellulose Nanocrystals and Colloid Titania—Synthesis and Antibacterial Properties

PubMed Central

Svensson, Fredric G.; Agafonov, Alexander V.; Håkansson, Sebastian; Seisenbaeva, Gulaim A.

2018-01-01

Spherical cellulose nanocrystal-based hybrids grafted with titania nanoparticles were successfully produced for topical drug delivery. The conventional analytical filter paper was used as a precursor material for cellulose nanocrystals (CNC) production. Cellulose nanocrystals were extracted via a simple and quick two-step process based on first the complexation with Cu(II) solution in aqueous ammonia followed by acid hydrolysis with diluted H2SO4. Triclosan was selected as a model drug for complexation with titania and further introduction into the nanocellulose based composite. Obtained materials were characterized by a broad variety of microscopic, spectroscopic, and thermal analysis methods. The drug release studies showed long-term release profiles of triclosan from the titania based nanocomposite that agreed with Higuchi model. The bacterial susceptibility tests demonstrated that released triclosan retained its antibacterial activity against Escherichia coli and Staphylococcus aureus. It was found that a small amount of titania significantly improved the antibacterial activity of obtained nanocomposites, even without immobilization of model drug. Thus, the developed hybrid patches are highly promising candidates for potential application as antibacterial agents. PMID:29642486

Synergism between COX-3 inhibitors in two animal models of pain.

PubMed

Muñoz, J; Navarro, C; Noriega, V; Pinardi, G; Sierralta, F; Prieto, J C; Miranda, H F

2010-04-01

The antinociception induced by the intraperitoneal coadministration in mice of combinations of metamizol and paracetamol was evaluated in the tail flick test and orofacial formalin test. The antinociception of each drugs alone and the interaction of the combinations was evaluated by isobolographic analysis in the tail-flick and in the formalin orofacial assay of mice. Mice pretreated with the drugs demonstrated that the antinociception of metamizol and paracetamol is dose-dependent. The potency range on the antinocifensive responses for metamizol or paracetamol was as follows: orofacial (Phase II) > orofacial (Phase I) > tail flick. In addition, the coadministration of metamizol with paracetamol induced a strong synergistic antinociception in the algesiometer assays. Both drugs showed effectiveness in inflammatory pain. These actions can be related to the differential selectivity of the drugs for inhibition of COX isoforms and also to the several additional antinociception mechanisms and pathways initiated by the analgesic drugs on pain transmission. Since the efficacy of the combination of metamizol with paracetamol has been demonstrated in the present study, this association could have a potential beneficial effect on the pharmacological treatment of clinical pain.

Hybrid Drug Delivery Patches Based on Spherical Cellulose Nanocrystals and Colloid Titania-Synthesis and Antibacterial Properties.

PubMed

Evdokimova, Olga L; Svensson, Fredric G; Agafonov, Alexander V; Håkansson, Sebastian; Seisenbaeva, Gulaim A; Kessler, Vadim G

2018-04-08

Spherical cellulose nanocrystal-based hybrids grafted with titania nanoparticles were successfully produced for topical drug delivery. The conventional analytical filter paper was used as a precursor material for cellulose nanocrystals (CNC) production. Cellulose nanocrystals were extracted via a simple and quick two-step process based on first the complexation with Cu(II) solution in aqueous ammonia followed by acid hydrolysis with diluted H₂SO₄. Triclosan was selected as a model drug for complexation with titania and further introduction into the nanocellulose based composite. Obtained materials were characterized by a broad variety of microscopic, spectroscopic, and thermal analysis methods. The drug release studies showed long-term release profiles of triclosan from the titania based nanocomposite that agreed with Higuchi model. The bacterial susceptibility tests demonstrated that released triclosan retained its antibacterial activity against Escherichia coli and Staphylococcus aureus . It was found that a small amount of titania significantly improved the antibacterial activity of obtained nanocomposites, even without immobilization of model drug. Thus, the developed hybrid patches are highly promising candidates for potential application as antibacterial agents.

Are You Morally Modified?

PubMed Central

Levy, Neil; Douglas, Thomas; Kahane, Guy; Terbeck, Sylvia; Cowen, Philip J.; Hewstone, Miles; Savulescu, Julian

2015-01-01

A number of concerns have been raised about the possible future use of pharmaceuticals designed to enhance cognitive, affective, and motivational processes, particularly where the aim is to produce morally better decisions or behavior. In this article, we draw attention to what is arguably a more worrying possibility: that pharmaceuticals currently in widespread therapeutic use are already having unintended effects on these processes, and thus on moral decision making and morally significant behavior. We review current evidence on the moral effects of three widely used drugs or drug types: (i) propranolol, (ii) selective serotonin reuptake inhibitors, and (iii) drugs that effect oxytocin physiology. This evidence suggests that the alterations to moral decision making and behavior caused by these agents may have important and difficult-to-evaluate consequences, at least at the population level. We argue that the moral effects of these and other widely used pharmaceuticals warrant further empirical research and ethical analysis. PMID:25892904

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.

Rationale for nebivolol/valsartan combination for hypertension: review of preclinical and clinical data.

PubMed

Giles, Thomas D; Cockcroft, John R; Pitt, Bertram; Jakate, Abhijeet; Wright, Harold M

2017-09-01

: To treat hypertension, combining two or more antihypertensive drugs from different classes is often necessary. β-Blockers and renin-angiotensin-aldosterone system inhibitors, when combined, have been deemed 'less effective' based on partially overlapping mechanisms of action and limited evidence. Recently, the single-pill combination (SPC) of nebivolol (Neb) 5 mg - a vasodilatory β1-selective antagonist/β3 agonist - and valsartan 80 mg, an angiotensin II receptor blocker, was US Food and Drug Administration-approved for hypertension. Pharmacological profiles of Neb and valsartan, alone and combined, are well characterized. In addition, a large 8-week randomized trial in stages I-II hypertensive patients (N = 4161) demonstrated greater blood pressure-reducing efficacy for Neb/valsartan SPCs than component monotherapies with comparable tolerability. In a biomarkers substudy (N = 805), Neb/valsartan SPCs prevented valsartan-induced increases in plasma renin, and a greater reduction in plasma aldosterone was observed with the highest SPC dose vs. valsartan 320 mg/day. This review summarizes preclinical and clinical evidence supporting Neb/valsartan as an efficacious and well tolerated combination treatment for hypertension.

Joint Counterdrug Operations

DTIC Science & Technology

1998-02-17

II-8 • Marijuana (Cannabis) Industry ................................................................................ II-9...High Intensity Drug Trafficking Areas ................................................................ III-26 • Organized Crime Drug Enforcement...IV-4 • Legal or Regulatory Considerations ....................................................................... IV-5 • Major

75 FR 10312 - Importer of Controlled Substances Notice of Registration

Federal Register 2010, 2011, 2012, 2013, 2014

2010-03-05

... DEPARTMENT OF JUSTICE Drug Enforcement Administration Importer of Controlled Substances Notice of... by renewal to the Drug Enforcement Administration (DEA) to be registered as an importer of the basic classes of controlled substances listed in schedule II: Drug Schedule Opium, raw (9600) II Poppy Straw...

Antimalarial evaluation of copper(II) nanohybrid solids: inhibition of plasmepsin II, a hemoglobin-degrading malarial aspartic protease from Plasmodium falciparum.

PubMed

Mohapatra, Subash Chandra; Tiwari, Hemandra Kumar; Singla, Manisha; Rathi, Brijesh; Sharma, Arun; Mahiya, Kuldeep; Kumar, Mukesh; Sinha, Saket; Chauhan, Shyam Singh

2010-03-01

A new class of copper(II) nanohybrid solids, LCu(CH(3)COO)(2) and LCuCl(2), have been synthesized and characterized by transmission electron microscopy, dynamic light scattering, and IR spectroscopy, and have been found to be capped by a bis(benzimidazole) diamide ligand (L). The particle sizes of these nanohybrid solids were found to be in the ranges 5-10 and 60-70 nm, respectively. These nanohybrid solids were evaluated for their in vitro antimalarial activity against a chloroquine-sensitive isolate of Plasmodium falciparum (MRC 2). The interactions between these nanohybrid solids and plasmepsin II (an aspartic protease and a plausible novel target for antimalarial drug development), which is believed to be essential for hemoglobin degradation by the parasite, have been assayed by UV-vis spectroscopy and inhibition kinetics using Lineweaver-Burk plots. Our results suggest that these two compounds have antimalarial activities, and the IC(50) values (0.025-0.032 microg/ml) are similar to the IC(50) value of the standard drug chloroquine used in the bioassay. Lineweaver-Burk plots for inhibition of plasmepsin II by LCu(CH(3)COO)(2) and LCuCl(2) show that the inhibition is competitive with respect to the substrate. The inhibition constants of LCu(CH(3)COO)(2) and LCuCl(2) were found to be 10 and 13 microM, respectively. The IC(50) values for inhibition of plasmepsin II by LCu(CH(3)COO)(2) and LCuCl(2) were found to be 14 and 17 microM, respectively. Copper(II) metal capped by a benzimidazole group, which resembles the histidine group of copper proteins (galactose oxidase, beta-hydroxylase), could provide a suitable anchoring site on the nanosurface and thus could be useful for inhibition of target enzymes via binding to the S1/S3 pocket of the enzyme hydrophobically. Both copper(II) nanohybrid solids were found to be nontoxic against human hepatocellular carcinoma cells and were highly selective for plasmepsin II versus human cathepsin D. The pivotal mechanism of antimalarial activity of these compounds via plasmepsin II inhibition in the P. falciparum malaria parasite is demonstrated.

The University of Kansas High-Throughput Screening Laboratory. Part II: enabling collaborative drug-discovery partnerships through cutting-edge screening technology

PubMed Central

McDonald, Peter R; Roy, Anuradha; Chaguturu, Rathnam

2011-01-01

The University of Kansas High-Throughput Screening (KU HTS) core is a state-of-the-art drug-discovery facility with an entrepreneurial open-service policy, which provides centralized resources supporting public- and private-sector research initiatives. The KU HTS core was established in 2002 at the University of Kansas with support from an NIH grant and the state of Kansas. It collaborates with investigators from national and international academic, nonprofit and pharmaceutical organizations in executing HTS-ready assay development and screening of chemical libraries for target validation, probe selection, hit identification and lead optimization. This is part two of a contribution from the KU HTS laboratory. PMID:21806374

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

Goldstein, R.Z.; Craig, A.D.; Bechara, A.

More than 80% of addicted individuals fail to seek treatment, which might reflect impairments in recognition of severity of disorder. Considered by some as intentional deception, such 'denial' might instead reflect dysfunction of brain networks subserving insight and self-awareness. Here we review the scant literature on insight in addiction and integrate this perspective with the role of: (i) the insula in interoception, self-awareness and drug craving; (ii) the anterior cingulate in behavioral monitoring and response selection (relevant to disadvantageous choices in addiction); (iii) the dorsal striatum in automatic habit formation; and (iv) drug-related stimuli that predict emotional behavior in addictedmore » individuals, even without conscious awareness. We discuss implications for clinical treatment including the design of interventions to improve insight into illness severity in addiction.« less

PubMed

Balmaceda, Carlos; Espinoza, Manuel A; Diaz, Janepsy

2015-12-01

Bioequivalence has become a standard request for drug commercialization in most high income countries, and significant efforts have been made to implement it in many low and middle income countries. In Chile, the requirement of bioequivalency has been gradually implemented since 2008, associated to a communicational campaign to inform the general population about its scope and importance. The objective of this study is to estimate the effect of the implementation of bioequivalence on the prices of products that have been affected by this policy. We conducted a difference in difference study in a set of 30 chronic use drugs, selected from the eighty clinical guidelines published by the Chilean Ministry of Health. The effect was assessed according to the date when the corresponding ministerial decree was published. A control drugs was selected for each analyzed medication in order to estimate the effect of implementation independently of other factors of the market. We identified three groups of drugs: (i) those which experimented a significant increment of price due to bioequivalence; (ii) those where prices decreased; and (iii) those where prices did not (significantly changed) decrease. A sensitivity analysis complemented the study results and identified the significant effect of the date when the bioequivalence was implemented. It is concluded that the implementation of bioequivalence in Chile had a significant effect on prices of some medications. However, the magnitude and direction of such effect depends on the characteristics of the particular market defined by each drug. Copyright © 2015 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.

QSAR studies in the discovery of novel type-II diabetic therapies.

PubMed

Abuhammad, Areej; Taha, Mutasem O

2016-01-01

Type-II diabetes mellitus (T2DM) is a complex chronic disease that represents a major therapeutic challenge. Despite extensive efforts in T2DM drug development, therapies remain unsatisfactory. Currently, there are many novel and important antidiabetic drug targets under investigation by many research groups worldwide. One of the main challenges to develop effective orally active hypoglycemic agents is off-target effects. Computational tools have impacted drug discovery at many levels. One of the earliest methods is quantitative structure-activity relationship (QSAR) studies. QSAR strategies help medicinal chemists understand the relationship between hypoglycemic activity and molecular properties. Hence, QSAR may hold promise in guiding the synthesis of specifically designed novel ligands that demonstrate high potency and target selectivity. This review aims to provide an overview of the QSAR strategies used to model antidiabetic agents. In particular, this review focuses on drug targets that raised recent scientific interest and/or led to successful antidiabetic agents in the market. Special emphasis has been made on studies that led to the identification of novel antidiabetic scaffolds. Computer-aided molecular design and discovery techniques like QSAR have a great potential in designing leads against complex diseases such as T2DM. Combined with other in silico techniques, QSAR can provide more useful and rational insights to facilitate the discovery of novel compounds. However, since T2DM is a complex disease that includes several faulty biological targets, multi-target QSAR studies are recommended in the future to achieve efficient antidiabetic therapies.

Anti-inflammatory drugs interacting with Zn(II), Cd(II) and Pt(II) metal ions.

PubMed

Dendrinou-Samara, C; Tsotsou, G; Ekateriniadou, L V; Kortsaris, A H; Raptopoulou, C P; Terzis, A; Kyriakidis, D A; Kessissoglou, D P

1998-09-01

Complexes of Zn(II), Cd(II) and Pt(II) metal ions with the anti-inflammatory drugs, 1-methyl-5-(p-toluoyl)-1H-pyrrole-2-acetic acid (Tolmetin), alpha-methyl-4-(2-methylpropyl)benzeneacetic acid (Ibuprofen), 6-methoxy-alpha-methylnaphthalene-2-acetic acid (Naproxen) and 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid (indomethacin) have been synthesized and characterized. In the structurally characterized Cd(naproxen)2 complex the anti-inflammatory drugs acts as bidentate chelate ligand coordinatively bound to metal ions through the deprotonated carboxylate group. Crystal data for 1: [C32H26O8Cd], orthorhombic, space group P22(1)2(1), a = 5.693(2) (A), b = 8.760(3) (A), c = 30.74(1) (A), V = 1533(1) A3, Z = 2. Antibacterial and growth inhibitory activity is higher than that of the parent ligands or the platinum(II) diamine compounds.

21 CFR 520.2475 - Toceranib.

Code of Federal Regulations, 2011 CFR

2011-04-01

... Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS... initial dose of 3.25 mg per kilogram (1.48 mg per pound) body weight, orally every other day. (ii) Indications for use. For the treatment of Patnaik grade II or III, recurrent, cutaneous mast cell tumors with...

Fragment Screening of Human Kynurenine Aminotransferase-II.

PubMed

Jayawickrama, Gayan S; Nematollahi, Alireza; Sun, Guanchen; Church, W Bret

2018-03-01

Kynurenine aminotransferase-II (KAT-II) is a pyridoxal 5'-phosphate (PLP)-dependent enzyme that acts in the tryptophan metabolic pathway by catalyzing the transamination of kynurenine into kynurenic acid (KYNA). It is one of four isoforms in the KAT family, of which it is the primary homologue responsible for KYNA production in the mammalian brain. KAT-II is targeted for inhibition as KYNA is implicated in diseases such as schizophrenia, where it is found in elevated concentrations. Previously, many different approaches have been taken to develop KAT-II inhibitors, and herein fragment-based drug design (FBDD) approaches have been exploited to provide further lead compounds that can be designed into novel inhibitors. Surface plasmon resonance (SPR) was used to screen a fragment library containing 1000 compounds, of which 41 hits were identified. These hits were further evaluated with SPR, and 18 were selected for inhibition studies. From these hits, two fragments, F6037-0164 and F0037-7280, were pursued and determined to have an IC 50 of 524.5 (± 25.6) μM and 115.2 (± 4.5) μM, respectively. This strategy shows the viability of using FBDD in gleaning knowledge about KAT-II inhibition and generating leads for the production of KAT-II inhibitors.

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

Discovery of novel acetanilide derivatives as potent and selective beta3-adrenergic receptor agonists.

PubMed

Maruyama, Tatsuya; Onda, Kenichi; Hayakawa, Masahiko; Matsui, Tetsuo; Takasu, Toshiyuki; Ohta, Mitsuaki

2009-06-01

In the search for potent and selective human beta3-adrenergic receptor (AR) agonists as potential drugs for the treatment of obesity and noninsulin-dependent (type II) diabetes, a novel series of acetanilide-based analogues were prepared and their biological activities were evaluated at the human beta3-, beta2-, and beta1-ARs. Among these compounds, 2-pyridylacetanilide (2f), pyrimidin-2-ylacetanilide (2u), and pyrazin-2-ylacetanilide (2v) derivatives exhibited potent agonistic activity at the beta3-AR with functional selectivity over the beta1- and beta2-ARs. In particular, compound 2u was found to be the most potent and selective beta3-AR agonist with an EC(50) value of 0.11 microM and no agonistic activity for either the beta1- or beta2-AR. In addition, 2f, 2u, and 2v showed significant hypoglycemic activity in a rodent diabetic model.

In vitro cytotoxicity and differential cellular sensitivity of derivatives of diamino acids. II. N1-methyl, N1-allyl, N1-(2-chloroethyl) and N1-propargyl nitrosoureas.

PubMed

Dulude, H; Salvador, R; Gallant, G

1995-01-01

The in vitro cytotoxicity and differential cellular sensitivity of a series of new N1-methyl, N1-allyl, N1-2-chloroethyl and N1-propargyl nitrosourea derivatives of diamino acids were determined in the National Cancer Institute's primary antitumor drug screen. The compounds tested showed an in vitro anticancer activity similar to commercialized nitrosoureas such as CCNU, BCNU, MeCCNU, chlorozotocin, streptozotocin and PCNU. The alkylating moiety of the nitrosoureas seems to play a role in the general selectivity of our compounds. The N1-methyl and N1-2-chloroethyl nitrosourea derivatives are more selective for central nervous system cell lines, the N1-allyl nitrosourea derivatives are more selective for lung cancer cell lines and the N1-propargyl nitrosoureas are more selective for leukemia cell lines.

Pediatric off-label drug use in China: risk factors and management strategies.

PubMed

Zhang, Lingli; Li, Youping; Liu, Yi; Zeng, Linan; Hu, Die; Huang, Liang; Chen, Min; Lv, Juan; Yang, Chunsong

2013-02-01

To analyze the risk factors of pediatric off-label drug use, and propose management strategies for policy making of the pediatric off-label drug use in China. (i) We applied stratified random sampling to select recipes of children aged 0 to 18 years in pediatric clinics and wards of the West China Second University Hospital in 2010. (ii) All included prescriptions were categorized as off-label use or on-label use, according to the latest package insert licensed by the State Food and Drug Administration. (iii) Risk factors and the weights were calculated using logistic regression. (iv) The correlation between risk factors and the different kinds of off-label prescriptions was presented using adjusted odds ratio, and the impact of the risk factors was measured using standardized partial regression coefficient. (v) SPSS 16.0 was used for statistic analysis. (vi) From the perspective of the medical institutions, pharmaceutical enterprises, professional institutions, and the public, we combined the results of the Evidence-based research on the policy of the off-label drug use in 15 countries and the results of risk factor analysis, in order to propose management strategies for the policy making of pediatric off-label drug use in China. (i) Using the method of sampling, we received 2640 recipes from outpatients and 14,374 prescriptions from 749 inpatients. (ii) The neonates (0 to 27 days) had higher risk in off-label drug use than the other three children age groups. (iii) The dermatological medicines (D), nervous system medicines (N), traditional Chinese medicines, and respiratory drugs (R) were high-risk off-label medicines whose labels should be updated more frequently. (iv) The great factors of off-label drug use are those influence health status and relate to health services (ICD-10:Z00-Z99) (mainly in the clinic of child care and growth development, and in the ward of chemotherapy). (v) Off-label drug use in the ward was 4.4 times than that in clinic service (P < 0.001), which suggested that off-label drug use in the ward may be a key point of the management of medical institutions. (vi) The risk of off-label essential drug use was 1.67 times than that of non-essential drug use. (vii) The risk of off-label Rx drug use was 3.2% higher than that of OTC (Over-The-Counter) drug use, without a significant difference. (i) A management guideline for off-label drug use is urgently needed, with which we can guide medical institutions to establish the management regulations of off-label drug use. (ii) Pediatric clinical research should be promoted actively, and pharmaceutical enterprises should be encouraged to completely provide pediatric drug information. (iv) Academic organizations should be invited to join in for best professional drug use. (v) Pediatric patients and their families should receive the education on rational drug use. © 2013 Wiley Publishing Asia Pty Ltd and Chinese Cochrane Center, West China Hospital of Sichuan University.

Peptide- and saccharide-conjugated dendrimers for targeted drug delivery: a concise review

PubMed Central

Liu, Jie; Gray, Warren D.; Davis, Michael E.; Luo, Ying

2012-01-01

Dendrimers comprise a category of branched materials with diverse functions that can be constructed with defined architectural and chemical structures. When decorated with bioactive ligands made of peptides and saccharides through peripheral chemical groups, dendrimer conjugates are turned into nanomaterials possessing attractive binding properties with the cognate receptors. At the cellular level, bioactive dendrimer conjugates can interact with cells with avidity and selectivity, and this function has particularly stimulated interests in investigating the targeting potential of dendrimer materials for the design of drug delivery systems. In addition, bioactive dendrimer conjugates have so far been studied for their versatile capabilities to enhance stability, solubility and absorption of various types of therapeutics. This review presents a brief discussion on three aspects of the recent studies to use peptide- and saccharide-conjugated dendrimers for drug delivery: (i) synthesis methods, (ii) cell- and tissue-targeting properties and (iii) applications of conjugated dendrimers in drug delivery nanodevices. With more studies to elucidate the structure–function relationship of ligand–dendrimer conjugates in transporting drugs, the conjugated dendrimers hold promise to facilitate targeted delivery and improve drug efficacy for discovery and development of modern pharmaceutics. PMID:23741608

Past and current perspective on new therapeutic targets for Type-II diabetes.

PubMed

Patil, Pradip D; Mahajan, Umesh B; Patil, Kalpesh R; Chaudhari, Sandip; Patil, Chandragouda R; Agrawal, Yogeeta O; Ojha, Shreesh; Goyal, Sameer N

2017-01-01

Loss of pancreatic β-cell function is a hallmark of Type-II diabetes mellitus (DM). It is a chronic metabolic disorder that results from defects in both insulin secretion and insulin action. Recently, United Kingdom Prospective Diabetes Study reported that Type-II DM is a progressive disorder. Although, DM can be treated initially by monotherapy with oral agent; eventually, it may require multiple drugs. Additionally, insulin therapy is needed in many patients to achieve glycemic control. Pharmacological approaches are unsatisfactory in improving the consequences of insulin resistance. Single therapeutic approach in the treatment of Type-II DM is unsuccessful and usually a combination therapy is adopted. Increased understanding of biochemical, cellular and pathological alterations in Type-II DM has provided new insight in the management of Type-II DM. Knowledge of underlying mechanisms of Type-II DM development is essential for the exploration of novel therapeutic targets. Present review provides an insight into therapeutic targets of Type-II DM and their role in the development of insulin resistance. An overview of important signaling pathways and mechanisms in Type-II DM is provided for the better understanding of disease pathology. This review includes case studies of drugs that are withdrawn from the market. The experience gathered from previous studies and knowledge of Type-II DM pathways can guide the anti-diabetic drug development toward the discovery of clinically viable drugs that are useful in Type-II DM.

Chemotherapeutic response to cisplatin-like drugs in human breast cancer cells probed by vibrational microspectroscopy.

PubMed

Batista de Carvalho, A L M; Pilling, M; Gardner, P; Doherty, J; Cinque, G; Wehbe, K; Kelley, C; Batista de Carvalho, L A E; Marques, M P M

2016-06-23

Studies of drug-cell interactions in cancer model systems are essential in the preclinical stage of rational drug design, which relies on a thorough understanding of the mechanisms underlying cytotoxic activity and biological effects, at a molecular level. This study aimed at applying complementary vibrational spectroscopy methods to evaluate the cellular impact of two Pt(ii) and Pd(ii) dinuclear chelates with spermine (Pt2Spm and Pd2Spm), using cisplatin (cis-Pt(NH3)2Cl2) as a reference compound. Their effects on cellular metabolism were monitored in a human triple-negative metastatic breast cancer cell line (MDA-MB-231) by Raman and synchrotron-radiation infrared microspectroscopies, for different drug concentrations (2-8 μM) at 48 h exposure. Multivariate data analysis was applied (unsupervised PCA), unveiling drug- and concentration-dependent effects: apart from discrimination between control and drug-treated cells, a clear separation was obtained for the different agents studied - mononuclear vs. polynuclear, and Pt(ii) vs. Pd(ii). Spectral biomarkers of drug action were identified, as well as the cellular response to the chemotherapeutic insult. The main effect of the tested compounds was found to be on DNA, lipids and proteins, the Pd(ii) agent having a more significant impact on proteins while its Pt(ii) homologue affected the cellular lipid content at lower concentrations, which suggests the occurrence of distinct and unconventional pathways of cytotoxicity for these dinuclear polyamine complexes. Raman and FTIR microspectroscopies were confirmed as powerful non-invasive techniques to obtain unique spectral signatures of the biochemical impact and physiological reaction of cells to anticancer agents.

ERBB-Receptors and Drug Response in Breast Cancer

DTIC Science & Technology

1997-09-01

in topoisomerase II a (topo II a ) levels seen may be understood by global changes in DNA repair enzymes, brought about by signaling through the EGFR...ErbB-mediated signaling and topoisomerase II a levels specifically as they relate to drug sensitivity/resistance. This information will allow the use...topoisomerase II a levels and increased sensitivity to doxorubicin. In order to determine which, if any, of the specific receptors involved are

The topoisomerase II-Hsp90 complex: a new chemotherapeutic target?

PubMed

Barker, Catherine R; Hamlett, Jane; Pennington, Stephen R; Burrows, Francis; Lundgren, Karen; Lough, Rachel; Watson, Alastair J M; Jenkins, John R

2006-06-01

The modulation of DNA topology by topoisomerase II plays a crucial role during chromosome condensation and segregation in mitosis and has thus become a highly attractive target for chemotherapeutic drugs. However, these drugs are highly toxic, and so new approaches are required. One such strategy is to target topoisomerase II-interacting proteins. Here we report the identification of potential topoisomerase II-associated proteins using immunoprecipitation, followed by 1-D and 2-D gel electrophoresis and MALDI-TOF mass spectrometry. A total of 23 proteins were identified and, of these, 17 were further validated as topoisomerase IIalpha-associated proteins by coimmunoprecipitation and Western blot. Six of the interacting proteins were cellular chaperones, including 3 members of the heat shock protein-90 (Hsp90) family, and so the effect of Hsp90 modulation on the antitumor activity of topoisomerase II drugs was tested using the sulforhodamine B assay, clonogenic assays and a xenograft model. The Hsp90 inhibitors geldanamycin, 17-AAG (17-allylamino-17-demethoxygeldanamycin) and radicicol significantly enhanced the activity of the topoisomerase II poisons etoposide and mitoxantrone in vitro and in vivo. Thus, our method of identifying topoisomerase II-interacting proteins appears to be effective, and at least 1 novel topoisomerase IIalpha-associated protein, Hsp90, may represent a valid drug target in the context of topoisomerase II-directed chemotherapy.

Anticancer activity and tissue distribution of platinum (II) complex with lignin-derived polymer of benzene-poly-carboxylic acids.

PubMed

Solovyev, Nikolay D; Fedoros, Elena I; Drobyshev, Evgenii J; Ivanenko, Natalya B; Pigarev, Sergey E; Tyndyk, Margarita L; Anisimov, Vladimir N; Vilpan, Yury A; Panchenko, Andrey V

2017-09-01

Platinum-containing antineoplastic agents with physiologically active ligands seem to be a promising direction in anticancer drug design. PDBA is a novel promising antineoplastic agent, containing polymer ligand of natural origin (international patent WO2013/143549 A1). Polymer ligand of PDBA has a highly functionalised polyphenolic backbone, which exerts its own pharmacological effect via immune modulation and regulation of gene expression. PDBA is a cis-diammineplatinum(II) complex, containing mono-deprotonated benzene-poly-carboxylic acids, derived from lignin, and hydroxyl group as O-donor ligands (approximate bulk formula C 83 H 70 N 2 O 27 Pt). The agent is being evaluated in Phase II controlled clinical trials in metastatic breast cancer patients. In the present study, tissue distribution and tumour growth inhibition effects of PDBA, cisplatin and carboplatin were compared in SHR female mice, bearing inoculated solid Ehrlich carcinoma. The agents were administered subcutaneously every second day for the period of 10days (5 injections) at 62.5mg/kg, 3.0mg/kg and 18.5mg/kg for PDBA, cisplatin and carboplatin, respectively. Experimental animals were sacrificed on the Days 11, 16 and 23 after the inoculation of the tumour. The doses of all studied drugs were selected to obtain similar antitumour efficacy with ca. 50% growth inhibition of the Ehrlich tumour at the end of the study. The efficacy of a single platinum reactive moiety [cis-diammineplatinum(II)] was shown to be the highest for cisplatin, followed by PDBA and finally carboplatin. However, the toxicity of PDBA was considerably lower than that of carboplatin and especially cisplatin. The drugs were mainly distributed in lungs, kidneys, liver, spleen and tumour tissue. PDBA showed quite high accumulation in the tumour tissue, possibly, owing to the effect of the lignin-derived ligand. Copyright © 2016 Elsevier GmbH. All rights reserved.

Design of a novel bilayered gastric mucoadhesive system for localized and unidirectional release of lamotrigine

PubMed Central

Mohana Raghava Srivalli, K.; Lakshmi, P.K.; Balasubramaniam, J.

2012-01-01

Lamotrigine is a BCS class II drug with pH dependent solubility. The bilayered gastric mucoadhesive tablets of lamotrigine were designed such that the drug and controlled release polymers were incorporated in the upper layer and the lower layer had the mucoadhesive polymers. The major ingredients selected for the upper layer were the drug and control release polymer (either HPMC K15M or polyox) while the lower MA layer predominantly comprised of Carbopol 974P. A 23 full factorial design was constructed for this study and the tablets were optimized for parameters like tablet size, shape, ex vivo mucoadhesive properties and unidirectional drug release. Oval tablets with an average size of 14 mm diameter were set optimum. Maximum mucoadhesive bond strength of 79.3 ± 0.91 * 103 dyn/cm2 was achieved with carbopol when used in combination with a synergistic resin polymer. All the tested formulations presented a mucoadhesion time of greater than 12 h. The incorporation of methacrylic polymers in the lower layer ensured unidirectional drug release from the bilayered tablets. The unidirectional drug release was confirmed after comparing the dissolution results of paddle method with those of a modified basket method. Model independent similarity and dissimilarity factor methods were used for the comparison of dissolution results. Controlled drug release profiles with zero order kinetics were obtained with polyox and HPMC K15M which reported t90% at 6th and 12th hours, respectively. The “n” value with polyox was 0.992 and that with HPMC K15M was 0.946 indicating an approximate case II transport. These two formulations showed the potential for oral administration of lamotrigine as bilayered gastric mucoadhesive tablets by yielding highest similarity factor values, 96.06 and 92.47, respectively, between the paddle and modified basket method dissolution release profiles apart from reporting the best tablet physical properties and maximum mucoadhesive strength. PMID:24109205

In vitro DNA binding, pBR322 plasmid cleavage and molecular modeling study of chiral benzothiazole Schiff-base-valine Cu(II) and Zn(II) complexes to evaluate their enantiomeric biological disposition for molecular target DNA.

PubMed

Alizadeh, Rahman; Afzal, Mohd; Arjmand, Farukh

2014-10-15

Bicyclic heterocyclic compounds viz. benzothiazoles are key components of deoxyribonucleic acid (DNA) molecules and participate directly in the encoding of genetic information. Benzothiazoles, therefore, represent a potent and selective class of antitumor compounds. The design and synthesis of chiral antitumor chemotherapeutic agents of Cu(II) and Zn(II), L- and -D benzothiazole Schiff base-valine complexes 1a &b and 2a &b, respectively were carried out and thoroughly characterized by spectroscopic and analytical techniques. Interaction of 1a and b and 2a and b with CT DNA by employing UV-vis, florescence, circular dichroic methods and cleavage studies of 1a with pBR322 plasmid, molecular docking were done in order to demonstrate their enantiomeric disposition toward the molecular drug target DNA. Interestingly, these studies unambiguously demonstrated the greater potency of L-enantiomer in comparison to D-enantiomer. Copyright © 2014 Elsevier B.V. All rights reserved.

Integrating ADNI Results into Alzheimer’s Disease Drug Development Programs

PubMed Central

Cummings, Jeffrey L.

2010-01-01

The Alzheimer’s Disease Neuroimaging Initiative (ADNI) is providing critical new information on biomarkers in cognitively normal elderly, persons with mild cognitive impairment (MCI), and patients with mild Alzheimer’s disease (AD). The data provide insights into the progression of the pathology of AD over time, assist in understanding which biomarkers might be most useful in clinical trials, and facilitate development of disease-modifying treatments. ADNI results are intended to support new AD Treatments development; this paper considers how ADNI information can be integrated in AD drug development programs. Cerebrospinal fluid (CSF) amyloid beta protein (Aβ) measures can be used in Phase I studies to detect any short term effects on Aβ levels in the CSF. Phase II studies may benefit most from biomarker measures that can inform decisions about Phase III. CSF Aβ levels, CSF total tau and phospotau measures, fluorodexoyglucose positron emission tomography (FDG PET), Pittsburgh Compound B (PIB) amyloid imaging, or magnetic resonance imaging (MRI) may be employed to select patient in enriched trials or as outcomes for specific disease-modifying interventions. Use of biomarkers may allow Phase II trials to be conducted more efficiently with smaller populations of patients or shorted treatment times. New drug applications (NDA) may include biomarker outcomes of phase III trials. ADNI patients are highly educated and are nearly all of Caucasian ethnicity limiting the generalizability of the results to other populations commonly included in global clinical trials. ADNI has inspired or collaborates with biomarker investigations worldwide and together these studies will provide biomarker information that can reduce development times and costs, improve drug safety, optimize drug efficacy, and bring new treatments to patients with or at risk for AD. PMID:20447734

Patterns of recreational drug use at dance events in Edinburgh, Scotland.

PubMed

Riley, S C; James, C; Gregory, D; Dingle, H; Cadger, M

2001-07-01

To describe the patterns of drug use at dance (rave) events in terms of prevalence, frequency, type of drugs used, patterns of use, access and risk-associated behaviours. Self-selecting participant-completed survey. Three dance events in Edinburgh, Scotland, UK. One hundred and twenty-two drug users (57% males, 43% females), 90% of whom were in employment or education, with an age range of 16-47, 80% between 18 and 23 years. Participants who answered 'yes' to the question 'Have you used drugs for dance events in the past year' reported (i) the prevalence, types and frequency of drugs used; (ii) prevalence and contents of mixing drugs; (iii) accessing drugs; and (iv) engagement with drug-associated risk behaviours. Over 80% of the participants had used ecstasy and amphetamine, over 30% cocaine and LSD; over 10% nitrites, psilocybin and ketamine and less than 5% had used crack or tranquillizers. Participants reported regular consumption of ecstasy and amphetamine (e.g. 35% used ecstasy and 25% amphetamine on a weekly basis) often taken in combination, with the occasional use of cocaine, LSD, ketamine and psilocybin. Poly- and mixing-drug behaviours were significantly more likely than monodrug usage. Drugs were accessed through friends than from any other source. Eighty-five per cent reported mixing drugs and/or alcohol, 35% driving on drugs, 36% having a bad experience on drugs; 30% unprotected sex; and 0.9% injecting drugs. Women in the sample reported higher consumption than men. Dance-drug use has a characteristic pattern that has implications for health promotion and criminal policy.

76 FR 16425 - Guidance for Industry and Food and Drug Administration Staff; Class II Special Controls Guidance...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-03-23

...: Ovarian Adnexal Mass Assessment Score Test System; Availability AGENCY: Food and Drug Administration, HHS... assessment score test system into class II (special controls) under section 513(f)(2) of the Federal Food... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2011-D-0028...

Nonmuscle myosin IIB as a therapeutic target for the prevention of relapse to methamphetamine use

PubMed Central

Young, Erica J.; Blouin, Ashley M.; Briggs, Sherri B.; Sillivan, Stephanie E.; Lin, Li; Cameron, Michael D.; Rumbaugh, Gavin; Miller, Courtney A.

2015-01-01

Memories associated with drug use increase vulnerability to relapse in substance use disorder (SUD) and there are no pharmacotherapies for the prevention of relapse. Previously, we reported a promising finding that storage of memories associated with methamphetamine (METH), but not memories for fear or food reward, is vulnerable to disruption by actin depolymerization in the basolateral amygdala complex (BLC). However, actin is not a viable therapeutic target because of its numerous functions throughout the body. Here we report the discovery of a viable therapeutic target, nonmuscle myosin II (NMIIB), a molecular motor that supports memory by directly driving synaptic actin polymerization. A single intra-BLC treatment with Blebbistatin, a small molecule inhibitor of class II myosin isoforms, including NMIIB, produced a long-lasting disruption of context-induced drug seeking (at least 30 days). Further, post-consolidation genetic knockdown of Myh10, the heavy chain of the most highly expressed NMII in the BLC, was sufficient to produce METH-associated memory loss. Blebbistatin was found to be highly brain penetrant. A single systemic injection of the compound selectively disrupted the storage of METH-associated memory and reversed the accompanying increase in BLC spine density. This effect was specific to METH-associated memory, as it had no effect on an auditory fear memory. The effect was also independent of retrieval, as METH-associated memory was disrupted twenty-four hours after a single systemic injection of Blebbistatin delivered in the home cage. Together, these results argue for the further development of small molecule inhibitors of nonmuscle myosin II as potential therapeutics for the prevention of SUD relapse triggered by drug associations. PMID:26239291

Drug Modulation of Water–Heme Interactions in Low-Spin P450 Complexes of CYP2C9d and CYP125A1

PubMed Central

Conner, Kip P.; Cruce, Alex A.; Krzyaniak, Matthew D.; Schimpf, Alina M.; Frank, Daniel J.; de Montellano, Paul Ortiz; Atkins, William M.; Bowman, Michael K.

2015-01-01

Azoles and pyridines are commonly incorporated into small molecule inhibitor scaffolds that target cytochromes P450 (CYPs) as a strategy to increase drug binding affinity, impart isoform-dependent selectivity, and improve metabolic stability. Optical absorbance spectra of the CYP–inhibitor complex are widely used to infer whether these inhibitors are ligated directly to the heme iron as catalytically inert, low-spin (type II) complexes. Here, we show that the low-spin complex between a drug-metabolizing CYP2C9 variant and 4-(3-phenyl-propyl)-1H-1,2,3-triazole (PPT) retains an axial water ligand despite exhibiting elements of “classic” type II optical behavior. Hydrogens of the axial water ligand are observed by pulsed electron paramagnetic resonance (EPR) spectroscopy for both inhibitor-free and inhibitor-bound species and show that inhibitor binding does not displace the axial water. A 15N label incorporated into PPT is 0.444 nm from the heme iron, showing that PPT is also in the active site. The reverse type I inhibitor, LP10, of CYP125A1 from Mycobacterium tuberculosis, known from X-ray crystal structures to form a low-spin water-bridged complex, is found by EPR and by visible and near-infrared magnetic circular dichroism spectroscopy to retain the axial water ligand in the complex in solution. PMID:25591012

Copper(II) complexes of methimazole, an anti Grave's disease drug. Synthesis, characterization and its potential biological behavior as alkaline phosphatase inhibitor.

PubMed

Urquiza, Nora M; Manca, Silvia G; Moyano, María A; Dellmans, Raquel Arrieta; Lezama, Luis; Rojo, Teófilo; Naso, Luciana G; Williams, Patricia A M; Ferrer, Evelina G

2010-04-01

Methimazole (MeimzH) is an anti-thyroid drug and the first choice for patients with Grave's disease. Two new copper(II) complexes of this drug: [Cu(MeimzH)(2)(NO(3))(2)]*0.5H(2)O and [Cu(MeimzH)(2)(H(2)O)(2)](NO(3))(2)*H(2)O were synthesized and characterized by elemental analysis, dissolution behavior, thermogravimetric analysis and UV-vis, diffuse reflectance, FTIR and EPR spectroscopies. As it is known that copper(II) cation can act as an inhibitor of alkaline phosphatase (ALP), the inhibitory effect of methimazole and its copper(II) complexes on ALP activity has also been investigated.

Pharmaceutical Applications of Relaxation Filter-Selective Signal Excitation Methods for ¹⁹F Solid-State Nuclear Magnetic Resonance: Case Study With Atorvastatin in Dosage Formulation.

PubMed

Asada, Mamiko Nasu; Nemoto, Takayuki; Mimura, Hisashi

2016-03-01

We recently developed several new relaxation filter-selective signal excitation (RFS) methods for (13)C solid-state nuclear magnetic resonance (NMR) that allow (13)C signal extraction of the target components from pharmaceuticals. These methods were successful in not only qualification but also quantitation over the wide range of 5% to 100%. Here, we aimed to improve the sensitivity of these methods and initially applied them to (19)F solid-state NMR, on the basis that the fluorine atom is one of the most sensitive NMR-active nuclei. For testing, we selected atorvastatin calcium (ATC), an antilipid BCS class II drug that inhibits 3-hydroxy-3-methylglutaryl-coenzyme A reductase and is marketed in crystalline and amorphous forms. Tablets were obtained from 2 generic drug suppliers, and the ATC content occurred mainly as an amorphous form. Using the RFS method with (19)F solid-state NMR, we succeeded in qualifying trace amounts (less than 0.5% w/w level) of crystalline phase (Form I) of ATC in the tablets. RFS methods with (19)F solid-state NMR are practical and time efficient and can contribute not only to the study of pharmaceutical drugs, including those with small amounts of a highly potent active ingredient within a formulated product, but also to the study of fluoropolymers in material sciences. Copyright © 2016 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Selective hair therapy: bringing science to the fiction.

PubMed

Vogt, Annika; Blume-Peytavi, Ulrike

2014-02-01

Investigations on carrier-based drug delivery systems for higher selectivity in hair therapy have clearly evolved from dye release and model studies to highly sophisticated approaches, many of which specifically tackle hair indications and the delivery of hair-relevant molecules. Here, we group recent hair disease-oriented work into efforts towards (i) improved delivery of conventional drugs, (ii) delivery of novel drug classes, for example biomolecules and (iii) targeted delivery on the cellular/molecular level. Considering the solid foundation of experimental work, it does not take a large step outside the current box of thinking to follow the idea of using large carriers (>500 nm, unlikely to penetrate as a whole) for follicular penetration, retention and protection of sensitive compounds. Yet, reports on particles <200 nm being internalized by keratinocytes and dendritic cells at sites of barrier disruption (e.g., hair follicles) combined with recent advances in nanodermatology add interesting new facets to the possibilities carrier technologies could offer, for example, unprecedented levels of selectivity. The authors provide thought-provoking ideas on how smart delivery technologies and advances in our molecular understanding of hair pathophysiology could result in a whole new era of hair therapeutics. As the field still largely remains in preclinical investigation, determined efforts towards production of medical grade material and truly translational work are needed to demonstrate surplus value of carrier systems for clinical applications. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

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

Hevener, Kirk E.; Mehboob, Shahila; Boci, Teuta

The rapid rise in bacterial drug resistance coupled with the low number of novel antimicrobial compounds in the discovery pipeline has led to a critical situation requiring the expedient discovery and characterization of new antimicrobial drug targets. Enzymes in the bacterial fatty acid synthesis pathway, FAS-II, are distinct from their mammalian counterparts, FAS-I, in terms of both structure and mechanism. As such, they represent attractive targets for the design of novel antimicrobial compounds. Enoyl-acyl carrier protein reductase II, FabK, is a key, rate-limiting enzyme in the FAS-II pathway for several bacterial pathogens. The organism, Porphyromonas gingivalis, is a causative agentmore » of chronic periodontitis that affects up to 25% of the US population and incurs a high national burden in terms of cost of treatment. P. gingivalis expresses FabK as the sole enoyl reductase enzyme in its FAS-II cycle, which makes this a particularly appealing target with potential for selective antimicrobial therapy. Herein we report the molecular cloning, expression, purification and characterization of the FabK enzyme from P. gingivalis, only the second organism from which this enzyme has been isolated. Characterization studies have shown that the enzyme is a flavoprotein, the reaction dependent upon FMN and NADPH and proceeding via a Ping-Pong Bi-Bi mechanism to reduce the enoyl substrate. A sensitive assay measuring the fluorescence decrease of NADPH as it is converted to NADP{sup +} during the reaction has been optimized for high-throughput screening. Finally, protein crystallization conditions have been identified which led to protein crystals that diffract x-rays to high resolution.« less

Photoexpulsion of surface-grafted ruthenium complexes and subsequent release of cytotoxic cargos to cancer cells from mesoporous silica nanoparticles.

PubMed

Frasconi, Marco; Liu, Zhichang; Lei, Juying; Wu, Yilei; Strekalova, Elena; Malin, Dmitry; Ambrogio, Michael W; Chen, Xinqi; Botros, Youssry Y; Cryns, Vincent L; Sauvage, Jean-Pierre; Stoddart, J Fraser

2013-08-07

Ruthenium(II) polypyridyl complexes have emerged both as promising probes of DNA structure and as anticancer agents because of their unique photophysical and cytotoxic properties. A key consideration in the administration of those therapeutic agents is the optimization of their chemical reactivities to allow facile attack on the target sites, yet avoid unwanted side effects. Here, we present a drug delivery platform technology, obtained by grafting the surface of mesoporous silica nanoparticles (MSNPs) with ruthenium(II) dipyridophenazine (dppz) complexes. This hybrid nanomaterial displays enhanced luminescent properties relative to that of the ruthenium(II) dppz complex in a homogeneous phase. Since the coordination between the ruthenium(II) complex and a monodentate ligand linked covalently to the nanoparticles can be cleaved under irradiation with visible light, the ruthenium complex can be released from the surface of the nanoparticles by selective substitution of this ligand with a water molecule. Indeed, the modified MSNPs undergo rapid cellular uptake, and after activation with light, the release of an aqua ruthenium(II) complex is observed. We have delivered, in combination, the ruthenium(II) complex and paclitaxel, loaded in the mesoporous structure, to breast cancer cells. This hybrid material represents a promising candidate as one of the so-called theranostic agents that possess both diagnostic and therapeutic functions.

In vitro kinetic studies on the mechanism of oxygen-dependent cellular uptake of copper radiopharmaceuticals.

PubMed

Holland, Jason P; Giansiracusa, Jeffrey H; Bell, Stephen G; Wong, Luet-Lok; Dilworth, Jonathan R

2009-04-07

The development of hypoxia-selective radiopharmaceuticals for use as therapeutic and/or imaging agents is of vital importance for both early identification and treatment of cancer and in the design of new drugs. Radiotracers based on copper for use in positron emission tomography have received great attention due to the successful application of copper(II) bis(thiosemicarbazonato) complexes, such as [(60/62/64)Cu(II)ATSM] and [(60/62/64)Cu(II)PTSM], as markers for tumour hypoxia and blood perfusion, respectively. Recent work has led to the proposal of a revised mechanism of hypoxia-selective cellular uptake and retention of [Cu(II)ATSM]. The work presented here describes non-steady-state kinetic simulations in which the reported pO(2)-dependent in vitro cellular uptake and retention of [(64)Cu(II)ATSM] in EMT6 murine carcinoma cells has been modelled by using the revised mechanistic scheme. Non-steady-state (NSS) kinetic analysis reveals that the model is in very good agreement with the reported experimental data with a root-mean-squared error of less than 6% between the simulated and experimental cellular uptake profiles. Estimated rate constants are derived for the cellular uptake and washout (k(1) = 9.8 +/- 0.59 x 10(-4) s(-1) and k(2) = 2.9 +/- 0.17 x 10(-3) s(-1)), intracellular reduction (k(3) = 5.2 +/- 0.31 x 10(-2) s(-1)), reoxidation (k(4) = 2.2 +/- 0.13 mol(-1) dm(3) s(-1)) and proton-mediated ligand dissociation (k(5) = 9.0 +/- 0.54 x 10(-5) s(-1)). Previous mechanisms focused on the reduction and reoxidation steps. However, the data suggest that the origins of hypoxia-selective retention may reside with the stability of the copper(I) anion with respect to protonation and ligand dissociation. In vitro kinetic studies using the nicotimamide adenine dinucleotide (NADH)-dependent ferredoxin reductase enzyme PuR isolated from the bacterium Rhodopseudomonas palustris have also been conducted. NADH turnover frequencies are found to be dependent on the structure of the ligand and the results confirm that the proposed reduction step in the mechanism of hypoxia selectivity is likely to be mediated by NADH-dependent enzymes. Further understanding of the mechanism of hypoxia selectivity may facilitate the development of new imaging and radiotherapeutic agents with increased specificity for tumour hypoxia.

In vitro kinetic studies on the mechanism of oxygen-dependent cellular uptake of copper radiopharmaceuticals

NASA Astrophysics Data System (ADS)

Holland, Jason P.; Giansiracusa, Jeffrey H.; Bell, Stephen G.; Wong, Luet-Lok; Dilworth, Jonathan R.

2009-04-01

The development of hypoxia-selective radiopharmaceuticals for use as therapeutic and/or imaging agents is of vital importance for both early identification and treatment of cancer and in the design of new drugs. Radiotracers based on copper for use in positron emission tomography have received great attention due to the successful application of copper(II) bis(thiosemicarbazonato) complexes, such as [60/62/64Cu(II)ATSM] and [60/62/64Cu(II)PTSM], as markers for tumour hypoxia and blood perfusion, respectively. Recent work has led to the proposal of a revised mechanism of hypoxia-selective cellular uptake and retention of [Cu(II)ATSM]. The work presented here describes non-steady-state kinetic simulations in which the reported pO2-dependent in vitro cellular uptake and retention of [64Cu(II)ATSM] in EMT6 murine carcinoma cells has been modelled by using the revised mechanistic scheme. Non-steady-state (NSS) kinetic analysis reveals that the model is in very good agreement with the reported experimental data with a root-mean-squared error of less than 6% between the simulated and experimental cellular uptake profiles. Estimated rate constants are derived for the cellular uptake and washout (k1 = 9.8 ± 0.59 × 10-4 s-1 and k2 = 2.9 ± 0.17 × 10-3 s-1), intracellular reduction (k3 = 5.2 ± 0.31 × 10-2 s-1), reoxidation (k4 = 2.2 ± 0.13 mol-1 dm3 s-1) and proton-mediated ligand dissociation (k5 = 9.0 ± 0.54 × 10-5 s-1). Previous mechanisms focused on the reduction and reoxidation steps. However, the data suggest that the origins of hypoxia-selective retention may reside with the stability of the copper(I) anion with respect to protonation and ligand dissociation. In vitro kinetic studies using the nicotimamide adenine dinucleotide (NADH)-dependent ferredoxin reductase enzyme PuR isolated from the bacterium Rhodopseudomonas palustris have also been conducted. NADH turnover frequencies are found to be dependent on the structure of the ligand and the results confirm that the proposed reduction step in the mechanism of hypoxia selectivity is likely to be mediated by NADH-dependent enzymes. Further understanding of the mechanism of hypoxia selectivity may facilitate the development of new imaging and radiotherapeutic agents with increased specificity for tumour hypoxia.

Influence of negative affect on selective attention to smoking-related cues and urge to smoke in cigarette smokers.

PubMed

Bradley, Brendan P; Garner, Matthew; Hudson, Laura; Mogg, Karin

2007-07-01

According to recent models of addiction, negative affect plays an important role in maintaining drug dependence. The study investigated the effect of negative mood on attentional biases for smoking-related cues and smoking urge in cigarette smokers. Eye movements to smoking-related and control pictures, and manual response times to probes, were recorded during a visual probe task. Smoking urges and mood were assessed by self-report measures. Negative affect was manipulated experimentally as a within-participants independent variable; that is, each participant received negative and neutral mood induction procedures, in counterbalanced order in separate sessions, before the attentional task. There were two groups of participants: smokers and nonsmokers. Smokers showed (i) a greater tendency to shift gaze initially towards smoking-related cues, and (ii) greater urge to smoke when they were in negative mood compared with neutral mood. Manual response time data suggested that smokers showed a greater tendency than nonsmokers to maintain attention on smoking-related cues, irrespective of mood. The results offer partial support for the view that negative mood increases selective attention to drug cues, and urge to smoke, in smokers. The findings are discussed in relation to an affective processing model of negative reinforcement in drug dependence.

Development of an achiral supercritical fluid chromatography method with ultraviolet absorbance and mass spectrometric detection for impurity profiling of drug candidates. Part II. Selection of an orthogonal set of stationary phases.

PubMed

Lemasson, Elise; Bertin, Sophie; Hennig, Philippe; Boiteux, Hélène; Lesellier, Eric; West, Caroline

2015-08-21

Impurity profiling of organic products that are synthesized as possible drug candidates requires complementary analytical methods to ensure that all impurities are identified. Supercritical fluid chromatography (SFC) is a very useful tool to achieve this objective, as an adequate selection of stationary phases can provide orthogonal separations so as to maximize the chances to see all impurities. In this series of papers, we have developed a method for achiral SFC-MS profiling of drug candidates, based on a selection of 160 analytes issued from Servier Research Laboratories. In the first part of this study, focusing on mobile phase selection, a gradient elution with carbon dioxide and methanol comprising 2% water and 20mM ammonium acetate proved to be the best in terms of chromatographic performance, while also providing good MS response [1]. The objective of this second part was the selection of an orthogonal set of ultra-high performance stationary phases, that was carried out in two steps. Firstly, a reduced set of analytes (20) was used to screen 23 columns. The columns selected were all 1.7-2.5μm fully porous or 2.6-2.7μm superficially porous particles, with a variety of stationary phase chemistries. Derringer desirability functions were used to rank the columns according to retention window, column efficiency evaluated with peak width of selected analytes, and the proportion of analytes successfully eluted with good peak shapes. The columns providing the worst performances were thus eliminated and a shorter selection of columns (11) was obtained. Secondly, based on 160 tested analytes, the 11 columns were ranked again. The retention data obtained on these columns were then compared to define a reduced set of the best columns providing the greatest orthogonality, to maximize the chances to see all impurities within a limited number of runs. Two high-performance columns were thus selected: ACQUITY UPC(2) HSS C18 SB and Nucleoshell HILIC. Copyright © 2015 Elsevier B.V. All rights reserved.

Evaluation and selection of bio-relevant dissolution media for a poorly water-soluble new chemical entity.

PubMed

Tang, L; Khan, S U; Muhammad, N A

2001-11-01

The purpose of this work is to develop a bio-relevant dissolution method for formulation screening in order to select an enhanced bioavailable formulation for a poorly water-soluble drug. The methods used included a modified rotating disk apparatus for measuring intrinsic dissolution rate of the new chemical entity (NCE) and the USP dissolution method II for evaluating dissolution profiles of the drug in three different dosage forms. The in vitro dissolution results were compared with the in vivo bioavailability for selecting a bio-relevant medium. The results showed that the solubility of the NCE was proportional to the concentration of sodium lauryl sulfate (SLS) in the media. The apparent intrinsic dissolution rate of the NCE was linear to the rotational speed of the disk, which indicated that the dissolution of the drug is a diffusion-controlled mechanism. The apparent intrinsic dissolution rate was also linear to the surfactant concentration in the media, which was interpreted using the Noyes and Whitney Empirical Theory. Three formulations were studied in three different SLS media using the bulk drug as a reference. The dissolution results were compared with the corresponding bioavailability results in dogs. In the 1% SLS--sink conditions--the drug release from all the formulations was complete and the dissolution results were discriminative for the difference in particle size of the drug in the formulations. However, the data showed poor IVIV correlation. In the 0.5% SLS medium--non-sink conditions--the dissolution results showed the same rank order among the tested formulations as the bioavailability. The best IVIV correlation was obtained from the dissolution in 0.25% SLS medium, an over-saturated condition. The conclusions are: a surfactant medium increases the apparent intrinsic dissolution rate of the NCE linearly due to an increase in solubility. A low concentration of surfactant in the medium (0.25%) is more bio-relevant than higher concentrations of surfactant in the media for the poorly water-soluble drug. Creating sink conditions (based on bulk drug solubilities) by using a high concentration of a surfactant in the dissolution medium may not be a proper approach in developing a bio-relevant dissolution method for a poorly water-soluble drug.

Depression as Measured by the Beck Depression Inventory-II among Injecting Drug Users

ERIC Educational Resources Information Center

Johnson, Mark E.; Neal, David B.; Brems, Christiane; Fisher, Dennis G.

2006-01-01

This study conducts a confirmatory factor analysis of the Beck Depression Inventory-II (BDI-II) with a sample of 598 individuals who reported recent injecting drug use. Findings indicate that out of four models tested, the best model for this sample is a three-factor solution (somatic, affective, and cognitive) previously reported by Buckley,…

Evaluation of anti-inflammatory effect of statins in chronic periodontitis.

PubMed

Suresh, Snophia; Narayana, Satya; Jayakumar, P; Sudhakar, Uma; Pramod, V

2013-01-01

Statins are the group of lipid-lowering drugs commonly used to control cardiovascular and cerebrovascular diseases. Statins have potential anti-inflammatory effect by blocking the intermediate metabolites of the mevalonate pathway. The objective of this study was to evaluate the anti-inflammatory effect of statin medication in chronic periodontitis patients. Thirty patients of age group between 40 and 60 years were selected from the outpatient pool of Department of Periodontics, Thaimoogambigai Dental College and Hospital, Chennai. Thirty patients selected were grouped into two groups, Group-I consists of patients with generalized chronic periodontitis and on statin medication and Group-II consists of patients with generalized chronic periodontitis. Clinical parameters were recorded and gingival crevicular fluid (GCF) samples were analyzed for interleukin (IL)-1β using commercially available enzyme-linked immunosorbent assay. The mean GCF IL-1β levels in generalized chronic periodontitis patients who are on statin medication (Group-I) were lower than the generalized chronic periodontitis patients without statin medication (Group-II). Reduction of GCF IL-1β levels in statin users indicate that statins have anti-inflammatory effect on periodontal disease.

Obligatory role for GPER in cardiovascular aging and disease^

PubMed Central

Daniel, Christoph; Sharma, Geetanjali; Amann, Kerstin; Arterburn, Jeffrey B.; Barton, Matthias; Prossnitz, Eric R.

2016-01-01

Pharmacological activation of the heptahelical G protein-coupled receptor GPER by selective ligands counteracts multiple aspects of cardiovascular disease. We thus expected that genetic deletion or pharmacological inhibition of GPER would further aggravate such disease states, particularly with age. To the contrary, we found that genetic ablation of Gper in mice prevented cardiovascular pathologies associated with aging by reducing superoxide (.O2−) formation by NADPH oxidase (Nox) and reduced expression the Nox isoform Nox1. Blocking GPER activity pharmacologically with G36, a synthetic, small molecule, GPER-selective blocker (GRB), decreased Nox1 abundance and .O2− production to basal amounts in cells exposed to angiotensin II and in mice chronically infused with angiotensin II. Thus, this study revealed a role for GPER activity in regulating Nox1 abundance and associated .O2−-mediated structural and functional damage that contributes to disease pathology. Our results indicated that GRBs represent a new class of drugs that can indirectly reduce Nox activity and could be used for the treatment of chronic disease processes involving excessive .O2− formation, including arterial hypertension and diastolic heart failure. PMID:27803283

Open saccharin-based secondary sulfonamides as potent and selective inhibitors of cancer-related carbonic anhydrase IX and XII isoforms.

PubMed

D'Ascenzio, Melissa; Guglielmi, Paolo; Carradori, Simone; Secci, Daniela; Florio, Rosalba; Mollica, Adriano; Ceruso, Mariangela; Akdemir, Atilla; Sobolev, Anatoly P; Supuran, Claudiu T

2017-12-01

A large number of novel secondary sulfonamides based on the open saccharin scaffold were synthesized and evaluated as selective inhibitors of four different isoforms of human carbonic anhydrase (hCA I, II, IX and XII, EC 4.2.1.1). They were obtained by reductive ring opening of the newly synthesized N-alkylated saccharin derivatives and were shown to be inactive against the two cytosolic off-target hCA I and II (K i s > 10 µM). Interestingly, these compounds inhibited hCA IX in the low nanomolar range with K i s ranging between 20 and 298 nM and were extremely potent inhibitors of hCA XII isoenzyme (K i s ranging between 4.3 and 432 nM). Since hCA IX and XII are the cancer-related isoforms recently validated as drug targets, these results represent an important goal in the development of new anticancer candidates. Finally, a computational approach has been performed to better correlate the biological data to the binding mode of these inhibitors.

Ayurvedic approach for improving reaction time of attention deficit hyperactivity disorder affected children.

PubMed

Singhal, Harish Kumar; Neetu; Kumar, Abhimanyu; Rai, Moti

2010-07-01

Attention deficit/hyperactivity disorder (ADHD) is a behavioral disorder of children. It is the most common neurological disorder of childhood. The present study was conducted to examine the increase in attention span in 43 ADHD-affected children treated with different approaches. The reaction time was measured using a Vernier chronoscope (electronic). Selected children of both sexes in the age-group of 6-16 years were divided into three groups. In group A, 17 patients received syrup Ayurvedic compound I; in group B, 14 patients were treated with syrup Ayurvedic compound I + Shirodhara with milk; and in group C, 12 patients received syrup Ayurvedic compound II (placebo). The dose of the drug was 1.0 ml/kg body weight and the duration of treatment was 3 months. Group B showed highly significant (P<.001) improvement in total reaction time, while in group C the change was statistically nonsignificant P > 0.10. It was found that while the drug and Shirodhara were both effective in improving the reaction time of ADHD-affected children, the drug combined with Shirodhara was superior to the drug used alone.

Ayurvedic approach for improving reaction time of attention deficit hyperactivity disorder affected children

PubMed Central

Singhal, Harish Kumar; Neetu; Kumar, Abhimanyu; Rai, Moti

2010-01-01

Attention deficit/hyperactivity disorder (ADHD) is a behavioral disorder of children. It is the most common neurological disorder of childhood. The present study was conducted to examine the increase in attention span in 43 ADHD-affected children treated with different approaches. The reaction time was measured using a Vernier chronoscope (electronic). Selected children of both sexes in the age-group of 6–16 years were divided into three groups. In group A, 17 patients received syrup Ayurvedic compound I; in group B, 14 patients were treated with syrup Ayurvedic compound I + Shirodhara with milk; and in group C, 12 patients received syrup Ayurvedic compound II (placebo). The dose of the drug was 1.0 ml/kg body weight and the duration of treatment was 3 months. Group B showed highly significant (P<.001) improvement in total reaction time, while in group C the change was statistically nonsignificant P > 0.10. It was found that while the drug and Shirodhara were both effective in improving the reaction time of ADHD-affected children, the drug combined with Shirodhara was superior to the drug used alone. PMID:22131736

How Do Antihypertensive Drugs Work? Insights from Studies of the Renal Regulation of Arterial Blood Pressure

PubMed Central

Digne-Malcolm, Holly; Frise, Matthew C.; Dorrington, Keith L.

2016-01-01

Though antihypertensive drugs have been in use for many decades, the mechanisms by which they act chronically to reduce blood pressure remain unclear. Over long periods, mean arterial blood pressure must match the perfusion pressure necessary for the kidney to achieve its role in eliminating the daily intake of salt and water. It follows that the kidney is the most likely target for the action of most effective antihypertensive agents used chronically in clinical practice today. Here we review the long-term renal actions of antihypertensive agents in human studies and find three different mechanisms of action for the drugs investigated. (i) Selective vasodilatation of the renal afferent arteriole (prazosin, indoramin, clonidine, moxonidine, α-methyldopa, some Ca++-channel blockers, angiotensin-receptor blockers, atenolol, metoprolol, bisoprolol, labetolol, hydrochlorothiazide, and furosemide). (ii) Inhibition of tubular solute reabsorption (propranolol, nadolol, oxprenolol, and indapamide). (iii) A combination of these first two mechanisms (amlodipine, nifedipine and ACE-inhibitors). These findings provide insights into the actions of antihypertensive drugs, and challenge misconceptions about the mechanisms underlying the therapeutic efficacy of many of the agents. PMID:27524972

Design, development, and validation of a high-throughput drug-screening assay for targeting of human leukemia

PubMed Central

Karjalainen, Katja; Pasqualini, Renata; Cortes, Jorge E.; Kornblau, Steven M.; Lichtiger, Benjamin; O'Brien, Susan; Kantarjian, Hagop M.; Sidman, Richard L.; Arap, Wadih; Koivunen, Erkki

2015-01-01

Background We introduce an ex vivo methodology to perform drug library screening against human leukemia. Method Our strategy relies on human blood or bone marrow cultures under hypoxia; under these conditions, leukemia cells deplete oxygen faster than normal cells, causing a hemoglobin oxygenation shift. We demonstrate several advantages: (I) partial recapitulation of the leukemia microenvironment, (ii) use of native hemoglobin oxygenation as real-time sensor/reporter, (iii) cost-effectiveness, (iv) species-specificity, and (v) format that enables high-throughput screening. Results As a proof-of-concept, we screened a chemical library (size ∼20,000) against human leukemia cells. We identified 70 compounds (“hit” rate=0.35%; Z-factor=0.71) with activity; we examined 20 to find 18 true-positives (90%). Finally, we show that carbonohydraxonic diamide group-containing compounds are potent anti-leukemia agents that induce cell death in leukemia cells and patient-derived samples. Conclusions This unique functional assay can identify novel drug candidates as well as find future applications in personalized drug selection for leukemia patients. PMID:24496871

Thiopental and Phenytoin as Novel Ionophores for Potentiometric Determination of Lead (II) Ions

PubMed Central

Rizk, Nashwa M.H.; Abbas, Samah S.; Hamza, Salem M.; Abd EL-Karem, Yasser M.

2009-01-01

Two novel polymeric membrane sensors for the analysis of Pb(II) have been developed based on two therapeutic drugs, thiopental (TP) and phenytoin (PT) as two new ionophores and potassium tetrakis(p-chlorophenyl) borate (KTpClPB) as a lipophilic additive, in plasticized PVC membranes. The sensors show a Nernstian response for Pb(II) ions over the wide concentration ranges of 1×10−2 – 7×10−6 M and 1×10−2 – 8×10−6 M for the sensors based on thiopental and phenytoin, respectively. The proposed sensors have a fast response time and can be used for more than nine weeks without any considerable divergence in potentials. The sensors exhibit comparatively good selectivity with respect to alkaline, alkaline earth and some transition and heavy metal ions. They were employed for direct determination of lead in solder alloys and in galena rocks with a good agreement with the obtained results by atomic absorption spectroscopy. PMID:22573991

Using phase II data for the analysis of phase III studies: An application in rare diseases.

PubMed

Wandel, Simon; Neuenschwander, Beat; Röver, Christian; Friede, Tim

2017-06-01

Clinical research and drug development in orphan diseases are challenging, since large-scale randomized studies are difficult to conduct. Formally synthesizing the evidence is therefore of great value, yet this is rarely done in the drug-approval process. Phase III designs that make better use of phase II data can facilitate drug development in orphan diseases. A Bayesian meta-analytic approach is used to inform the phase III study with phase II data. It is particularly attractive, since uncertainty of between-trial heterogeneity can be dealt with probabilistically, which is critical if the number of studies is small. Furthermore, it allows quantifying and discounting the phase II data through the predictive distribution relevant for phase III. A phase III design is proposed which uses the phase II data and considers approval based on a phase III interim analysis. The design is illustrated with a non-inferiority case study from a Food and Drug Administration approval in herpetic keratitis (an orphan disease). Design operating characteristics are compared to those of a traditional design, which ignores the phase II data. An analysis of the phase II data reveals good but insufficient evidence for non-inferiority, highlighting the need for a phase III study. For the phase III study supported by phase II data, the interim analysis is based on half of the patients. For this design, the meta-analytic interim results are conclusive and would justify approval. In contrast, based on the phase III data only, interim results are inconclusive and require further evidence. To accelerate drug development for orphan diseases, innovative study designs and appropriate methodology are needed. Taking advantage of randomized phase II data when analyzing phase III studies looks promising because the evidence from phase II supports informed decision-making. The implementation of the Bayesian design is straightforward with public software such as R.

76 FR 44594 - Guidance for Industry and Food and Drug Administration Staff; Class II Special Controls Guidance...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-07-26

... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2011-D-0465] Guidance for Industry and Food and Drug Administration Staff; Class II Special Controls Guidance Document... guidance document will serve as the special control for rTMS systems. Section 513(f)(2) of the Federal Food...

Bactericidal activity of OPC-67683 against drug-tolerant Mycobacterium tuberculosis.

PubMed

Saliu, Oluwabunmi Y; Crismale, Catina; Schwander, Stephan K; Wallis, Robert S

2007-11-01

There is an urgent need for drugs that hasten sterilization in tuberculosis; however, we presently lack indicators of this activity to guide early drug development. We previously described a novel in vitro assay to study mycobacterial phenotypic drug tolerance, in which sterilizing activity could be assessed. OPC-67,683 is a novel imidazooxazole that accelerates sterilization in the mouse tuberculosis model. The present study was conducted to determine the activity of OPC-67,683 in the in vitro tolerance model using drug-tolerant clinical Mycobacterium tuberculosis strains. Tolerance was assessed in Bactec radiometric culture as: (i) delayed decline in growth index during 14 days of drug exposure; (ii) shorter time to positivity of subcultures following drug exposure. Four isolates were selected from among 16 surveyed, based on delayed killing by isoniazid and OPC-67,683. Unlike isoniazid and rifampicin, whose rates of killing were concentration-independent, OPC-67,683 showed concentration-dependent effects that, at the highest dose levels tested (1.0 microg/mL), were superior to isoniazid and equal to rifampicin. The sterilizing activity of OPC-67683 against drug-tolerant M. tuberculosis in the Bactec model is consistent with its activity in mice. Further studies are warranted to examine the effects of OPC-67683 on mycobacterial persistence in tuberculous patients and to determine the biological basis of tolerance in the model.

Effects of Selective and Non-Selective Glucocorticoid Receptor II Antagonists on Rapid-Onset Diabetes in Young Rats

PubMed Central

Beaudry, Jacqueline L.; Dunford, Emily C.; Teich, Trevor; Zaharieva, Dessi; Hunt, Hazel; Belanoff, Joseph K.; Riddell, Michael C.

2014-01-01

The blockade of glucocorticoid (GC) action through antagonism of the glucocorticoid receptor II (GRII) has been used to minimize the undesirable effects of chronically elevated GC levels. Mifepristone (RU486) is known to competitively block GRII action, but not exclusively, as it antagonizes the progesterone receptor. A number of new selective GRII antagonists have been developed, but limited testing has been completed in animal models of overt type 2 diabetes mellitus. Therefore, two selective GRII antagonists (C113176 and C108297) were tested to determine their effects in our model of GC-induced rapid-onset diabetes (ROD). Male Sprague-Dawley rats (∼ six weeks of age) were placed on a high-fat diet (60%), surgically implanted with pellets containing corticosterone (CORT) or wax (control) and divided into five treatment groups. Each group was treated with either a GRII antagonist or vehicle for 14 days after surgery: CORT pellets (400 mg/rat) + antagonists (80 mg/kg/day); CORT pellets + drug vehicle; and wax pellets (control) + drug vehicle. After 10 days of CORT treatment, body mass gain was increased with RU486 (by ∼20% from baseline) and maintained with C113176 administration, whereas rats given C108297 had similar body mass loss (∼15%) to ROD animals. Fasting glycemia was elevated in the ROD animals (>20 mM), normalized completely in animals treated with RU486 (6.2±0.1 mM, p<0.05) and improved in animals treated with C108297 and C113176 (14.0±1.6 and 8.8±1.6 mM, p<0.05 respectively). Glucose intolerance was normalized with RU486 treatment, whereas acute insulin response was improved with RU486 and C113176 treatment. Also, peripheral insulin resistance was attenuated with C113176 treatment along with improved levels of β-cell function while C108297 antagonism only provided modest improvements. In summary, C113176 is an effective agent that minimized some GC-induced detrimental metabolic effects and may provide an alternative to the effective, but non-selective, GRII antagonist RU486. PMID:24642683

Detection of the arylpropionamide-derived selective androgen receptor modulator (SARM) S-4 (Andarine) in a black-market product.

PubMed

Thevis, Mario; Geyer, Hans; Kamber, Matthias; Schänzer, Wilhelm

2009-08-01

Non-steroidal and tissue-selective anabolic agents such as selective androgen receptor modulators (SARMs) represent a promising class of therapeutics for the treatment of various diseases such as sarcopenia or cancer cachexia. Advanced compounds of SARMs are based on an arylpropionamide-derived structure and leading drug candidates have successfully completed phase-II-clinical trials. Although none of these therapeutics have been approved, their performance-enhancing qualities and the black-market availability of these products makes them a viable target for misuse in the athletic community. In 2008, SARMs were added to the Prohibited List established by the World Anti-Doping Agency (WADA). That SARMs are the subject of misuse even without clinical approval was proved for the first time by the detection of the drug candidate Andarine (also referred to as S-4, S-3-(4-acetylamino-phenoxy)-2-hydroxy-2-methyl-N-(4-nitro-3-trifluoromethyl-phenyl)-propionamide), advertised, sold and supplied via the Internet. The oily liquids, declared as green tea extracts and face moisturizer, were assayed using state-of-the-art analytical procedures and S-4 was found at concentrations of approximately 150 mg/mL. The authenticity of the product was demonstrated in comparison to reference material by liquid chromatography, high resolution/high accuracy (tandem) mass spectrometry using positive and negative electrospray ionization, and comparison to reference material. Moreover, an impurity resulting from poor product purification was detected, accounting for approximately 10% of S-4. This consisted of 2-hydroxy-2-methyl-N-(4-nitro-3-trifluoromethyl-phenyl)-3-(4-nitro-3-trifluoromethyl-phenylamino)-propionamide. The ease of purchasing non-approved drug candidates that could potentially increase athletic performance demonstrates the need to operate proactively in the continued fight against doping. The early inclusion of emerging drugs into routine sports drug testing procedures is a key element of preventive doping research, limiting the options for cheating athletes who aim to undermine the doping control system. Copyright 2009 John Wiley & Sons, Ltd.

Significance of excipients to enhance the bioavailability of poorly water-soluble drugs in oral solid dosage forms: A Review

NASA Astrophysics Data System (ADS)

Vadlamudi, Manoj Kumar; Dhanaraj, Sangeetha

2017-11-01

Nowadays most of the drug substances are coming into the innovation pipeline with poor water solubility. Here, the influence of excipients will play a significant role to improve the dissolution of poorly aqueous soluble compounds. The drug substance needs to be dissolved in gastric fluids to get the better absorption and bioavailability of an orally administered drug. Dissolution is the rate-controlling stage for drugs which controls the rate and degree of absorption. Usually, poorly soluble oral administrated drugs show a slower dissolution rate, inconsistent and incomplete absorption which can lead to lower bioavailability. The low aqueous solubility of BCS class II and IV drugs is a major challenge in the drug development and delivery process. Several technologies have been used in an attempt to progress the bioavailability of poorly water-soluble drug compounds which include solid dispersions, lipid-based formulations, micronization, solvent evaporation, co-precipitation, ordered mixing, liquid-solid compacts, solvent deposition inclusion complexation, and steam aided granulation. In fact, most of the technologies require excipient as a carrier which plays a significant role in improving the bioavailability using Hypromellose acetate succinate, Cyclodextrin, Povidone, Copovidone, Hydroxypropyl cellulose, Hydroxypropyl methylcellulose, Crospovidone, Starch, Dimethylacetamide, Polyethylene glycol, Sodium lauryl sulfate, Polysorbate, Poloxamer. Mesoporous silica and so on. This review deliberates about the excipients significance on bioavailability enhancement of drug products in a single platform along with pragmatically proved applications so that user can able to select the right excipients as per the molecule.

Effect of (E)-5-(2-bromovinyl)-2'-deoxyuridine on several parameters of Epstein-Barr virus infection.

PubMed

Zhang, Z X; Liu, Y X; Chen, H C; Allaudeen, H S; De Clercq, E

1984-01-01

The selective and potent anti-herpesvirus drug, (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVdU), has been examined for its inhibitory effects on several parameters of Epstein-Barr virus (EBV) infection in the lymphoblastoid cell lines Raji, P3HR-1, B-95-8 and P3 hybrid cells (a human embryo oropharyngeal cell line fused with a nasopharyngeal carcinoma cell line). At a dosage of 0.03 to 0.1 mM, BVdU caused a marked inhibition of (i) spontaneous viral capsid antigen (VCA) expression in B-95-8 and P3 hybrid cells, (ii) VCA expression and DNA synthesis in B-95-8 cells induced with croton oil and n-butyrate, (iii) early antigen (EA) expression and DNA synthesis in Raji cells superinfected with EBV, and (iv) VCA expression and DNA synthesis in B-95-8 cells superinfected with EBV. In its inhibitory effects on these various parameters of EBV infection, BVdU appears to be comparable to acyclovir [9-(2-hydroxyethoxymethyl)guanine], another selective anti-herpesvirus drug which has been previously recognized as an effective inhibitor of EBV replication.

Pharmacological targeting of CDK9 in cardiac hypertrophy.

PubMed

Krystof, Vladimír; Chamrád, Ivo; Jorda, Radek; Kohoutek, Jirí

2010-07-01

Cardiac hypertrophy allows the heart to adapt to workload, but persistent or unphysiological stimulus can result in pump failure. Cardiac hypertrophy is characterized by an increase in the size of differentiated cardiac myocytes. At the molecular level, growth of cells is linked to intensive transcription and translation. Several cyclin-dependent kinases (CDKs) have been identified as principal regulators of transcription, and among these CDK9 is directly associated with cardiac hypertrophy. CDK9 phosphorylates the C-terminal domain of RNA polymerase II and thus stimulates the elongation phase of transcription. Chronic activation of CDK9 causes not only cardiac myocyte enlargement but also confers predisposition to heart failure. Due to the long interest of molecular oncologists and medicinal chemists in CDKs as potential targets of anticancer drugs, a portfolio of small-molecule inhibitors of CDK9 is available. Recent determination of CDK9's crystal structure now allows the development of selective inhibitors and their further optimization in terms of biochemical potency and selectivity. CDK9 may therefore constitute a novel target for drugs against cardiac hypertrophy.

Knowledge-Based, Central Nervous System (CNS) Lead Selection and Lead Optimization for CNS Drug Discovery

PubMed Central

2011-01-01

The central nervous system (CNS) is the major area that is affected by aging. Alzheimer’s disease (AD), Parkinson’s disease (PD), brain cancer, and stroke are the CNS diseases that will cost trillions of dollars for their treatment. Achievement of appropriate blood–brain barrier (BBB) penetration is often considered a significant hurdle in the CNS drug discovery process. On the other hand, BBB penetration may be a liability for many of the non-CNS drug targets, and a clear understanding of the physicochemical and structural differences between CNS and non-CNS drugs may assist both research areas. Because of the numerous and challenging issues in CNS drug discovery and the low success rates, pharmaceutical companies are beginning to deprioritize their drug discovery efforts in the CNS arena. Prompted by these challenges and to aid in the design of high-quality, efficacious CNS compounds, we analyzed the physicochemical property and the chemical structural profiles of 317 CNS and 626 non-CNS oral drugs. The conclusions derived provide an ideal property profile for lead selection and the property modification strategy during the lead optimization process. A list of substructural units that may be useful for CNS drug design was also provided here. A classification tree was also developed to differentiate between CNS drugs and non-CNS oral drugs. The combined analysis provided the following guidelines for designing high-quality CNS drugs: (i) topological molecular polar surface area of <76 Å2 (25–60 Å2), (ii) at least one (one or two, including one aliphatic amine) nitrogen, (iii) fewer than seven (two to four) linear chains outside of rings, (iv) fewer than three (zero or one) polar hydrogen atoms, (v) volume of 740–970 Å3, (vi) solvent accessible surface area of 460–580 Å2, and (vii) positive QikProp parameter CNS. The ranges within parentheses may be used during lead optimization. One violation to this proposed profile may be acceptable. The chemoinformatics approaches for graphically analyzing multiple properties efficiently are presented. PMID:22267984

Rationale for nebivolol/valsartan combination for hypertension: review of preclinical and clinical data

PubMed Central

Giles, Thomas D.; Cockcroft, John R.; Pitt, Bertram; Jakate, Abhijeet; Wright, Harold M.

2017-01-01

To treat hypertension, combining two or more antihypertensive drugs from different classes is often necessary. β-Blockers and renin–angiotensin–aldosterone system inhibitors, when combined, have been deemed ‘less effective’ based on partially overlapping mechanisms of action and limited evidence. Recently, the single-pill combination (SPC) of nebivolol (Neb) 5 mg – a vasodilatory β1-selective antagonist/β3 agonist – and valsartan 80 mg, an angiotensin II receptor blocker, was US Food and Drug Administration-approved for hypertension. Pharmacological profiles of Neb and valsartan, alone and combined, are well characterized. In addition, a large 8-week randomized trial in stages I–II hypertensive patients (N = 4161) demonstrated greater blood pressure-reducing efficacy for Neb/valsartan SPCs than component monotherapies with comparable tolerability. In a biomarkers substudy (N = 805), Neb/valsartan SPCs prevented valsartan-induced increases in plasma renin, and a greater reduction in plasma aldosterone was observed with the highest SPC dose vs. valsartan 320 mg/day. This review summarizes preclinical and clinical evidence supporting Neb/valsartan as an efficacious and well tolerated combination treatment for hypertension. PMID:28509722

New treatment options in the management of hypertension: appraising the potential role of azilsartan medoxomil

PubMed Central

Volpe, Massimo; Savoia, Carmine

2012-01-01

Renin–angiotensin–system (RAS) activation plays a key role in the development of hypertension and cardiovascular disease. Drugs that antagonize the RAS (angiotensin-converting enzyme [ACE] inhibitors and angiotensin receptor blockers [ARBs]) have proven clinical efficacy in reducing blood pressure values and cardiovascular morbidity and mortality. ACE inhibitors partially inhibit plasma ACE, and angiotensin II generation. Thus, ARBs, which block selectively type 1 angiotensin II receptor (AT1R), have been developed and used in the clinical management of hypertension and cardiovascular disease. Experimental and clinical trials with ARBs indicate that this class of drug represents an effective, safe and well tolerated therapeutic option for the prevention and care of hypertension, even though there is no proven superiority as compared to ACE inhibitors except for the better tolerability. Most ARBs may not completely inhibit the AT1R at the approved clinical doses. Azilsartan medoxomil is a newly approved ARB for the management of hypertension. This ARB induces a potent and long-lasting antihypertensive effect and may have cardioprotective properties. This article reviews the current evidence on the clinical effectiveness of azilsartan in hypertension. PMID:22457601

A Liver-centric Multiscale Modeling Framework for Xenobiotics ...

EPA Pesticide Factsheets

We describe a multi-scale framework for modeling acetaminophen-induced liver toxicity. Acetaminophen is a widely used analgesic. Overdose of acetaminophen can result in liver injury via its biotransformation into toxic product, which further induce massive necrosis. Our study focuses on developing a multi-scale computational model to characterize both phase I and phase II metabolism of acetaminophen, by bridging Physiologically Based Pharmacokinetic (PBPK) modeling at the whole body level, cell movement and blood flow at the tissue level and cell signaling and drug metabolism at the sub-cellular level. To validate the model, we estimated our model parameters by fi?tting serum concentrations of acetaminophen and its glucuronide and sulfate metabolites to experiments, and carried out sensitivity analysis on 35 parameters selected from three modules. Our study focuses on developing a multi-scale computational model to characterize both phase I and phase II metabolism of acetaminophen, by bridging Physiologically Based Pharmacokinetic (PBPK) modeling at the whole body level, cell movement and blood flow at the tissue level and cell signaling and drug metabolism at the sub-cellular level. This multiscale model bridges the CompuCell3D tool used by the Virtual Tissue project with the httk tool developed by the Rapid Exposure and Dosimetry project.

Enhancement of selectivity for photodynamic therapy

NASA Astrophysics Data System (ADS)

Bedwell, Joanne

Photodynamic Therapy (PDT) is a technique for producing localised tissue damage with low power light following prior administration of a photosensitising drug. The promise of PDT has been based on the selective retention of photosensitisers by tumours, but this aspect has been over-emphasised with a maximum ratio of photosensitiser concentration of 3:1, tumour to normal, for extracranial tumours and current drugs. This makes selective tumour necrosis difficult to achieve. This thesis explores ways in which selectivity may be improved. Aluminium sulphonated phthalocyanine (AlSPc) has better photochemical properties than the widely used HpD and Photofrin II, but has the same tumour selectivity, although the ratio was improved marginally using its disulphonated component. However, when used in conjunction with the radioprotective drug W7, in a rat colon cancer model, tumour necrosis was the same as without W7 while there was no damage to adjacent normal colon. A radical new approach is to give 5-aminolaevulinic acid (ALA) which induces endogenous production of the photosensitiser protoporphyrin IX. This improves selectivity in the rat colon cancer to 6:1 (tumour to normal mucosa), but also sensitises the mucosa selectively compared with the underlying muscle (10:1), giving a tumour to muscle ratio of 60:1. This has enormous potential for treating small tumours or areas of dysplasia in a range of hollow organs. ALA also has the major advantages of a short optimum drug to light time (typically 4-6 hours), short duration of skin sensitivity (approximately 24 hours) and it can be given orally with minimal systemic toxicity. This work has also shown in vitro that PDT with AlSPc sensitisation can kill helicohacter pylori at doses unlikely to affect gastric mucosa. In conclusion, by careful choice of photosensitising agents and treatment regimes, it is possible to limit PDT effects to abnormal tissues, and even if there is some normal tissue damage, in most cases, this heals without significant sequelae. In the gastrointestinal tract, PDT may have a role in the eradication of small tumours unsuitable for surgery, in the treatment of dysplasia and possibly even in the management of conditions related to helicobacter pylori infection. There is now sufficient information to start clinical trials with ALA.

The Multirole of Liposomes in Therapy and Prevention of Infectious Diseases

PubMed Central

Nisini, Roberto; Poerio, Noemi; Mariotti, Sabrina; De Santis, Federica; Fraziano, Maurizio

2018-01-01

Liposomes are closed bilayer structures spontaneously formed by hydrated phospholipids that are widely used as efficient delivery systems for drugs or antigens, due to their capability to encapsulate bioactive hydrophilic, amphipathic, and lipophilic molecules into inner water phase or within lipid leaflets. The efficacy of liposomes as drug or antigen carriers has been improved in the last years to ameliorate pharmacokinetics and capacity to release their cargo in selected target organs or cells. Moreover, different formulations and variations in liposome composition have been often proposed to include immunostimulatory molecules, ligands for specific receptors, or stimuli responsive compounds. Intriguingly, independent research has unveiled the capacity of several phospholipids to play critical roles as intracellular messengers in modulating both innate and adaptive immune responses through various mechanisms, including (i) activation of different antimicrobial enzymatic pathways, (ii) driving the fusion–fission events between endosomes with direct consequences to phagosome maturation and/or to antigen presentation pathway, and (iii) modulation of the inflammatory response. These features can be exploited by including selected bioactive phospholipids in the bilayer scaffold of liposomes. This would represent an important step forward since drug or antigen carrying liposomes could be engineered to simultaneously activate different signal transduction pathways and target specific cells or tissues to induce antigen-specific T and/or B cell response. This lipid-based host-directed strategy can provide a focused antimicrobial innate and adaptive immune response against specific pathogens and offer a novel prophylactic or therapeutic option against chronic, recurrent, or drug-resistant infections. PMID:29459867

The patient's safety and access to experimental drugs after the termination of clinical trials: regulations and trends.

PubMed

da Silva, Ricardo Eccard; Amato, Angélica Amorim; Sousa, Thiago do Rego; de Carvalho, Marta Rodrigues; Novaes, Maria Rita Carvalho Garbi

2018-05-12

Participants' rights and safety must be guaranteed not only while a clinical trial is being conducted but also when a clinical trial finishes. The criteria for post-trial access to experimental drugs, however, are unclear in various countries. The objectives of this study were (i) to ascertain if there were regulations or guidelines related to patients' access to drugs after the end of clinical trials in the countries selected in the study and (ii) to analyze trends in post-trial access in countries classified by their level of economic development. This study is a retrospective review. The data are from the records of clinical trials from 2014 registered in the World Health Organization's International Clinical Trials Registry Platform (ICTRP) database. Among the countries selected, provision of drugs post-trial is mandatory only in Argentina, Brazil, Chile, Finland, and Peru. The plans for post-trial access tend to be more present in low- and middle-income and upper middle-income countries, in comparison with high-income countries. Studies involving vulnerable populations are 2.53 times more likely to have plans for post-trial access than studies which do not. The guaranteeing of post-trial access remains mandatory in few countries. Considering that individuals seen as vulnerable have been included in clinical trials without plans for post-trial access, stakeholders must discuss the need to develop regulations mandating the guaranteeing of post-trial access in specified situations.

Recruitment of participants through community pharmacies for a pharmacogenetic study of antihypertensive drug treatment.

PubMed

van Wieren-de Wijer, Diane B M A; Maitland-van der Zee, Anke-Hilse; de Boer, Anthonius; Stricker, Bruno H Ch; Kroon, Abraham A; de Leeuw, Peter W; Bozkurt, O; Klungel, Olaf H

2009-04-01

To describe the design, recruitment and baseline characteristics of participants in a community pharmacy based pharmacogenetic study of antihypertensive drug treatment. Participants enrolled from the population-based Pharmaco-Morbidity Record Linkage System. We designed a nested case-control study in which we will assess whether specific genetic polymorphisms modify the effect of antihypertensive drugs on the risk of myocardial infarction. In this study, cases (myocardial infarction) and controls were recruited through community pharmacies that participate in PHARMO. The PHARMO database comprises drug dispensing histories of about 2,000,000 subjects from a representative sample of Dutch community pharmacies linked to the national registrations of hospital discharges. In total we selected 31010 patients (2777 cases and 28233 controls) from the PHARMO database, of whom 15973 (1871 cases, 14102 controls) were approached through their community pharmacy. Overall response rate was 36.3% (n = 5791, 794 cases, 4997 controls), whereas 32.1% (n = 5126, 701 cases, 4425 controls) gave informed consent to genotype their DNA. As expected, several cardiovascular risk factors such as smoking, body mass index, hypercholesterolemia, and diabetes mellitus were more common in cases than in controls. Furthermore, cases more often used beta-blockers and calcium-antagonists, whereas controls more often used thiazide diuretics, ACE-inhibitors, and angiotensin-II receptor blockers. We have demonstrated that it is feasible to select patients from a coded database for a pharmacogenetic study and to approach them through community pharmacies, achieving reasonable response rates and without violating privacy rules.

Solid self-nanoemulsifying delivery systems as a platform technology for formulation of poorly soluble drugs.

PubMed

Bansal, Tripta; Mustafa, Gulam; Khan, Zeenat I; Ahmad, Farhaan J; Khar, Roop K; Talegaonkar, Sushama

2008-01-01

New drug discovery programs produce molecules with poor physico-chemical properties, making delivery of these molecules at the right proportion into the body a big challenge to the formulation scientist. The various options available to overcome the hurdle include solvent precipitation, micronisation/nanonization using high-pressure homogenization or jet milling, salt formation, use of microspheres, solid dispersions, cogrinding, complexation, and many others. Self-nanoemulsifying systems (SNES) form one of the most popular and commercially viable approaches for delivery of poorly soluble drugs exhibiting dissolution rate limited absorption, especially those belonging to the Biopharmaceutics Classification System II/IV. SNES are essentially an isotropic blend of oils, surfactants, and/or cosolvents that emulsify spontaneously to produce oil in water nanoemulsion when introduced into aqueous phase under gentle agitation. Conventional SNES consist of liquid forms filled in hard or soft gelatin capsules, which are least preferred due to leaching and leakage phenomenon, interaction with capsule shell components, handling difficulties, machinability, and stability problems. Solidification of these liquid systems to yield solid self-nanoemulsifying systems (SSNES) offer a possible solution to the mentioned complications, and that is why these systems have attracted wide attention. Other than the advantages and wide application of SSNEDS, the present paper focuses on formulation considerations, selection, and function of solidifying excipients; techniques of preparation; and case studies of drugs selected from different therapeutic categories. Developments in the techniques for in vitro evaluation of SSNEDS have also been discussed.

tetrahydrocannabinol (delta-9-THC)] in Schedule II. Final rule.

PubMed

2017-11-22

This final rule adopts without changes an interim final rule with request for comments published in the Federal Register on March 23, 2017. On July 1, 2016, the U.S. Food and Drug Administration (FDA) approved a new drug application for Syndros, a drug product consisting of dronabinol [(-)-delta-9-trans-tetrahydrocannabinol (delta-9-THC)] oral solution. The Drug Enforcement Administration (DEA) maintains FDA-approved products of oral solutions containing dronabinol in schedule II of the Controlled Substances Act.

Elucidation of the binding mechanism of renin using a wide array of computational techniques and biological assays.

PubMed

Tzoupis, Haralambos; Leonis, Georgios; Avramopoulos, Aggelos; Reis, Heribert; Czyżnikowska, Żaneta; Zerva, Sofia; Vergadou, Niki; Peristeras, Loukas D; Papavasileiou, Konstantinos D; Alexis, Michael N; Mavromoustakos, Thomas; Papadopoulos, Manthos G

2015-11-01

We investigate the binding mechanism in renin complexes, involving three drugs (remikiren, zankiren and enalkiren) and one lead compound, which was selected after screening the ZINC database. For this purpose, we used ab initio methods (the effective fragment potential, the variational perturbation theory, the energy decomposition analysis, the atoms-in-molecules), docking, molecular dynamics, and the MM-PBSA method. A biological assay for the lead compound has been performed to validate the theoretical findings. Importantly, binding free energy calculations for the three drug complexes are within 3 kcal/mol of the experimental values, thus further justifying our computational protocol, which has been validated through previous studies on 11 drug-protein systems. The main elements of the discovered mechanism are: (i) minor changes are induced to renin upon drug binding, (ii) the three drugs form an extensive network of hydrogen bonds with renin, whilst the lead compound presented diminished interactions, (iii) ligand binding in all complexes is driven by favorable van der Waals interactions and the nonpolar contribution to solvation, while the lead compound is associated with diminished van der Waals interactions compared to the drug-bound forms of renin, and (iv) the environment (H2O/Na(+)) has a small effect on the renin-remikiren interaction. Copyright © 2015 Elsevier Inc. All rights reserved.

Synthesis of Protein Bioconjugates via Cysteine-maleimide Chemistry.

PubMed

Mason, Alexander F; Thordarson, Pall

2016-07-20

The chemical linking or bioconjugation of proteins to fluorescent dyes, drugs, polymers and other proteins has a broad range of applications, such as the development of antibody drug conjugates (ADCs) and nanomedicine, fluorescent microscopy and systems chemistry. For many of these applications, specificity of the bioconjugation method used is of prime concern. The Michael addition of maleimides with cysteine(s) on the target proteins is highly selective and proceeds rapidly under mild conditions, making it one of the most popular methods for protein bioconjugation. We demonstrate here the modification of the only surface-accessible cysteine residue on yeast cytochrome c with a ruthenium(II) bisterpyridine maleimide. The protein bioconjugation is verified by gel electrophoresis and purified by aqueous-based fast protein liquid chromatography in 27% yield of isolated protein material. Structural characterization with MALDI-TOF MS and UV-Vis is then used to verify that the bioconjugation is successful. The protocol shown here is easily applicable to other cysteine - maleimide coupling of proteins to other proteins, dyes, drugs or polymers.

Pharmacological Aspects of Vipera xantina palestinae Venom

PubMed Central

Momic, Tatjana; Arlinghaus, Franziska T.; Arien-Zakay, Hadar; Katzhendler, Jeoshua; Eble, Johannes A.; Marcinkiewicz, Cezary; Lazarovici, Philip

2011-01-01

In Israel, Vipera xantina palestinae (V.x.p.) is the most common venomous snake, accounting for several hundred cases of envenomation in humans and domestic animals every year, with a mortality rate of 0.5 to 2%. In this review we will briefly address the research developments relevant to our present understanding of the structure and function of V.x.p. venom with emphasis on venom disintegrins. Venom proteomics indicated the presence of four families of pharmacologically active compounds: (i) neurotoxins; (ii) hemorrhagins; (iii) angioneurin growth factors; and (iv) different types of integrin inhibitors. Viperistatin, a α1β1selective KTS disintegrin and VP12, a α2β1 selective C-type lectin were discovered. These snake venom proteins represent promising tools for research and development of novel collagen receptor selective drugs. These discoveries are also relevant for future improvement of antivenom therapy towards V.x.p. envenomation. PMID:22174978

Worming our way to novel drug discovery with the Caenorhabditis elegans proteostasis network, stress response and insulin-signaling pathways.

PubMed

O'Reilly, Linda P; Benson, Joshua A; Cummings, Erin E; Perlmutter, David H; Silverman, Gary A; Pak, Stephen C

2014-09-01

Many human diseases result from a failure of a single protein to achieve the correct folding and tertiary conformation. These so-called 'conformational diseases' involve diverse proteins and distinctive cellular pathologies. They all engage the proteostasis network (PN), to varying degrees in an attempt to mange cellular stress and restore protein homeostasis. The insulin/insulin-like growth factor signaling (IIS) pathway is a master regulator of cellular stress response, which is implicated in regulating components of the PN. This review focuses on novel approaches to target conformational diseases. The authors discuss the evidence supporting the involvement of the IIS pathway in modulating the PN and regulating proteostasis in Caenorhabditis elegans. Furthermore, they review previous PN and IIS drug screens and explore the possibility of using C. elegans for whole organism-based drug discovery for modulators of IIS-proteostasis pathways. An alternative approach to develop individualized therapy for each conformational disease is to modulate the global PN. The involvement of the IIS pathway in regulating longevity and response to a variety of stresses is well documented. Increasing data now provide evidence for the close association between the IIS and the PN pathways. The authors believe that high-throughput screening campaigns, which target the C. elegans IIS pathway, may identify drugs that are efficacious in treating numerous conformational diseases.

21 CFR 1403.4 - Applicability.

Code of Federal Regulations, 2013 CFR

2013-04-01

... Drugs OFFICE OF NATIONAL DRUG CONTROL POLICY UNIFORM ADMINISTRATIVE REQUIREMENTS FOR GRANTS AND... National School Lunch Act: (i) School Lunch (section 4 of the Act), (ii) Commodity Assistance (section 6 of...), and (ii) School Breakfast (section 4 of the Act); (6) Entitlement grants for State Administrative...

21 CFR 1403.4 - Applicability.

Code of Federal Regulations, 2014 CFR

2014-04-01

... Drugs OFFICE OF NATIONAL DRUG CONTROL POLICY UNIFORM ADMINISTRATIVE REQUIREMENTS FOR GRANTS AND... National School Lunch Act: (i) School Lunch (section 4 of the Act), (ii) Commodity Assistance (section 6 of...), and (ii) School Breakfast (section 4 of the Act); (6) Entitlement grants for State Administrative...

21 CFR 1403.4 - Applicability.

Code of Federal Regulations, 2011 CFR

2011-04-01

... Drugs OFFICE OF NATIONAL DRUG CONTROL POLICY UNIFORM ADMINISTRATIVE REQUIREMENTS FOR GRANTS AND... National School Lunch Act: (i) School Lunch (section 4 of the Act), (ii) Commodity Assistance (section 6 of...), and (ii) School Breakfast (section 4 of the Act); (6) Entitlement grants for State Administrative...

21 CFR 1403.4 - Applicability.

Code of Federal Regulations, 2012 CFR

2012-04-01

... Drugs OFFICE OF NATIONAL DRUG CONTROL POLICY UNIFORM ADMINISTRATIVE REQUIREMENTS FOR GRANTS AND... National School Lunch Act: (i) School Lunch (section 4 of the Act), (ii) Commodity Assistance (section 6 of...), and (ii) School Breakfast (section 4 of the Act); (6) Entitlement grants for State Administrative...

21 CFR 1403.4 - Applicability.

Code of Federal Regulations, 2010 CFR

2010-04-01

... Drugs OFFICE OF NATIONAL DRUG CONTROL POLICY UNIFORM ADMINISTRATIVE REQUIREMENTS FOR GRANTS AND... National School Lunch Act: (i) School Lunch (section 4 of the Act), (ii) Commodity Assistance (section 6 of...), and (ii) School Breakfast (section 4 of the Act); (6) Entitlement grants for State Administrative...

Risk Management Plans: are they a tool for improving drug safety?

PubMed

Frau, Serena; Font Pous, Maria; Luppino, Maria Rosa; Conforti, Anita

2010-08-01

In 2005, new European legislation authorised Regulatory Agencies to require drug companies to submit a risk management plan (RMP) comprising detailed commitments for post-marketing pharmacovigilance. The aim of the study is to describe the characteristics of RMP for 15 drugs approved by the European Medicines Agency (EMA) and their impact on post-marketing safety issues. Of the 90 new Chemical Entities approved through a centralised procedure by the EMA during 2006 and 2007, 15 of them were selected and their safety aspects and relative RMPs analysed. All post-marketing communications released for safety reasons related to these drugs were also considered. A total of 157 safety specifications were established for the drugs assessed. Risk minimisation activities were foreseen for 5 drugs as training activities. Post-marketing safety issues emerged for 12 of them, leading to 39 type II variations in Summary of Product Characteristics (SPC). Nearly half of such variations, 19 (49%), concerned safety aspects not envisaged by the RMPs. Besides this, 9 Safety Communications were published for 6 out of 15 drugs assessed. The present study reveals several critical points on the way RMPs have been implemented. Several activities proposed by the RMPs do not appear to be adequate in dealing with the potential risks of drugs. Poor communication of risk to practitioners and to the public, and above all limited transparency for the total assessment of risk, seem to transform RMPs into a tool to reassure the public when inadequately evaluated drugs are granted premature marketing authorisation.

Design and syntheses of MMP inhibitors and photosensitive lipid nanoparticle formulations for drug delivery

NASA Astrophysics Data System (ADS)

Subramaniam, Rajesh

Drug administration without any compromise to the quality of life and lifespan is the ideal goal for disease management. The molecular mechanisms of several pathologies have shown that site-specific delivery of target-specific drugs seems to be a promising avenue to achieve this goal. This thesis describes the initial steps that we have taken toward that goal. Matrix metalloproteinases (MMPs) are a family of about 23 isozymes in humans that were actively targeted for treating a multitude of pathologies. Clinical studies carried out on cancer patients have revealed the complexity of the working of this enzyme family and necessitated the development of isozyme-specific MMP inhibitors. Our studies toward the development of isozyme-specific inhibitors have resulted in the development of several inhibitors that seem to be selective toward some MMP isozymes. Our understanding on the molecular mechanism that confers this selectivity is documented in this thesis. Another aspect of discussion in the thesis is the development of photosensitive liposomes for drug delivery that could be triggered to release the drug by irradiation with light of appropriate wavelength. Development of such delivery vehicles, in principle, would confer external spatiotemporal control on drug delivery. This could potentially lead to better disease management by minimizing side effects and enhancing patient compatibility. The thesis discusses our attempts toward the development of photosensitive liposomes. These liposomes incorporated a photosensitive lipid (PSL) that would be cleaved upon irradiation with UV light, causing liposomal destabilization and release of the enclosed drug. The discussion includes: (i) the syntheses of the PSLs, (ii) formulation of the photosensitive liposomes that contained a model drug, (iii) light-mediated release of the drug and (iv) the mechanism of photocleavage of the PSL that leads to content release from liposomes. The thesis concludes with suggestions toward the development of isozyme-specific inhibitors for MMPs and a PSL that could be potentially cleaved with near infrared light by two-photon absorption. Liposomes incorporating such a PSL could, in principle, confer precise spatiotemporally controlled drug delivery at greater tissue depths if the technology could find ways to mitigate light intensity loss due to scattering by tissues.

Balancing novelty with confined chemical space in modern drug discovery.

PubMed

Medina-Franco, José L; Martinez-Mayorga, Karina; Meurice, Nathalie

2014-02-01

The concept of chemical space has broad applications in drug discovery. In response to the needs of drug discovery campaigns, different approaches are followed to efficiently populate, mine and select relevant chemical spaces that overlap with biologically relevant chemical spaces. This paper reviews major trends in current drug discovery and their impact on the mining and population of chemical space. We also survey different approaches to develop screening libraries with confined chemical spaces balancing physicochemical properties. In this context, the confinement is guided by criteria that can be divided in two broad categories: i) library design focused on a relevant therapeutic target or disease and ii) library design focused on the chemistry or a desired molecular function. The design and development of chemical libraries should be associated with the specific purpose of the library and the project goals. The high complexity of drug discovery and the inherent imperfection of individual experimental and computational technologies prompt the integration of complementary library design and screening approaches to expedite the identification of new and better drugs. Library design approaches including diversity-oriented synthesis, biological-oriented synthesis or combinatorial library design, to name a few, and the design of focused libraries driven by target/disease, chemical structure or molecular function are more efficient if they are guided by multi-parameter optimization. In this context, consideration of pharmaceutically relevant properties is essential for balancing novelty with chemical space in drug discovery.

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

Adaptive clinical trial designs for European marketing authorization: a survey of scientific advice letters from the European Medicines Agency.

PubMed

Elsäßer, Amelie; Regnstrom, Jan; Vetter, Thorsten; Koenig, Franz; Hemmings, Robert James; Greco, Martina; Papaluca-Amati, Marisa; Posch, Martin

2014-10-02

Since the first methodological publications on adaptive study design approaches in the 1990s, the application of these approaches in drug development has raised increasing interest among academia, industry and regulators. The European Medicines Agency (EMA) as well as the Food and Drug Administration (FDA) have published guidance documents addressing the potentials and limitations of adaptive designs in the regulatory context. Since there is limited experience in the implementation and interpretation of adaptive clinical trials, early interaction with regulators is recommended. The EMA offers such interactions through scientific advice and protocol assistance procedures. We performed a text search of scientific advice letters issued between 1 January 2007 and 8 May 2012 that contained relevant key terms. Letters containing questions related to adaptive clinical trials in phases II or III were selected for further analysis. From the selected letters, important characteristics of the proposed design and its context in the drug development program, as well as the responses of the Committee for Human Medicinal Products (CHMP)/Scientific Advice Working Party (SAWP), were extracted and categorized. For 41 more recent procedures (1 January 2009 to 8 May 2012), additional details of the trial design and the CHMP/SAWP responses were assessed. In addition, case studies are presented as examples. Over a range of 5½ years, 59 scientific advices were identified that address adaptive study designs in phase II and phase III clinical trials. Almost all were proposed as confirmatory phase III or phase II/III studies. The most frequently proposed adaptation was sample size reassessment, followed by dropping of treatment arms and population enrichment. While 12 (20%) of the 59 proposals for an adaptive clinical trial were not accepted, the great majority of proposals were accepted (15, 25%) or conditionally accepted (32, 54%). In the more recent 41 procedures, the most frequent concerns raised by CHMP/SAWP were insufficient justifications of the adaptation strategy, type I error rate control and bias. For the majority of proposed adaptive clinical trials, an overall positive opinion was given albeit with critical comments. Type I error rate control, bias and the justification of the design are common issues raised by the CHMP/SAWP.

Extractive Spectrophotometric Determination of Nortriptyline Hydrochloride Using Sudan II, IV and Black B.

PubMed

Amin, A S; Saleh, H M

2017-08-17

A simple spectrophotometric methods has been developed for the determination of nortriptyline hydrochloride in pure and in pharmaceuticalformulations based on the formation of ion-pair complexes with sudun II (S II ), sudan (IV) (S IV ) and sudan black B (S BB ). The selectivity of the method was improved through extraction with chloroform. The optimum conditions for complete extracted colour development were assessed. The absorbance measurements were made at 534, 596 and 649 nm for S II , S IV and S BB complexes, respectively. The calibration graph was linear in the ranges 0.5- 280. 0.5- 37.5 and 0.5 - 31.0 μg ml -1 of the drug usiny the same reagents, respectively. The precision of the procedure was checked by calculating the relative standard deviation of ten replicate determinations on 15 μg ml -1 of nortriptyline HCI and was found to be 1.7, 1.3 and 1.55% using S II , S IV , and S BB complexes, respectively. The molar absorptivity and Sandell sensitivity for each ion-pair were calculated. The proposed methods were successfully applied to the deterniination of pure nortriptyline HCI and in pharmaceutical formulations, and the results demonstrated that the method is equally accurate, precise and reproducible as the official method.

Design of therapeutic vaccines as a novel antibody therapy for cardiovascular diseases.

PubMed

Nakagami, Hironori

2017-09-01

Vaccines are primarily used worldwide as a preventive medicine for infectious diseases and have recently been applied to cancer. We and others have developed therapeutic vaccines designed for cardiovascular diseases that are notably different from previous vaccines. In the case of cancer vaccines, a specific protein in cancer cells is a target antigen, and the activation of cytotoxic T cells (CTL) is required to kill and remove the antigen-presenting cancer cells. Our therapeutic vaccines work against hypertension by targeting angiotensin II (Ang II) as the antigen, which is an endogenous hormone. Therapeutic vaccines must avoid CTL activation and induce the blocking antibodies for Ang II. The goal of our therapeutic vaccine for cardiovascular diseases is to induce the specific antibody response toward the target protein without inducing T-cell or antibody-mediated inflammation through the careful selection of the target antigen, carrier protein and adjuvants. The goal of our therapeutic vaccine is similar to that of antibody therapy. Recently, multiple antibody-based drugs have been developed for cancer, immune-related diseases, and dyslipidemia, which are efficient but expensive. If the effect of a therapeutic vaccine is nearly equivalent to antibody therapy as an alternative approach, the lower medical cost and improvement in drug adherence can be advantages of therapeutic vaccines. In this review, we will describe our concept of therapeutic vaccines for cardiovascular diseases and the future directions of therapeutic vaccines as novel antibody therapies. Copyright © 2017. Published by Elsevier Ltd.

Construction of drug-polymer thermodynamic phase diagrams using Flory-Huggins interaction theory: identifying the relevance of temperature and drug weight fraction to phase separation within solid dispersions.

PubMed

Tian, Yiwei; Booth, Jonathan; Meehan, Elizabeth; Jones, David S; Li, Shu; Andrews, Gavin P

2013-01-07

Amorphous drug-polymer solid dispersions have the potential to enhance the dissolution performance and thus bioavailability of BCS class II drug compounds. The principle drawback of this approach is the limited physical stability of amorphous drug within the dispersion. Accurate determination of the solubility and miscibility of drug in the polymer matrix is the key to the successful design and development of such systems. In this paper, we propose a novel method, based on Flory-Huggins theory, to predict and compare the solubility and miscibility of drug in polymeric systems. The systems chosen for this study are (1) hydroxypropyl methylcellulose acetate succinate HF grade (HPMCAS-HF)-felodipine (FD) and (2) Soluplus (a graft copolymer of polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol)-FD. Samples containing different drug compositions were mixed, ball milled, and then analyzed by differential scanning calorimetry (DSC). The value of the drug-polymer interaction parameter χ was calculated from the crystalline drug melting depression data and extrapolated to lower temperatures. The interaction parameter χ was also calculated at 25 °C for both systems using the van Krevelen solubility parameter method. The rank order of interaction parameters of the two systems obtained at this temperature was comparable. Diagrams of drug-polymer temperature-composition and free energy of mixing (ΔG(mix)) were constructed for both systems. The maximum crystalline drug solubility and amorphous drug miscibility may be predicted based on the phase diagrams. Hyper-DSC was used to assess the validity of constructed phase diagrams by annealing solid dispersions at specific drug loadings. Three different samples for each polymer were selected to represent different regions within the phase diagram.

Care ideologies reflected in 4 conceptions of pharmaceutical care.

PubMed

Björkman, Ingeborg K; Bernsten, Cecilia B; Sanner, Margareta A

2008-12-01

Different ways to practice pharmaceutical care have been developed. One expression of this fact is the existence of many different classification systems to document drug-related problems (DRPs). Evidence suggests that classification systems have different characteristics and that these characteristics reflect different conceptions of pharmaceutical care. To increase the understanding of conceptions of pharmaceutical care, underlying values and beliefs (ideologies) can be explored. To explore various conceptions of pharmaceutical care to identify the care ideologies on which these conceptions are based. Representatives of 4 selected conceptions of pharmaceutical care were interviewed in face-to-face meetings. During the interviews, 4 basic questions were asked. Three were focused on pharmaceutical care and 1 on DRPs. Interview transcripts were analyzed by an inductive method inspired by grounded theory. The conceptions studied were Strand, Granada-II, PCNE v5.0, and Apoteket. In Strand, patients are given a more active role in the pharmaceutical care process, as compared to Granada-II, PCNE v5.0, and Apoteket. Pharmacists in all the conceptions of pharmaceutical care assume they have special knowledge that patients benefit from. However, they use their knowledge in different ways in the various pharmaceutical care conceptions. In Strand, individual goals of drug therapy are established together with the patient, whereas in Granada-II, PCNE, and Apoteket goals are not explicitly discussed. The identified differences correspond to different care ideologies. The pharmaceutical care conceptions are based on different care ideologies. The ideology is expressed in how therapy goals are set and patient needs defined. Strand is based on a patient-centered ideology; patient therapy goals and needs are defined by the patient together with the practitioners. Granada-II, PCNE, and Apoteket are based on an evidence-based medicine approach; patient therapy goals and needs are defined by the practitioners, based on available scientific knowledge.

Cost-effectiveness analysis of cisplatin plus etoposide and carboplatin plus paclitaxel in a phase III randomized trial for non-small cell lung cancer.

PubMed

Thongprasert, Sumitra; Permsuwan, Unchalee; Ruengorn, Chidchanok; Charoentum, Chaiyut; Chewaskulyong, Busyamas

2011-12-01

Carboplatin plus paclitaxel is a more costly chemotherapy regimen than cisplatin plus etoposide; however there have been reports of higher efficacy and less toxicity of this regimen. Thus, this study aimed to assess the cost-effectiveness of these two chemotherapy regimens in advanced non-small cell lung cancer (NSCLC). Using the perspective of Maharaj Nakorn Chiang Mai Hospital, Thailand, direct medical costs, including chemotherapy, drugs, medical service charges, costs of adverse events, concomitant medication and survival time were directly gathered from 65 patients enrolled from August 2005 to November 2008. A one-way sensitivity analysis was performed. An incremental cost-effectiveness ratio (ICER) was also calculated. Of these 65 patients, 30 received cisplatin plus etoposide (Arm I) and 35 received carboplatin plus paclitaxel (Arm II). The median survival time was not statistically significant (8.23 months vs 8.80 months in Arm I and II, respectively; P = 0.99). The total cost per patient in Arm II was about three times that in Arm I (95,548 Baht vs 29,692 Baht) while quality-adjusted life-years (QALY) in Arm II were slightly above those in Arm I (0.587 vs 0.412). The ICER was equal to 375,958 Baht per QALY. With a cost-effectiveness threshold of 100,000 Baht in Thailand, carboplatin plus paclitaxel was still not cost-effective. While the selection of a suitable regimen for individual patients should not rely on drug and hospital costs alone, the overall cost, including the burden on patients, should be taken into consideration. © 2011 Blackwell Publishing Asia Pty Ltd.

Photoexpulsion of Surface-Grafted Ruthenium Complexes and Subsequent Release of Cytotoxic Cargos to Cancer Cells from Mesoporous Silica Nanoparticles

PubMed Central

Frasconi, Marco; Liu, Zhichang; Lei, Juying; Wu, Yilei; Strekalova, Elena; Malin, Dmitry; Ambrogio, Michael W.; Chen, Xinqi; Botros, Youssry Y.; Cryns, Vincent L.; Sauvage, Jean-Pierre; Stoddart, J. Fraser

2014-01-01

Ruthenium(II) polypyridyl complexes have emerged both as promising probes of DNA structure and as anticancer agents because of their unique photophysical and cytotoxic properties. A key consideration in the administration of those therapeutic agents is the optimization of their chemical reactivities to allow facile attack on the target sites, yet avoid unwanted side effects. Here, we present a drug delivery platform technology, obtained by grafting the surface of mesoporous silica nanoparticles (MSNPs) with ruthenium(II) dipyridophenazine (dppz) complexes. This hybrid nanomaterial displays enhanced luminescent properties relative to that of the ruthenium(II) dppz complex in a homogeneous phase. Since the coordination between the ruthenium(II) complex and a monodentate ligand linked covalently to the nanoparticles can be cleaved under irradiation with visible light, the ruthenium complex can be released from the surface of the nanoparticles by selective substitution of this ligand with a water molecule. Indeed, the modified MSNPs undergo rapid cellular uptake, and after activation with light, the release of an aqua ruthenium(II) complex is observed. We have delivered, in combination, the ruthenium(II) complex and paclitaxel, loaded in the mesoporous structure, to breast cancer cells. This hybrid material represents a promising candidate as one of the so-called theranostic agents that possess both diagnostic and therapeutic functions. PMID:23815127

Simultaneous Spectrophotometric Estimation of Nitazoxanide and Ofloxacin in Tablets

PubMed Central

Game, Madhuri D.; Sakarkar, D. M.

2011-01-01

Two simple, accurate and precise spectrophotometric methods have been developed for simultaneous determination of nitazoxanide and ofloxacin in tablets. Method I is Q-absorbance ratio method which involves Q-absorbance at isobestic point (306.25 nm) and max (347.5 nm) of nitazoxanide, while method II is two wavelength method, where 244.6 nm and 273.0 nm were selected as 1 and 2 for determination of nitazoxanide and 294.3 nm and 388.1 nm were selected as 3 and 4 for determination of ofloxacin. Both drugs obeyed the Beer's law in the concentration range 2-30 μg/ml,correlation coefficient (r2<1). Both methods were validated statistically and recovery studies were carried out to confirm the accuracy. Commercial tablet formulation was successfully analyzed using the developed methods. PMID:22131624

Chemotherapeutic Drug Based Metal-Organic Particles for Microvesicle-Mediated Deep Penetration and Programmable pH/NIR/Hypoxia Activated Cancer Photochemotherapy.

PubMed

Zhang, Da; Wu, Ming; Cai, Zhixiong; Liao, Naishun; Ke, Kun; Liu, Hongzhi; Li, Ming; Liu, Gang; Yang, Huanghao; Liu, Xiaolong; Liu, Jingfeng

2018-02-01

A novel metal-organic particle (MOP) based nanodrug formed by mild self-assembly of chemotherapeutic drugs, including banoxantrone and doxorubicin, through Cu(II)-mediated coordination effects, is reported. In this nanodrug, Cu(II) acts as a bridge to join AQ4N and DOX, and then, self-assembly of [-AQ4N-Cu(II)-(DOX) 2 -Cu(II)-] n complexes forms nanosized MOPs (referred to as ADMOPs) through multiple interactions including host-metal-guest coordination, hydrophobic interactions, π-stacking, and van der Waals force. The ADMOPs reported here have several important features over conventional drugs, including tumor microenvironment pH-sensitive drug release that can be tracked by "turning on" the fluorescence of AQ4N or DOX through proton competition with Cu(II) to break the coordination bonds and much deeper penetration into solid tumors via microvesicle-mediated intercellular transfer. Most strikingly, the ADMOPs can serve as stimuli-responsive nanocarriers to efficiently load the photosensitizer phthalocyanine due to their inherent highly porous characteristics. Thus, the ADMOPs significantly enhance the chemotherapeutic efficacy by "on-demand" photodynamic therapy, which further induces a hypoxic environment that enhances the reduction of AQ4N to systematically increase the therapeutic efficiency. Taken together, the designed ADMOPs composed of chemotherapeutic drugs may serve as a potential programmable controlled synergistic agent for cancer therapy.

Investigation into the Emerging Role of the Basic Amino Acid L-Lysine in Enhancing Solubility and Permeability of BCS Class II and BCS Class IV Drugs.

PubMed

Abdelkader, Hamdy; Fathalla, Zeinab

2018-06-18

The search for a simple and scalable approach that can improve the two key biopharmaceutical processes (solubility and permeability) for BCS Class II and BCS Class IV has still been unmet need. In this study, L-lysine was investigated as a potential excipient to tackle problems with solubility and permeability. Bendazac (Class II); quercetin and rutin (Class IV) were employed. Drugs-lysine complexes in 1:1 M ratios were prepared by co-precipitation and co-grinding; characterized for solubility, partition coefficient, DSC, FTIR, SEM, dissolution rate and permeability. Chemical stability of quercetin-lysine and rutin-lysine was studied by assessing antioxidant capacity using Trolox and CUPRAC assays. Drugs-lysine salt/complexes were confirmed. Solubility enhancement factors ranged from 68- to 433-fold increases and dissolution rates were also significantly enhanced by up to 6-times, compared with drugs alone. With the exception of rutin-lysine, P app for bendazac-lysine and quercetin-lysine enhanced by 2.3- to 4-fold. P app for quercetin (Class IV) benefited more than bendazac (Class II) when complexed with lysine. This study warrants the use of L-lysine as a promising excipient for enhanced solubility and permeability of Class II and Class IV, providing that the solubility of the drug is ensured at 'the door step' of absorption sites.

Antibiotic resistance in Staphylococcus aureus. Current status and future prospects.

PubMed

Foster, Timothy J

2017-05-01

The major targets for antibiotics in staphylococci are (i) the cell envelope, (ii) the ribosome and (iii) nucleic acids. Several novel targets emerged from recent targeted drug discovery programmes including the ClpP protease and FtsZ from the cell division machinery. Resistance can either develop by horizontal transfer of resistance determinants encoded by mobile genetic elements viz plasmids, transposons and the staphylococcal cassette chromosome or by mutations in chromosomal genes. Horizontally acquired resistance can occur by one of the following mechanisms: (i) enzymatic drug modification and inactivation, (ii) enzymatic modification of the drug binding site, (iii) drug efflux, (iv) bypass mechanisms involving acquisition of a novel drug-resistant target, (v) displacement of the drug to protect the target. Acquisition of resistance by mutation can result from (i) alteration of the drug target that prevents the inhibitor from binding, (ii) derepression of chromosomally encoded multidrug resistance efflux pumps and (iii) multiple stepwise mutations that alter the structure and composition of the cell wall and/or membrane to reduce drug access to its target. This review focuses on development of resistance to currently used antibiotics and examines future prospects for new antibiotics and informed use of drug combinations. © FEMS 2017. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

A “Double-Edged” Scaffold: Antitumor Power within the 
Antibacterial Quinolone

PubMed Central

Bisacchi, Gregory S.; Hale, Michael R.

2016-01-01

In the late 1980s, reports emerged describing experimental antibacterial quinolones having significant potency against eukaryotic Type II topoisomerases (topo II) and showing cytotoxic activity against tumor cell lines. As a result, several pharmaceutical companies initiated quinolone anticancer programs to explore the potential of this class in comparison to conventional human topo II inhibiting antitumor drugs such as doxorubicin and etoposide. In this review, we present a modern re-evaluation of the anticancer potential of the quinolone class in the context of today’s predominantly pathway-based (rather than cytotoxicity-based) oncology drug R&D environment. The quinolone eukaryotic SAR is comprehensively discussed, contrasted with the corresponding prokaryotic data, and merged with recent structural biology information which is now beginning to help explain the basis for that SAR. Quinolone topo II inhibitors appear to be much less susceptible to efflux-mediated resistance, a current limitation of therapy with conventional agents. Recent advances in the biological understanding of human topo II isoforms suggest that significant progress might now be made in overcoming two other treatment-limiting disadvantages of conventional topo II inhibitors, namely cardiotoxicity and drug-induced secondary leukemias. We propose that quinolone class topo II inhibitors could have a useful future therapeutic role due to the continued need for effective topo II drugs in many cancer treatment settings, and due to the recent biological and structural advances which can now provide, for the first time, specific guidance for the design of a new class of inhibitors potentially superior to existing agents. PMID:26695512

Repurposing drugs to treat l-DOPA-induced dyskinesia in Parkinson's disease.

PubMed

Johnston, Tom H; Lacoste, Alix M B; Visanji, Naomi P; Lang, Anthony E; Fox, Susan H; Brotchie, Jonathan M

2018-06-01

In this review, we discuss the opportunity for repurposing drugs for use in l-DOPA-induced dyskinesia (LID) in Parkinson's disease. LID is a particularly suitable indication for drug repurposing given its pharmacological diversity, translatability of animal-models, availability of Phase II proof-of-concept (PoC) methodologies and the indication-specific regulatory environment. A compound fit for repurposing is defined as one with appropriate human safety-data as well as animal safety, toxicology and pharmacokinetic data as found in an Investigational New Drug (IND) package for another indication. We first focus on how such repurposing candidates can be identified and then discuss development strategies that might progress such a candidate towards a Phase II clinical PoC. We discuss traditional means for identifying repurposing candidates and contrast these with newer approaches, especially focussing on the use of computational and artificial intelligence (AI) platforms. We discuss strategies that can be categorised broadly as: in vivo phenotypic screening in a hypothesis-free manner; in vivo phenotypic screening based on analogy to a related disorder; hypothesis-driven evaluation of candidates in vivo and in silico screening with a hypothesis-agnostic component to the selection. To highlight the power of AI approaches, we describe a case study using IBM Watson where a training set of compounds, with demonstrated ability to reduce LID, were employed to identify novel repurposing candidates. Using the approaches discussed, many diverse candidates for repurposing in LID, originally envisaged for other indications, will be described that have already been evaluated for efficacy in non-human primate models of LID and/or clinically. Copyright © 2018 Elsevier Ltd. All rights reserved.

Genomes2Drugs: Identifies Target Proteins and Lead Drugs from Proteome Data

PubMed Central

Toomey, David; Hoppe, Heinrich C.; Brennan, Marian P.; Nolan, Kevin B.; Chubb, Anthony J.

2009-01-01

Background Genome sequencing and bioinformatics have provided the full hypothetical proteome of many pathogenic organisms. Advances in microarray and mass spectrometry have also yielded large output datasets of possible target proteins/genes. However, the challenge remains to identify new targets for drug discovery from this wealth of information. Further analysis includes bioinformatics and/or molecular biology tools to validate the findings. This is time consuming and expensive, and could fail to yield novel drugs if protein purification and crystallography is impossible. To pre-empt this, a researcher may want to rapidly filter the output datasets for proteins that show good homology to proteins that have already been structurally characterised or proteins that are already targets for known drugs. Critically, those researchers developing novel antibiotics need to select out the proteins that show close homology to any human proteins, as future inhibitors are likely to cross-react with the host protein, causing off-target toxicity effects later in clinical trials. Methodology/Principal Findings To solve many of these issues, we have developed a free online resource called Genomes2Drugs which ranks sequences to identify proteins that are (i) homologous to previously crystallized proteins or (ii) targets of known drugs, but are (iii) not homologous to human proteins. When tested using the Plasmodium falciparum malarial genome the program correctly enriched the ranked list of proteins with known drug target proteins. Conclusions/Significance Genomes2Drugs rapidly identifies proteins that are likely to succeed in drug discovery pipelines. This free online resource helps in the identification of potential drug targets. Importantly, the program further highlights proteins that are likely to be inhibited by FDA-approved drugs. These drugs can then be rapidly moved into Phase IV clinical studies under ‘change-of-application’ patents. PMID:19593435

75 FR 68364 - Guidance for Industry and Food and Drug Administration Staff; Class II Special Controls Guidance...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-11-05

... European Protocol for the Quality Control of the Physical and Technical Aspects of Mammography Screening... entitled ``Physical Laboratory Testing, Breast Compression System'' to follow the Mammography Quality...] Guidance for Industry and Food and Drug Administration Staff; Class II Special Controls Guidance Document...

76 FR 22906 - Guidance for Industry and Food and Drug Administration Staff; Class II Special Controls Guidance...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-04-25

...: Topical Oxygen Chamber for Extremities; Availability AGENCY: Food and Drug Administration, HHS. ACTION... entitled, ``Class II Special Controls Guidance Document: Topical Oxygen Chamber for Extremities.'' This guidance document was developed as a special control to support the reclassification of the topical oxygen...

76 FR 64228 - Draft Guidance for Industry and Food and Drug Administration Staff; Class II Special Controls...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-10-17

...: External Pacemaker Pulse Generator; Availability AGENCY: Food and Drug Administration, HHS. ACTION: Notice... entitled ``Class II Special Controls Guidance Document: External Pacemaker Pulse Generator.'' This draft guidance document describes a means by which external pacemaker pulse generators may comply with the...

76 FR 43332 - Guidance for Industry and Food and Drug Administration Staff; Class II Special Controls Guidance...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-07-20

...: Focused Ultrasound Stimulator System for Aesthetic Use; Availability AGENCY: Food and Drug Administration... the guidance entitled, ``Class II Special Controls Guidance Document: Focused Ultrasound Stimulator System for Aesthetic Use.'' This guidance document describes a means by which focused ultrasound...

Preparation, spectroscopic, thermal, antihepatotoxicity, hematological parameters and liver antioxidant capacity characterizations of Cd(II), Hg(II), and Pb(II) mononuclear complexes of paracetamol anti-inflammatory drug

NASA Astrophysics Data System (ADS)

El-Megharbel, Samy M.; Hamza, Reham Z.; Refat, Moamen S.

2014-10-01

Keeping in view that some metal complexes are found to be more potent than their parent drugs, therefore, our present paper aimed to synthesized Cd(II), Hg(II) and Pb(II) complexes of paracetamol (Para) anti-inflammatory drug. Paracetamol complexes with general formula [M(Para)2(H2O)2]·nH2O have been synthesized and characterized on the basis of elemental analysis, conductivity, IR and thermal (TG/DTG), 1H NMR, electronic spectral studies. The conductivity data of these complexes have non-electrolytic nature. Comparative antimicrobial (bacteria and fungi) behaviors and molecular weights of paracetamol with their complexes have been studied. In vivo the antihepatotoxicity effect and some liver function parameters levels (serum total protein, ALT, AST, and LDH) were measured. Hematological parameters and liver antioxidant capacities of both Para and their complexes were performed. The Cd2+ + Para complex was recorded amelioration of antioxidant capacities in liver homogenates compared to other Para complexes treated groups.

Synthesis, spectroscopic, thermal and anticancer studies of metal-antibiotic chelations: Ca(II), Fe(III), Pd(II) and Au(III) chloramphenicol complexes

NASA Astrophysics Data System (ADS)

Al-Khodir, Fatima A. I.; Refat, Moamen S.

2016-09-01

Four Ca(II), Fe(III), Pd(II) and Au(III) complexes of chloramphenicol drug have been synthesized and well characterized using elemental analyses, (infrared, electronic, and 1H-NMR) spectra, magnetic susceptibility measurement, and thermal analyses. Infrared spectral data show that the chloramphenicol drug coordinated to Ca(II), Pd(II) and Au(III) metal ions through two hydroxyl groups with 1:1 or 1:2 M ratios, but Fe(III) ions chelated towards chloramphenicol drug via the oxygen and nitrogen atoms of amide group with 1:2 ratio based on presence of keto↔enol form. The X-ray powder diffraction (XRD), scanning electron microscope (SEM) and transmission electron microscopy (TEM) techniques were used to identify the nano-size particles of both iron(III) and gold(III) chloramphenicol complexes. The antimicrobial assessments of the chloramphenicol complexes were scanned and collected the results against of some kind of bacteria and fungi. The cytotoxic activity of the gold(III) complex was tested against the human colon carcinoma (HCT-116) and human hepatocellular carcinoma (HepG-2) tumor cell lines.

Text mining-based in silico drug discovery in oral mucositis caused by high-dose cancer therapy.

PubMed

Kirk, Jon; Shah, Nirav; Noll, Braxton; Stevens, Craig B; Lawler, Marshall; Mougeot, Farah B; Mougeot, Jean-Luc C

2018-08-01

Oral mucositis (OM) is a major dose-limiting side effect of chemotherapy and radiation used in cancer treatment. Due to the complex nature of OM, currently available drug-based treatments are of limited efficacy. Our objectives were (i) to determine genes and molecular pathways associated with OM and wound healing using computational tools and publicly available data and (ii) to identify drugs formulated for topical use targeting the relevant OM molecular pathways. OM and wound healing-associated genes were determined by text mining, and the intersection of the two gene sets was selected for gene ontology analysis using the GeneCodis program. Protein interaction network analysis was performed using STRING-db. Enriched gene sets belonging to the identified pathways were queried against the Drug-Gene Interaction database to find drug candidates for topical use in OM. Our analysis identified 447 genes common to both the "OM" and "wound healing" text mining concepts. Gene enrichment analysis yielded 20 genes representing six pathways and targetable by a total of 32 drugs which could possibly be formulated for topical application. A manual search on ClinicalTrials.gov confirmed no relevant pathway/drug candidate had been overlooked. Twenty-five of the 32 drugs can directly affect the PTGS2 (COX-2) pathway, the pathway that has been targeted in previous clinical trials with limited success. Drug discovery using in silico text mining and pathway analysis tools can facilitate the identification of existing drugs that have the potential of topical administration to improve OM treatment.

Study of osteoarthritis treatment with anti-inflammatory drugs: cyclooxygenase-2 inhibitor and steroids.

PubMed

Cho, Hongsik; Walker, Andrew; Williams, Jeb; Hasty, Karen A

2015-01-01

Patients with osteoarthritis (OA), a condition characterized by cartilage degradation, are often treated with steroids, nonsteroidal anti-inflammatory drugs (NSAIDs), and cyclooxygenase-2 (COX-2) selective NSAIDs. Due to their inhibition of the inflammatory cascade, the drugs affect the balance of matrix metalloproteinases (MMPs) and inflammatory cytokines, resulting in preservation of extracellular matrix (ECM). To compare the effects of these treatments on chondrocyte metabolism, TNF-α was incubated with cultured chondrocytes to mimic a proinflammatory environment with increasing production of MMP-1 and prostaglandin E2 (PGE2). The chondrocytes were then treated with either a steroid (prednisone), a nonspecific COX inhibitor NSAID (piroxicam), or a COX-2 selective NSAID (celecoxib). Both prednisone and celecoxib decreased MMP-1 and PGE-2 production while the nonspecific piroxicam decreased only the latter. Both prednisone and celecoxib decreased gene expression of MMP-1 and increased expression of aggrecan. Increased gene expression of type II collagen was also noted with celecoxib. The nonspecific piroxicam did not show these effects. The efficacy of celecoxib in vivo was investigated using a posttraumatic OA (PTOA) mouse model. In vivo, celecoxib increases aggrecan synthesis and suppresses MMP-1. In conclusion, this study demonstrates that celecoxib and steroids exert similar effects on MMP-1 and PGE2 production in vitro and that celecoxib may demonstrate beneficial effects on anabolic metabolism in vivo.

Simultaneous determination of bifonazole and tinctures of calendula flower in pharmaceutical creams by reversed-phase liquid chromatography.

PubMed

Ferreyra, Carola F; Ortiz, Cristina S

2005-01-01

The aim of this research was to develop and validate a sensitive, rapid, easy, and precise reversed-phase liquid chromatography (LC) method for stability studies of bifonazole (I) formulated with tinctures of calendula flower (II). The method was especially developed for the analysis and quantitative determination of I and II in pure and combined forms in cream pharmaceutical formulations without using gradient elution and at room temperature. The influence on the stability of compound I of temperature, artificial radiation, and drug II used for the new pharmaceutical design was evaluated. The LC separation was carried out using a Supelcosil LC-18 column (25 cm x 4.6 mm id, 5 microm particle size); the mobile phase was composed of methanol-0.1 M ammonium acetate buffer (85 + 15, v/v) pumped isocratically at a flow rate of 1 mL/min; and ultraviolet detection was at 254 nm. The analysis time was less than 10 min. Calibration graphs were found to be linear in the 0.125-0.375 mg/mL (rI = 0.9991) and 0.639-1.916 mg/mL (rII = 0.9995) ranges for I and II, respectively. The linearity, precision, recovery, and limits of detection and quantification were satisfactory for I and II. The results obtained suggested that the developed LC method is selective and specific for the analysis of I and II in pharmaceutical products, and that it can be applied to stability studies.

Prospective, comparative cohort studies and their contribution to the benefit assessments of therapeutic options: heart failure treatment with and without Hawthorn special extract WS 1442.

PubMed

Habs, M

2004-08-01

In addition to testing a drug for its efficacy, pharmacological quality and safety, current policies are increasingly demanding evaluations of the therapeutic benefits provided by a drug in general practice with "non-selected" patients and increasingly restrictive economic considerations. One of the trials which addresses this task is the WISO cohort study (Efficacy and socio-economic relevance of treatment of chronic heart failure stage NYHA II with Crataegus extract WS 1442). It compares two different therapeutic strategies in the treatment of heart failure stage NYHA II, i.e. a conventional medication and a therapy which also includes hawthorn special extract WS 1442 (Crataegutt novo 450) in addition to chemical-synthetic drugs. In contrast to clinical trials, the patients in cohort studies are expressly not randomised and the physician in charge independently chooses the administered treatment. This comparative, non-interventional observation provides well-founded evidence of the "real-world effectiveness" of the tested preparation. 952 patients with heart failure (NYHA II) were enrolled in the study by 217 general practitioners. 588 patients received Crataegus special extract WS 1442 (Crataegutt novo 450) either as an add-on therapy or as a monotherapy (Crataegus cohort) and 364 patients received therapy without hawthorn (comparative cohort). These two groups had the same indication (heart failure NYHA II) but were significantly different regarding gender, age and concomitant cardiovascular disease. Basically, in view of the free choice of therapy made by the physician in charge, such differences are to be expected in comparative observational studies. A sufficient degree of patient comparability was provided by means of the matched-pairs technique, which replaced the randomisation procedure normally used in clinical studies. After 2 years, 130 patient pairs generated by this technique could be included in the interim assessment. The clinical symptoms with regard to all parameters investigated showed the same or a more pronounced improvement in the Crataegus cohort in the course of 2 years. After 2 years, the three cardinal symptoms of heart failure--fatigue (p = 0.036), stress dyspnoea (p = 0.020) and palpitations (p = 0.048)--were significantly less marked in the Crataegus cohort than in the comparative cohort. The particular design of the cohort study also provides valuable additional information: (1) Hawthorn special extract WS 1442 was prescribed in registered cardiological practices for the treatment of patients with heart failure stage NYHA II, partly as an alternative and partly as a supplement to the used chemical-synthetic drugs. (2) Favourable effects on the clinical symptoms were achieved although the patients in the Crataegus cohort received markedly fewer chemical-synthetic drugs than the patients in the comparative cohort (ACE-inhibitors: 36 vs. 54%, p = 0.004; cardiac glycosides: 18 vs. 37%, p = 0.001; diuretics: 49 vs. 61%, p = 0.061; beta-blockers: 22 vs. 33%, p = 0.052). The data show a clear benefit for patients with heart failure stage NYHA II treated with WS 1442. The single or add-on administration in addition to a chemical-synthetic medication resulted in objective improvements at comparable costs. Copyright 2004 S. Karger GmbH, Freiburg

The ATP-binding site of type II topoisomerases as a target for antibacterial drugs.

PubMed

Maxwell, Anthony; Lawson, David M

2003-01-01

DNA topoisomerases are essential enzymes in all cell types and have been found to be valuable drug targets both for antibacterial and anti-cancer chemotherapy. Type II topoisomerases possess a binding site for ATP, which can be exploited as a target for chemo-therapeutic agents. High-resolution structures of protein fragments containing this site complexed with antibiotics or an ATP analogue have provided vital information for the understanding of the action of existing drugs and for the potential development of novel anti-bacterial agents. In this article we have reviewed the structure and function of the ATPase domain of DNA gyrase (bacterial topoisomerase II), particularly highlighting novel information that has been revealed by structural studies. We discuss the efficacy and mode of action of existing drugs and consider the prospects for the development of novel agents.

Schedules of Controlled Substances: Placement of FDA-Approved Products of Oral Solutions Containing Dronabinol [(-)-delta-9-transtetrahydrocannabinol (delta-9-THC)] in Schedule II. Interim final rule, with request for comments.

PubMed

2017-03-23

On July 1, 2016, the U.S. Food and Drug Administration (FDA) approved a new drug application for Syndros, a drug product consisting of dronabinol [(-)-delta-9-trans-tetrahydrocannabinol (delta-9-THC)] oral solution. Thereafter, the Department of Health and Human Services (HHS) provided the Drug Enforcement Administration (DEA) with a scheduling recommendation that would result in Syndros (and other oral solutions containing dronabinol) being placed in schedule II of the Controlled Substances Act (CSA). In accordance with the CSA, as revised by the Improving Regulatory Transparency for New Medical Therapies Act, DEA is hereby issuing an interim final rule placing FDA-approved products of oral solutions containing dronabinol in schedule II of the CSA.

Computational investigations of trans-platinum(II) oxime complexes used as anticancer drug

NASA Astrophysics Data System (ADS)

Sayin, Koray; Karakaş, Duran

2018-01-01

Some platinum oxime complexes are optimized at HF/CEP-31G level which has been reported as the best level for these type complexes in the gas phase. IR spectrum is calculated and the new scale factor is derived. NMR spectrum is calculated at the same level of theory and examined in detail. Quantum chemical parameters which have been mainly used are investigated and their formulas are given in detail. Additionally, selected quantum chemical parameters of studied complexes are calculated. New theoretical IC50% formulas are derived and biological activity rankings of mentioned complexes are investigated.

Valsartan.

PubMed

Ardiana, Febry; Suciati; Indrayanto, Gunawan

2015-01-01

Valsartan is an antihypertensive drug which selectively inhibits angiotensin receptor type II. Generally, valsartan is available as film-coated tablets. This review summarizes thermal analysis, spectroscopy characteristics (UV, IR, MS, and NMR), polymorphism forms, impurities, and related compounds of valsartan. The methods of analysis of valsartan in pharmaceutical dosage forms and in biological fluids using spectrophotometer, CE, TLC, and HPLC methods are discussed in details. Both official and nonofficial methods are described. It is recommended to use LC-MS method for analyzing valsartan in complex matrices such as biological fluids and herbal preparations; in this case, MRM is preferred than SIM method. © 2015 Elsevier Inc. All rights reserved.

IDSA update from the city of brotherly love.

PubMed

Ghandi, R

2000-01-01

Data from a major new trial called START II (Selection of Thymidine Analog Therapy), was presented at this year's Infectious Diseases Society of America (IDSA) conference. One trial compared d4T/ddI/IDV combination therapy with AZT/3TC/IDV in treatment-naive individuals. A second trial, CNA 3003, compared triple NRTI therapy with AZT/3TC/abacavir to dual therapy with AZT/3TC; patients who added abacavir to the treatment showed decreased viral loads. Additional clinical trials using 3TC are detailed. Drug resistance, investigational agents, HIV diagnostic testing, and opportunistic infections are also discussed.

Maximum tolerated dose evaluation of the AMPA modulator Org 26576 in healthy volunteers and depressed patients: a summary and method analysis of bridging research in support of phase II dose selection.

PubMed

Nations, Kari R; Bursi, Roberta; Dogterom, Peter; Ereshefsky, Larry; Gertsik, Lev; Mant, Tim; Schipper, Jacques

2012-09-01

A key challenge to dose selection in early central nervous system (CNS) clinical drug development is that patient tolerability profiles often differ from those of healthy volunteers (HVs), yet HVs are the modal population for determining doses to be investigated in phase II trials. Without clear tolerability data from the target patient population, first efficacy trials may include doses that are either too high or too low, creating undue risk for study participants and the development program overall. Bridging trials address this challenge by carefully investigating safety and tolerability in the target population prior to full-scale proof-of-concept trials. Org 26576 is an alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor positive allosteric modulator that acts by modulating ionotropic AMPA-type glutamate receptors to enhance glutamatergic neurotransmission. In preparation for phase II efficacy trials in major depressive disorder (MDD), two separate phase I trials were conducted to evaluate safety, tolerability, and pharmacokinetics in HVs and in the target patient population. Both trials were randomized and placebo controlled, and included multiple rising-dose cohorts (HV range 100-400 mg bid; MDD range 100-600 mg bid). HVs (n = 36) and patients with MDD (n = 54) were dosed under similarly controlled conditions in an inpatient facility, HVs for up to 14 days and MDD patients for up to 28 days. Safety, tolerability, and pharmacokinetics were assessed frequently. Despite comparable pharmacokinetic profiles, the maximum tolerated dose (MTD) in depressed patients was 450 mg bid, twice the MTD established in HVs. No clinically relevant safety issues associated with Org 26576 were noted. This article presents safety, tolerability, and pharmacokinetic data from two different populations examined under similar dosing conditions. The important implications of such bridging work in phase II dose selection are discussed, as are study design and data interpretation challenges.

Enhancing Photodynamyc Therapy Efficacy by Combination Therapy: Dated, Current and Oncoming Strategies

PubMed Central

Postiglione, Ilaria; Chiaviello, Angela; Palumbo, Giuseppe

2011-01-01

Combination therapy is a common practice in many medical disciplines. It is defined as the use of more than one drug to treat the same disease. Sometimes this expression describes the simultaneous use of therapeutic approaches that target different cellular/molecular pathways, increasing the chances of killing the diseased cell. This short review is concerned with therapeutic combinations in which PDT (Photodynamyc Therapy) is the core therapeutic partner. Besides the description of the principal methods used to assess the efficacy attained by combinations in respect to monotherapy, this review describes experimental results in which PDT was combined with conventional drugs in different experimental conditions. This inventory is far from exhaustive, as the number of photosensitizers used in combination with different drugs is very large. Reports cited in this work have been selected because considered representative. The combinations we have reviewed include the association of PDT with anti-oxidants, chemotherapeutics, drugs targeting topoisomerases I and II, antimetabolites and others. Some paragraphs are dedicated to PDT and immuno-modulation, others to associations of PDT with angiogenesis inhibitors, receptor inhibitors, radiotherapy and more. Finally, a look is dedicated to combinations involving the use of natural compounds and, as new entries, drugs that act as proteasome inhibitors. PMID:24212824

Utility of NBD-Cl for the spectrophotometric determination of some skeletal muscle relaxant and antihistaminic drugs

NASA Astrophysics Data System (ADS)

Saleh, Hanaa M.; EL-Henawee, Magda M.; Ragab, Gamal H.; El-Hay, Soad S. Abd

2007-08-01

A simple, accurate, precise and sensitive colorimetric method for the determination of some skeletal muscle relaxant drugs, namely orphenadrine citrate ( I), baclofen ( II), antihistaminic drugs as acrivastine ( III) and fexofenadine hydrochloride ( IV) is described. This method is based on the formation of charge transfer complex with 4-chloro-7-nitro-2,1,3-benzoxadiazole (NBD-Cl) in non-aqueous medium. The orange color products were measured at 472, 465, 475 and 469 nm for drugs I, II, III and IV, respectively. The optimization of various experimental conditions was described. Beer's Law was obeyed in the range (2.5-17.5), (5-70), (2.5-25) and (10-50) μg/ml for drugs I, II, III and IV, respectively. The molar absorptivity ( ɛ), sandell sensitivity, detection (LOD) and quantitation limits (LOQ) are calculated. The procedure was favorably applied for determination of certain pharmaceutical dosage forms containing the studied drugs. The obtained results were compared with the official and reported methods. There were no significant differences between proposed, reported and the official methods.

A review of lapatinib ditosylate in the treatment of refractory or advanced breast cancer

PubMed Central

Nelson, Michael H; Dolder, Christian R

2007-01-01

Breast cancer remains a leading cause of disease and death among women throughout the world. Despite advances in drug therapy, development of novel and improved drugs for breast cancer continues to be of great interest. Lapatinib is a novel dual receptor tyrosine kinase inhibitor that is a selective and potent inhibitor of ErbB-1 and ErbB-2 tyrosine kinases, both of which are growth promoting factors overexpressed in some breast cancers. Cell-based assays have proven lapatinib to be a potent inhibitor of ErbB-1 and ErbB-2 activation and breast cancer cell proliferation. In pharmacokinetic studies, lapatinib has shown mostly linear elimination kinetics over the daily dose range of 10–1600 mg and is metabolized by CYP3A4/5 and CYP2C19. Phase I, II, and III clinical trials involving lapatinib as monotherapy or in combination have shown promise for the treatment of advanced and metastatic breast cancer. Drug-drug interactions may occur secondary to concomitant administration of either CYP450 inhibitors or inducers. While lapatinib appear to be a promising addition to breast cancer therapy, several questions remain to be answered before its optimal role is elucidated. PMID:18472989

A review of lapatinib ditosylate in the treatment of refractory or advanced breast cancer.

PubMed

Nelson, Michael H; Dolder, Christian R

2007-08-01

Breast cancer remains a leading cause of disease and death among women throughout the world. Despite advances in drug therapy, development of novel and improved drugs for breast cancer continues to be of great interest. Lapatinib is a novel dual receptor tyrosine kinase inhibitor that is a selective and potent inhibitor of ErbB-1 and ErbB-2 tyrosine kinases, both of which are growth promoting factors overexpressed in some breast cancers. Cell-based assays have proven lapatinib to be a potent inhibitor of ErbB-1 and ErbB-2 activation and breast cancer cell proliferation. In pharmacokinetic studies, lapatinib has shown mostly linear elimination kinetics over the daily dose range of 10-1600 mg and is metabolized by CYP3A4/5 and CYP2C19. Phase I, II, and III clinical trials involving lapatinib as monotherapy or in combination have shown promise for the treatment of advanced and metastatic breast cancer. Drug-drug interactions may occur secondary to concomitant administration of either CYP450 inhibitors or inducers. While lapatinib appear to be a promising addition to breast cancer therapy, several questions remain to be answered before its optimal role is elucidated.

The Antinociceptive and Antiinflammatory Properties of 3-furan-2-yl-N-p-tolyl-acrylamide, a Positive Allosteric Modulator of α7 Nicotinic Acetylcholine Receptors in Mice

PubMed Central

Bagdas, Deniz; Targowska-Duda, Katarzyna M.; López, Jhon J.; Perez, Edwin G.; Arias, Hugo R.; Damaj, M. Imad

2016-01-01

BACKGROUND Positive allosteric modulators (PAMs) facilitate endogenous neurotransmission and/or enhance the efficacy of agonists without directly acting on the orthosteric binding sites. In this regard, selective α7 nicotinic acetylcholine receptor type II PAMs display antinociceptive activity in rodent chronic inflammatory and neuropathic pain models. This study investigates whether 3-furan-2-yl-N-p-tolyl-acrylamide (PAM-2), a new putative α7-selective type II PAM, attenuates experimental inflammatory and neuropathic pains in mice. METHODS We tested the activity of PAM-2 after intraperitoneal administration in 3 pain assays: the carrageenan-induced inflammatory pain, the complete Freund adjuvant induced inflammatory pain, and the chronic constriction injury–induced neuropathic pain in mice. We also tested whether PAM-2 enhanced the effects of the selective α7 agonist choline in the mouse carrageenan test given intrathecally. Because the experience of pain has both sensory and affective dimensions, we also evaluated the effects of PAM-2 on acetic acid–induced aversion by using the conditioned place aversion test. RESULTS We observed that systemic administration of PAM-2 significantly reversed mechanical allodynia and thermal hyperalgesia in inflammatory and neuropathic pain models in a dose- and time-dependent manner without motor impairment. In addition, by attenuating the paw edema in inflammatory models, PAM-2 showed antiinflammatory properties. The antinociceptive effect of PAM-2 was inhibited by the selective competitive antagonist methyllycaconitine, indicating that the effect is mediated by α7 nicotinic acetylcholine receptors. Furthermore, PAM-2 enhanced the antiallodynic and antiinflammatory effects of choline, a selective α7 agonist, in the mouse carrageenan test. PAM-2 was also effective in reducing acetic acid induced aversion in the conditioned place aversion assay. CONCLUSIONS These findings suggest that the administration of PAM-2, a new α7-selective type II PAM, reduces the neuropathic and inflammatory pain sensory and affective behaviors in the mouse. Thus, this drug may have therapeutic applications in the treatment and management of chronic pain. PMID:26280585

Obligatory role for GPER in cardiovascular aging and disease.

PubMed

Meyer, Matthias R; Fredette, Natalie C; Daniel, Christoph; Sharma, Geetanjali; Amann, Kerstin; Arterburn, Jeffrey B; Barton, Matthias; Prossnitz, Eric R

2016-11-01

Pharmacological activation of the heptahelical G protein-coupled estrogen receptor (GPER) by selective ligands counteracts multiple aspects of cardiovascular disease. We thus expected that genetic deletion or pharmacological inhibition of GPER would further aggravate such disease states, particularly with age. To the contrary, we found that genetic ablation of Gper in mice prevented cardiovascular pathologies associated with aging by reducing superoxide (⋅O 2 - ) formation by NADPH oxidase (Nox) specifically through reducing the expression of the Nox isoform Nox1 Blocking GPER activity pharmacologically with G36, a synthetic, small-molecule, GPER-selective blocker (GRB), decreased Nox1 abundance and ⋅O 2 - production to basal amounts in cells exposed to angiotensin II and in mice chronically infused with angiotensin II, reducing arterial hypertension. Thus, this study revealed a role for GPER activity in regulating Nox1 abundance and associated ⋅O 2 - -mediated structural and functional damage that contributes to disease pathology. Our results indicated that GRBs represent a new class of drugs that can reduce Nox abundance and activity and could be used for the treatment of chronic disease processes involving excessive ⋅O 2 - formation, including arterial hypertension and heart failure. Copyright © 2016, American Association for the Advancement of Science.

[The role of gamma-aminobutyric acid in the mechanism of action of anticonvulsant drugs].

PubMed

Chmielewska, B

2000-01-01

Decreased activity of gamma-aminobutyric acid, the major inhibitory neurotransmitter in CNS can be epileptogenic. Manipulation of the GABA system has been a target for development of antiepileptic drugs. The different ways for augmenting gabaergic inhibition by conventional and new AEDs are presented in this paper. Among the I generation, barbiturates and benzodiazepines are potent anticonvulsants that act as GABA modulators in postsynaptic GABA-A receptor complex but their usefulness is limited by dependence and tolerance to antiseizure activity. The II generation drugs vigabatrin and tiagabine, and to some extent gabapentin have been developed by a rationale strategy and none of them exert direct action in GABA receptors. Only two former drugs exhibit selective, strictly defined activity: vigabatrine is an irreversible inhibitor of GABA-aminotransferase and tiagabine acts as a GABA-uptake inhibitor from synaptic cleft into neurons and glia. Gabapentin binds to a novel receptors in epileptogenic areas in CNS and enhances GABA turnover. Drugs with multiple mechanisms of action, felbamate and topiramate not only potentiate gabaergic inhibition in several ways but also diminish the activity of excitatory amino acids at their NMDA or AMPA receptors; the later mechanism seems to be essential for their potential neuroprotective activity in epileptogenesis. None of gabamimetic drugs provide optimal seizure control but better tolerability of newer ones and well-established mechanisms of action provide possible harmless therapy.

Distribution of genetic polymorphisms of genes encoding drug metabolizing enzymes & drug transporters - a review with Indian perspective.

PubMed

Umamaheswaran, Gurusamy; Kumar, Dhakchinamoorthi Krishna; Adithan, Chandrasekaran

2014-01-01

Phase I and II drug metabolizing enzymes (DME) and drug transporters are involved in the absorption, distribution, metabolism as well as elimination of many therapeutic agents, toxins and various pollutants. Presence of genetic polymorphisms in genes encoding these proteins has been associated with marked inter-individual variability in their activity that could result in variation in drug response, toxicity as well as in disease predisposition. The emergent field pharmacogenetics and pharmacogenomics (PGx) is a promising discipline, as it predicts disease risk, selection of proper medication with regard to response and toxicity, and appropriate drug dosage guidance based on an individual's genetic make-up. Consequently, genetic variations are essential to understand the ethnic differences in disease occurrence, development, prognosis, therapeutic response and toxicity. For that reason, it is necessary to establish the normative frequency of these genes in a particular population before unraveling the genotype-phenotype associations. Although a fair amount of allele frequency data are available in Indian populations, the existing pharmacogenetic data have not been compiled into a database. This review was intended to compile the normative frequency distribution of the variants of genes encoding DMEs (CYP450s, TPMT, GSTs, COMT, SULT1A1, NAT2 and UGTs) and transporter proteins (MDR1, OCT1 and SLCO1B1) with Indian perspective.

Mixed response and time-to-event endpoints for multistage single-arm phase II design.

PubMed

Lai, Xin; Zee, Benny Chung-Ying

2015-06-04

The objective of phase II cancer clinical trials is to determine if a treatment has sufficient activity to warrant further study. The efficiency of a conventional phase II trial design has been the object of considerable debate, particularly when the study regimen is characteristically cytostatic. At the time of development of a phase II cancer trial, we accumulated clinical experience regarding the time to progression (TTP) for similar classes of drugs and for standard therapy. By considering the time to event (TTE) in addition to the tumor response endpoint, a mixed-endpoint phase II design may increase the efficiency and ability of selecting promising cytotoxic and cytostatic agents for further development. We proposed a single-arm phase II trial design by extending the Zee multinomial method to fully use mixed endpoints with tumor response and the TTE. In this design, the dependence between the probability of response and the TTE outcome is modeled through a Gaussian copula. Given the type I and type II errors and the hypothesis as defined by the response rate (RR) and median TTE, such as median TTP, the decision rules for a two-stage phase II trial design can be generated. We demonstrated through simulation that the proposed design has a smaller expected sample size and higher early stopping probability under the null hypothesis than designs based on a single-response endpoint or a single TTE endpoint. The proposed design is more efficient for screening new cytotoxic or cytostatic agents and less likely to miss an effective agent than the alternative single-arm design.

76 FR 20992 - Guidance for Industry and Food and Drug Administration Staff; Class II Special Controls Guidance...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-04-14

...: Low Level Laser System for Aesthetic Use; Availability AGENCY: Food and Drug Administration, HHS... guidance entitled ``Class II Special Controls Guidance Document: Low Level Laser System for Aesthetic Use.'' This guidance document describes a means by which low level laser systems for aesthetic use may comply...

76 FR 69040 - Draft Guidance for Industry and Food and Drug Administration Staff; Class II Special Controls...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-11-07

...: In Vitro Diagnostic Devices for Yersinia Species Detection; Availability AGENCY: Food and Drug... availability of a draft guidance entitled ``Class II Special Controls Guidance Document: In Vitro Diagnostic Devices for Yersinia Species Detection.'' This draft guidance document describes a means by which in vitro...

76 FR 6622 - Guidance for Industry and Food and Drug Administration Staff; Class II Special Controls Guidance...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-02-07

...: Contact Cooling System for Aesthetic Use; Availability AGENCY: Food and Drug Administration, HHS. ACTION... entitled ``Class II Special Controls Guidance Document: Contact Cooling System for Aesthetic Use.'' This guidance document describes a means by which contact cooling systems for aesthetic use may comply with the...

75 FR 14188 - Importer of Controlled Substances; Notice of Application

Federal Register 2010, 2011, 2012, 2013, 2014

2010-03-24

... this Section to a bulk manufacturer of a controlled substance in schedule I or II, and prior to issuing... Manufacturing LLC., 3500 Dekalb Street, St. Louis, Missouri 63118, made application by renewal to the Drug... listed in schedules I and II: Drug Schedule Cathinone (1235) I Methcathinone (1237) I Aminorex (1585) I...

Neutron diffraction of acetazolamide-bound human carbonic anhydrase II reveals atomic details of drug binding

PubMed Central

Fisher, S. Zoë; Aggarwal, Mayank; Kovalevsky, Andrey Y.; Silverman, David N.; McKenna, Robert

2012-01-01

Carbonic anhydrases (CAs) catalyze the hydration of CO2 forming HCO3− and a proton, an important reaction for many physiological processes including respiration, fluid secretion, and pH regulation. As such, CA isoforms are prominent clinical targets for treating various diseases. The clinically used acetazolamide (AZM) is a sulfonamide that binds with high affinity to human CA isoform II (HCA II). There are several X-ray structures available of AZM bound to various CA isoforms, but these complexes do not show the charged state of AZM, or hydrogen (H) atom positions of the protein and solvent. Neutron diffraction is a useful technique for directly observing H atoms and the mapping of H-bonding networks that can greatly contribute to rational drug design. To this end the neutron structure of H/D exchanged HCA II crystals in complex with AZM was determined. The structure reveals the molecular details of AZM binding and the charged state of the bound drug. This represents the first determined neutron structure of a clinically used drug bound to its target. PMID:22928733

[Atherosclerotic renovascular hypertension: clinical findings and results of treatment over 15 years].

PubMed

Alfonzo, J P; Rosario, M N; Ugarte, C; Banasco, J; Fraxedas, R; Lahera, J

2003-01-01

The aim of this study was to present our clinical experience and results of different treatments in 83 atherosclerotic renovascular hypertensive patients treated in the last 15 years in the Instituto de nefrologia in Havana. Regardless of the type of treatment the patients were divided in two groups. Group I: 52 (62.3%) cases with standard oral hypotensive drugs alone and control of other cardiovascular risk factors (mean age 53 years old, sex m/f 50/50%, race white/no-white 75/25%, mean known hypertension follow-up 10.2 +/- 10 years, mean SBP 208 +/- 30 mmHg, mean DBP 123 +/- 17 mmHg, mean serum creatinina 1.62 mg/dl and increase peripheral plasma renin value in 61.6% of patients) and group II: 31 (37.7%) cases treated with revascularización procedures (PTA or surgery) or nephrectomy in selected patients (mean age 50 years old, sex m/f 68/32%, race white/no-white 16/84%, mean known hypertension follow-up 8.5 +/- 8.6 years, mean SBP 214 +/- 32 mmHg, mean DBP 1.31 +/- 16 mmHg, mean serum creatinina 1.85 mg/dl and increase peripheral plasma renin value 78.3% of patients). As end point for treatment results we selected: 1) hypertension cure or control, 2) evolution of the serum creatinine value and 3) kidney and patients survival. In those cases with a follow up for more than one year, in 82.9% the blood pressure was cure (21.4%) or controlled (61.4%). The proportion of failed was superior in group I (20.9%) than in group II (11.1%). All 18 cases treated by PTA with a follow up period longer than a year, blood pressure cure in 10 (55.6%), ameliorate in 5 (27.8%) and in 3 (16.6%) was unchanged (one patient lost of follow up). Nine patients were treated by surgery (3 revascularization and 6 nephrectomy), 5 (55.5%) cases cured and 4 (44.5%) ameliorate his blood pressure. Patients in group II maintain normal renal function in more cases than in group I (48.4% vs 30.8%). Both group had similar percentage of normal-normal + pathology-normal renal function (G I: 65.4% vs G II: 77.4%) p = 0.29. When chronic renal function was present at the base line study none of the revascularization procedure were superior. Patient and Kidney actuarial survivals rate do not showed superiority for any treatment procedure after 10 years of follow up. In atherosclerosis renovascular hypertension patients treated with intervention procedure had better BP control than those treated by hypotensive drugs. Not significant different between intervention procedures and drugs treatment in renal function preservation or in patient and kidney actuarial survival rate were found in these patients.

Entry of substances into perilymph through the bone of the otic capsule following intratympanic applicatons in guinea pigs: Implications for local drug delivery in humans

PubMed Central

Mikulec, Anthony A; Plontke, Stefan K.; Hartsock, Jared J.; Salt, Alec N.

2008-01-01

Introduction Drugs applied intratympanically in humans are believed to enter the cochlea primarily through the round window membrane (RWM). Local drug treatments of the ear are commonly evaluated in rodent models. The otic capsule is much thinner at the cochlear apex in rodents than in humans. We therefore investigated whether drugs applied to the middle ear could enter perilymph through the otic capsule as well as through the RWM. Methods The distribution of gentamicin and the marker trimethylphenylammonium (TMPA) along the guinea pig cochlea was assessed with sequential apical perilymph sampling following two delivery paradigms that included i) completely filling the tympanic bulla with solution, and ii) applying the solution to the RWM only. In addition, TMPA entry into perilymph of the third turn was measured with ion-selective electrodes while the bulla was filled with TMPA solution. Results In application protocols that allowed drug to contact the otic capsule (by completely filling the bulla) markedly higher drug concentrations were found in the apical, low-frequency regions of the cochlea compared with drug applications to the RWM only. Conclusions Gentamicin and TMPA can enter perilymph of guinea pigs through the RWM and simultaneously through the bony otic capsule. Drug distribution along the cochlea following intratympanic applications will therefore be dramatically different in rodents and humans. Results obtained from intratympanic drug treatments of animals, in which the bulla is filled with solution and contacts the bony capsule of the cochlea, do not provide a good model for the human situation. PMID:19180674

ApoA-II modulates the association of HDL with class B scavenger receptors SR-BI and CD36.

PubMed

de Beer, Maria C; Castellani, Lawrence W; Cai, Lei; Stromberg, Arnold J; de Beer, Frederick C; van der Westhuyzen, Deneys R

2004-04-01

The class B scavenger receptors SR-BI and CD36 exhibit a broad ligand binding specificity. SR-BI is well characterized as a HDL receptor that mediates selective cholesteryl ester uptake from HDL. CD36, a receptor for oxidized LDL, also binds HDL and mediates selective cholesteryl ester uptake, although much less efficiently than SR-BI. Apolipoprotein A-II (apoA-II), the second most abundant HDL protein, is considered to be proatherogenic, but the underlying mechanisms are unclear. We previously showed that apoA-II modulates SR-BI-dependent binding and selective uptake of cholesteryl ester from reconstituted HDL. To investigate the effect of apoA-II in naturally occurring HDL on these processes, we compared HDL without apoA-II (from apoA-II null mice) with HDLs containing differing amounts of apoA-II (from C57BL/6 mice and transgenic mice expressing a mouse apoA-II transgene). The level of apoA-II in HDL was inversely correlated with HDL binding and selective cholesteryl ester uptake by both scavenger receptors, particularly CD36. Interestingly, for HDL lacking apoA-II, the efficiency with which CD36 mediated selective uptake reached a level similar to that of SR-BI. These results demonstrate that apoA-II exerts a marked effect on HDL binding and selective lipid uptake by the class B scavenger receptors and establishes a potentially important relationship between apoA-II and CD36.

Novel 20(S)-sulfonylamidine derivatives of camptothecin and the use thereof as a potent antitumor agent: a patent evaluation of WO2015048365 (A1).

PubMed

Beretta, Giovanni Luca; Zaffaroni, Nadia; Varchi, Greta

2016-05-01

A series of camptothecin (CPT) derivatives featuring acyl-esterification of the 20(S)-hydroxyl group with a residue containing a sulfonylamidine moiety is synthesized via a Cu catalyzed three-component reaction. The compounds show remarkable cytotoxicity against a panel of tumor cells, including a cell line exhibiting Multi-Drug Resistant (MDR) phenotype. The patent develops 9a, the best derivative of the series, that i) selectively poisons DNA Topoisomerase I (TopoI); ii) induces cell-cycle S-phase arrest with activation of the DNA damage response pathway and apoptosis induction and iii) shows considerable in vivo antitumor potency. We envision that the peculiar modification of the 20(S)-hydroxyl group of CPT with a sulfonylamidine residue will play a continuing role in affording new TopoI poison drug candidates for therapeutic applications.

Optimization and design of ibuprofen-loaded nanostructured lipid carriers using a hybrid-design approach for ocular drug delivery

NASA Astrophysics Data System (ADS)

Rathod, Vishal

The objective of the present project was to develop the Ibuprofen-loaded Nanostructured Lipid Carrier (IBU-NLCs) for topical ocular delivery based on substantial pre-formulation screening of the components and understanding the interplay between the formulation and process variables. The BCS Class II drug: Ibuprofen was selected as the model drug for the current study. IBU-NLCs were prepared by melt emulsification and ultrasonication technique. Extensive pre-formulation studies were performed to screen the lipid components (solid and liquid) based on drug's solubility and affinity as well as components compatibility. The results from DSC & XRD assisted in selecting the most suitable ratio to be utilized for future studies. DynasanRTM 114 was selected as the solid lipid & MiglyolRTM 840 was selected as the liquid lipid based on preliminary lipid screening. The ratio of 6:4 was predicted to be the best based on its crystallinity index and the thermal events. As there are many variables involved for further optimization of the formulation, a single design approach is not always adequate. A hybrid-design approach was applied by employing the Plackett Burman design (PBD) for preliminary screening of 7 critical variables, followed by Box-Behnken design (BBD), a sub-type of response surface methodology (RSM) design using 2 relatively significant variables from the former design and incorporating Surfactant/Co-surfactant ratio as the third variable. Comparatively, KolliphorRTM HS15 demonstrated lower Mean Particle Size (PS) & Polydispersity Index (PDI) and KolliphorRTM P188 resulted in Zeta Potential (ZP) < -20 mV during the surfactant screening & stability studies. Hence, Surfactant/Cosurfactant ratio was employed as the third variable to understand its synergistic effect on the response variables. We selected PS, PDI, and ZP as critical response variables in the PBD since they significantly influence the stability & performance of NLCs. Formulations prepared using BBD were further characterized and evaluated concerning PS, PDI, ZP and Entrapment Efficiency (EE) to identify the multi-factor interactions between selected formulation variables. In vitro release studies were performed using Spectra/por dialysis membrane on Franz diffusion cell and Phosphate Saline buffer (7.4 pH) as the medium. Samples for assay, EE, Loading Capacity (LC), Solubility studies & in-vitro release were filtered using Amicon 50K and analyzed via UPLC system (Waters) at a detection wavelength of 220 nm. Significant variables were selected through PBD, and the third variable was incorporated based on surfactant screening & stability studies for the next design. Assay of the BBD based formulations was found to be within 95-104% of the theoretically calculated values. Further studies were investigated for PS, PDI, ZP & EE. PS was found to be in the range of 103-194 nm with PDI ranging from 0.118 to 0.265. The ZP and EE were observed to be in the range of -22.2 to -11 mV & 90 to 98.7 % respectively. Drug release of 30% was observed from the optimized formulation in the first 6 hr of in-vitro studies, and the drug release showed a sustained release of ibuprofen thereafter over several hours. These values also confirm that the production method, and all other selected variables, effectively promoted the incorporation of ibuprofen in NLC. Quality by Design (QbD) approach was successfully implemented in developing a robust ophthalmic formulation with superior physicochemical and morphometric properties. NLCs as the nanocarrier demonstrated promising perspective for topical delivery of poorly water-soluble drugs.

Assessment of the environmental fate and effects of azilsartan, a selective antagonist of angiotensin II type 1.

PubMed

Weltman, R; Brands, C M J; Corral, E; Desmares-Koopmans, M J E; Migchielsen, M H J; Oudhoff, K A; de Roode, D F

2012-06-01

In this paper the results of a thorough evaluation of the environmental fate and effects of azilsartan are presented. Azilsartan medoxomil is administered as a pro-drug for the treatment of patients with essential hypertension. The pro-drug is converted by hydrolysis to the active pharmaceutical ingredient azilsartan. Laboratory tests to evaluate the environmental fate and effects of azilsartan medoxomil were conducted with azilsartan and performed in accordance with OECD test guidelines. The predicted environmental concentration (PEC) in surface water was estimated at 0.32 μg L(-1) (above the action limit of 0.01 μg L(-1)), triggering a Phase II assessment. Azilsartan is not readily biodegradable. Results of the water sediment study demonstrated significant shifting of azilsartan metabolites to sediment. Based on the equilibrium partitioning method, metabolites are unlikely to pose a risk to sediment-dwelling organisms. Ratios of the predicted environmental concentrations (PECs) to the predicted-no-effect concentrations (PNECs) did not exceed the relevant triggers, and the risk to aquatic, sewage treatment plant (STP), groundwater and sediment compartments was concluded acceptable. A terrestrial assessment was not triggered. Azilsartan poses an acceptable risk to the environment. Copyright © 2012 Elsevier Ltd. All rights reserved.

Azilsartan as a Potent Antihypertensive Drug with Possible Pleiotropic Cardiometabolic Effects: A Review Study

PubMed Central

Georgiopoulos, Georgios; Katsi, Vasiliki; Oikonomou, Dimitrios; Vamvakou, Georgia; Koutli, Evangelia; Laina, Aggeliki; Tsioufis, Constantinos; Nihoyannopoulos, Petros; Tousoulis, Dimitrios

2016-01-01

Background: Hypertension related cardiovascular (CV) complications could be amplified by the presence of metabolic co-morbidities. Azilsartan medoxomil (AZL-M) is the eighth approved member of angiotensin II receptor blockers (ARBs), a drug class of high priority in the management of hypertensive subjects with diabetes mellitus type II (DMII). Methods: Under this prism, we performed a systematic review of the literature for all relevant articles in order to evaluate the efficacy, safety, and possible clinical role of AZL-M in hypertensive diabetic patients. Results: AZL-M was found to be more effective in terms of reducing indices of blood pressure over alternative ARBs or angiotensin-converting enzyme (ACE) inhibitors with minimal side effects. Preclinical studies have established pleiotropic effects for AZL-M beyond its primary antihypertensive role through differential gene expression, up-regulation of membrane receptors and favorable effect on selective intracellular biochemical and pro-atherosclerotic pathways. Conclusion: Indirect but accumulating evidence from recent literature supports the efficacy and safety of AZL-M among diabetic patients. However, no clinical data exist to date that evince a beneficial role of AZL-M in patients with metabolic disorders on top of its antihypertensive effect. Further clinical studies are warranted to assess the pleiotropic cardiometabolic benefits of AZL-M that are derived from preclinical research. PMID:27536242

Azilsartan as a Potent Antihypertensive Drug with Possible Pleiotropic Cardiometabolic Effects: A Review Study.

PubMed

Georgiopoulos, Georgios; Katsi, Vasiliki; Oikonomou, Dimitrios; Vamvakou, Georgia; Koutli, Evangelia; Laina, Aggeliki; Tsioufis, Constantinos; Nihoyannopoulos, Petros; Tousoulis, Dimitrios

2016-01-01

Hypertension related cardiovascular (CV) complications could be amplified by the presence of metabolic co-morbidities. Azilsartan medoxomil (AZL-M) is the eighth approved member of angiotensin II receptor blockers (ARBs), a drug class of high priority in the management of hypertensive subjects with diabetes mellitus type II (DMII). Under this prism, we performed a systematic review of the literature for all relevant articles in order to evaluate the efficacy, safety, and possible clinical role of AZL-M in hypertensive diabetic patients. AZL-M was found to be more effective in terms of reducing indices of blood pressure over alternative ARBs or angiotensin-converting enzyme (ACE) inhibitors with minimal side effects. Preclinical studies have established pleiotropic effects for AZL-M beyond its primary antihypertensive role through differential gene expression, up-regulation of membrane receptors and favorable effect on selective intracellular biochemical and pro-atherosclerotic pathways. Indirect but accumulating evidence from recent literature supports the efficacy and safety of AZL-M among diabetic patients. However, no clinical data exist to date that evince a beneficial role of AZL-M in patients with metabolic disorders on top of its antihypertensive effect. Further clinical studies are warranted to assess the pleiotropic cardiometabolic benefits of AZL-M that are derived from preclinical research.

Hypothesis testing for the validation of the kinetic spectrophotometric methods for the determination of lansoprazole in bulk and drug formulations via Fe(III) and Zn(II) chelates.

PubMed

Rahman, Nafisur; Kashif, Mohammad

2010-03-01

Point and interval hypothesis tests performed to validate two simple and economical, kinetic spectrophotometric methods for the assay of lansoprazole are described. The methods are based on the formation of chelate complex of the drug with Fe(III) and Zn(II). The reaction is followed spectrophotometrically by measuring the rate of change of absorbance of coloured chelates of the drug with Fe(III) and Zn(II) at 445 and 510 nm, respectively. The stoichiometric ratio of lansoprazole to Fe(III) and Zn(II) complexes were found to be 1:1 and 2:1, respectively. The initial-rate and fixed-time methods are adopted for determination of drug concentrations. The calibration graphs are linear in the range 50-200 µg ml⁻¹ (initial-rate method), 20-180 µg ml⁻¹ (fixed-time method) for lansoprazole-Fe(III) complex and 120-300 (initial-rate method), and 90-210 µg ml⁻¹ (fixed-time method) for lansoprazole-Zn(II) complex. The inter-day and intra-day precision data showed good accuracy and precision of the proposed procedure for analysis of lansoprazole. The point and interval hypothesis tests indicate that the proposed procedures are not biased. Copyright © 2010 John Wiley & Sons, Ltd.

Benefits of nanoencapsulation for the hypercin-mediated photodetection of ovarian micrometastases.

PubMed

Zeisser-Labouèbe, Magali; Delie, Florence; Gurny, Robert; Lange, Norbert

2009-02-01

The high recurrence and lethality of ovarian cancer at advanced stages is problematic, especially due to the development of numerous micrometastases scattered throughout the abdominal cavity. Fluorescence photodetection (PD) used in combination with surgical resection of malignant tissues has been suggested to improve recovery. Based on promising in vivo results for the detection of bladder cancer, hypericin (Hy), a natural photosensitizer (PS), stands as a good candidate for the photodetection of ovarian cancer. However, due to its hydrophobicity, systemic administration of Hy is problematic. Polymeric nanoparticles (NPs) help to overcome these delivery and stability problems and enable intravenous administration of Hy. In this study, Hy-loaded NPs of polylactic acid were produced with the following properties: (i) mean size of 268 nm, (ii) negative zeta potential, (iii) low residual surfactant and (iv) drug loading of 3.7 % (w/w). The potential of hypericin-loaded nanoparticles for the fluorescence photodetection of ovarian metastases in Fischer 344 rats bearing ovarian tumours was compared to free drug. The selectivity of Hy administered with both formulations was assessed first by fluorescence endoscopy, and then quantified after tissue extraction. The results showed an improved selective accumulation of Hy in ovarian micrometastases when NPs were used.

[Poisons of DNA topoisomerases I and II].

PubMed

Charcosset, J Y; Soues, S; Laval, F

1993-11-01

Over the past decade, DNA topoisomerase I and II appeared to be the targets of some antitumor agents: CPT-11 and Topotecan derived from Camptothecin which interact with topoisomerase I; Actinomycin D, Adriamycin and Daunorubicin, Elliptinium Acetate, Mitoxantrone, Etoposide and Teniposide, Amsacrine which interact with topoisomerase II. The multiple functions of these enzymes are important as they play a role during replication, transcription, recombination, repair and chromatine organisation. Particularly, they relax torsional constraints which appear when intertwined DNA strands are separated while replication fork or RNA polymerases are moving. To some extent, topoisomerase I and II are structurally and functionally different. Moreover, topoisomerase I is not indispensable for a living cell whereas topoisomerase II is. Drug-topoisomerase interaction which probably leads to antitumoral effect of the compounds studied in this review is not a trivial inhibition of the enzyme but rather a poisoning due to stabilization of cleavable complexes between the enzyme and DNA. These stabilized complexes are likely to induce apoptosis-like programmed cell death, which is characterised by DNA fragmentation. However, it appears that it is the collision of the replication fork with the drug-stabilized cleavable complex that is responsible for the cytotoxicity of the drug: poisoning of topoisomerases by antitumor agents leads to a new concept of "dynamic toxicity". Although they interact with a common target, topoisomerase II poisons have differential effects on macromolecules syntheses, cell cycle and chromosome fragmentation; a few compounds may produce free radicals. Because of these differential effects in addition to quantitative and qualitative variations of stabilized cleavable complexes, in particular DNA sequences on which topoisomerase II is stabilized, these antitumor agents do not resemble each other. Cellular resistance to topoisomerases poisons results of two principal types of alteration: target and/or drug transport modification. Decreased ability to form the cleavable complex in resistant cells may be the consequence of both decreased amount of topoisomerase or altered enzyme. On the other hand, overexpression of membrane P-glycoprotein, which pumps drugs out of the cell by an energy dependent process provokes a decreased accumulation of these drugs. Cross resistances to other drugs are mainly under control of these two different mechanisms of resistance. A complete knowledge of their individual effects and mechanisms of resistance would allow a better clinical use of topoisomerases poisons, especially when administered in combination chemotherapy.

Restrained management of copper level enhances the antineoplastic activity of imatinib in vitro and in vivo.

PubMed

Hassan, Iftekhar; Khan, Azmat Ali; Aman, Shazia; Qamar, Wajhul; Ebaid, Hossam; Al-Tamimi, Jameel; Alhazza, Ibrahim M; Rady, Ahmed M

2018-01-26

The present study was designed to investigate if elevated copper level can be targeted to enhance the efficacy of a significant anticancer drug, imatinib (ITB). The antineoplastic activity of this drug was assessed in the HepG2, HEK-293, MCF-7 and MDA-MD-231 cells targeting elevated copper level as their common drug target. The cell lines were treated with the different doses of copper chloride (Cu II) and disulfiram (DSF) alone as well as in their combinations with the drug for 24 h in standard culture medium and conditions. The treated cells were subjected to various assays including MTT, PARP, p-53, caspase-7, caspase-3, LDH and single cell electrophoresis. The study shows that DSF and Cu (II) synergizes the anticancer activity of ITB to a significant extent in a dose-specific way as evidenced by the combinations treated groups. Furthermore, the same treatment strategy was employed in cancer-induced rats in which the combinations of ITB-DSF and ITB-Cu II showed enhanced antineoplastic activity as compared to ITB alone. However, DSF was more effective than Cu (II) as an adjuvant to the drug. Hence, restrained manipulation of copper level in tumor cells can orchestrate the redox and molecular dispositions inside the cells favoring the induction of apoptosis.

The role of arsenic in the hydrolysis and DNA metalation processes in an arsenous acid-platinum(ii) anticancer complex.

PubMed

Marino, T; Parise, A; Russo, N

2017-01-04

Platinum(ii)-based molecules are the most commonly used anticancer drugs in the chemotherapeutic treatment of tumours but possess serious side effects and some cancer types exhibit resistance with respect to these compounds (e.g. cisplatin). For these reasons, the research of new compounds that can bypass this limitation is in continuous development. Recently, mixed Pt(ii)-As(iii) systems have been synthesized and tested as potential anticancer agents. The mechanism of action of these kinds of drugs is unclear. Since in other platinum(ii) containing drugs, hydrolysis plays an important role in the activation of the compound before it reaches DNA, we have explored the aquation process using density functional theory (DFT), focusing our attention on the arsenoplatin complex, [Pt(μ-NHC(CH 3 )O) 2 ClAs(OH) 2 ]. As DNA is believed to be the cellular target for Pt anticancer drugs, the metalation mechanism of DNA purine bases has been also investigated. Also for this new drug it appears that guanine is the preferred site with respect to adenine as with other platinum-containing compounds. A comparison with cisplatin is performed in order to highlight the contribution of arsenic in the anticancer activity of this new proposed anticancer agent.

76 FR 10067 - Importer of Controlled Substances; Notice of Application

Federal Register 2010, 2011, 2012, 2013, 2014

2011-02-23

... this Section to a bulk manufacturer of a controlled substance in schedule I or II, and prior to issuing... Manufacturing LLC., 3500 Dekalb Street, St. Louis, Missouri 63118, made application by renewal to the Drug...) I Amphetamine (1100) II Methamphetamine (1105) II Methylphenidate (1724) II Amobarbital (2125) II...

Three-dimensional structures in the design of therapeutics targeting parasitic protozoa: reflections on the past, present and future.

PubMed

Hol, Wim G J

2015-05-01

Parasitic protozoa cause a range of diseases which threaten billions of human beings. They are responsible for tremendous mortality and morbidity in the least-developed areas of the world. Presented here is an overview of the evolution over the last three to four decades of structure-guided design of inhibitors, leads and drug candidates aiming at targets from parasitic protozoa. Target selection is a crucial and multi-faceted aspect of structure-guided drug design. The major impact of advances in molecular biology, genome sequencing and high-throughput screening is touched upon. The most advanced crystallographic techniques, including XFEL, have already been applied to structure determinations of drug targets from parasitic protozoa. Even cryo-electron microscopy is contributing to our understanding of the mode of binding of inhibitors to parasite ribosomes. A number of projects have been selected to illustrate how structural information has assisted in arriving at promising compounds that are currently being evaluated by pharmacological, pharmacodynamic and safety tests to assess their suitability as pharmaceutical agents. Structure-guided approaches are also applied to incorporate properties into compounds such that they are less likely to become the victim of resistance mechanisms. A great increase in the number of novel antiparasitic compounds will be needed in the future. These should then be combined into various multi-compound therapeutics to circumvent the diverse resistance mechanisms that render single-compound, or even multi-compound, drugs ineffective. The future should also see (i) an increase in the number of projects with a tight integration of structural biology, medicinal chemistry, parasitology and pharmaceutical sciences; (ii) the education of more `medicinal structural biologists' who are familiar with the properties that compounds need to have for a high probability of success in the later steps of the drug-development process; and (iii) the expansion of drug-development capabilities in middle- and low-income countries.

Three-dimensional structures in the design of therapeutics targeting parasitic protozoa: reflections on the past, present and future

PubMed Central

Hol, Wim G. J.

2015-01-01

Parasitic protozoa cause a range of diseases which threaten billions of human beings. They are responsible for tremendous mortality and morbidity in the least-developed areas of the world. Presented here is an overview of the evolution over the last three to four decades of structure-guided design of inhibitors, leads and drug candidates aiming at targets from parasitic protozoa. Target selection is a crucial and multi-faceted aspect of structure-guided drug design. The major impact of advances in molecular biology, genome sequencing and high-throughput screening is touched upon. The most advanced crystallographic techniques, including XFEL, have already been applied to structure determinations of drug targets from parasitic protozoa. Even cryo-electron microscopy is contributing to our understanding of the mode of binding of inhibitors to parasite ribosomes. A number of projects have been selected to illustrate how structural information has assisted in arriving at promising compounds that are currently being evaluated by pharmacological, pharmacodynamic and safety tests to assess their suitability as pharmaceutical agents. Structure-guided approaches are also applied to incorporate properties into compounds such that they are less likely to become the victim of resistance mechanisms. A great increase in the number of novel antiparasitic compounds will be needed in the future. These should then be combined into various multi-compound therapeutics to circumvent the diverse resistance mechanisms that render single-compound, or even multi-compound, drugs ineffective. The future should also see (i) an increase in the number of projects with a tight integration of structural biology, medicinal chemistry, parasitology and pharmaceutical sciences; (ii) the education of more ‘medicinal structural biologists’ who are familiar with the properties that compounds need to have for a high probability of success in the later steps of the drug-development process; and (iii) the expansion of drug-development capabilities in middle- and low-income countries. PMID:25945701

A plant cell-based system that predicts aβ42 misfolding: potential as a drug discovery tool for Alzheimer's disease.

PubMed

Zhao, Tiehan; Zeng, Ying; Kermode, Allison R

2012-11-01

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the accumulation of amyloid β (Aβ) peptides and the failure of mechanisms to clear toxic aggregates. The Aβ42 peptide is considered to be a causative factor that underlies the pathophysiology of AD, in part due to its propensity for misfolding and aggregation; the small oligomers that result represent toxic species. Thus agents that prevent Aβ42 misfolding/aggregation or, alternatively improve Aβ42 oligomer clearance, may have significant therapeutic value. We have developed the basis for a drug screening system based on transgenic plant cells that express Aβ42 fusion proteins to serve as the reliable indicators of the general conformational status of Aβ42. Within cells of transgenic tobacco and Nicotiana benthamiana, misfolding of Aβ42 causes the misfolding of a GFP fusion partner, and consequently there is a loss of fluorescence associated with the native GFP protein. In a similar fusion consisting of Aβ42 linked to hygromycin phosphotransferase II (Hpt II), a hygromycin-resistance marker, misfolding of Aβ42 leads to a misfolded Hpt II, and consequently the transgenic cells are unable to grow on media containing hygromycin. Importantly, substitution of the 'aggregation-prone' Aβ42 with a missense mutant of Aβ42 (F19S/L34F) that is not prone to misfolding/aggregation, 'rescues' both fusion partners. Several 'positive control' chemicals that represent inhibitors of Aβ42 aggregation, including curcumin, epigallocatechin-3-gallate (EGCG), and resveratrol show efficacy in preventing the Aβ42-fusion proteins from misfolding/aggregating in the transgenic plant cells. We discuss the potential of the two fusion protein systems to serve as the basis for an inexpensive, selective, and efficient screening system in which a plant cell can fluoresce or survive only in the presence of drug candidates that are able to prevent Aβ42 misfolding/aggregation. Copyright © 2012 Elsevier Inc. All rights reserved.

Clinical trials in drug development: a minimalistic approach.

PubMed

Verweij, Jaap

2012-05-01

Drug development in oncology finds itself at the crossroad of unique opportunities and major challenges. The old paradigms should and can be replaced by a system that better matches the right patients to the right compounds and puts much more emphasis on the early stages of drug development. The clinical phases of drug development will no longer be split into phase I, II, and III studies, but rather into 'functional target pharmacology studies', followed by 'proof of concept studies'. The resulting development flow becomes Apollo-capsule shaped. Although randomized studies will still be needed for drugs using targets in the tumor environment, or for combinations of agents, drug registration might proceed without these if all of the following criteria are met in early development: availability of preclinical convincing evidence that the drug's target is the functional driver behind the disease phenotype, availability of a predictive biomarker that enables appropriate and actual patient selection in early pharmacology studies, a Response Evaluation Criteria In Solid Tumors (RECIST)-based single agent response rate of at least 50%, and/or a progression at first tumor assessment rate of 15% or less, a duration of absence of progression (stable disease) beyond doubt and considered clinically relevant, and no major safety concern. This set is not yet mature, but may be adapted over time. The concerns related to registering agents on the basis of small datasets can be adequately addressed by obligatory postmarketing hypothesis driven studies.

Amorphization strategy affects the stability and supersaturation profile of amorphous drug nanoparticles.

PubMed

Cheow, Wean Sin; Kiew, Tie Yi; Yang, Yue; Hadinoto, Kunn

2014-05-05

Amorphous drug nanoparticles have recently emerged as a promising bioavailability enhancement strategy of poorly soluble drugs attributed to the high supersaturation solubility generated by the amorphous state and fast dissolution afforded by the nanoparticles. Herein we examine the effects of two amorphization strategies in the nanoscale, i.e., (1) molecular mobility restrictions and (2) high energy surface occupation, both by polymer excipient stabilizers, on the (i) morphology, (ii) colloidal stability, (iii) drug loading, (iv) amorphous state stability after three-month storage, and (v) in vitro supersaturation profiles, using itraconazole (ITZ) as the model drug. Drug-polyelectrolyte complexation is employed in the first strategy to prepare amorphous ITZ nanoparticles using dextran sulfate as the polyelectrolyte (ITZ nanoplex), while the second strategy employs pH-shift precipitation using hydroxypropylmethylcellulose as the surface stabilizer (nano-ITZ), with both strategies resulting in >90% ITZ utilization. Both amorphous ITZ nanoparticles share similar morphology (∼300 nm spheres) with the ITZ nanoplex exhibiting better colloidal stability, albeit at lower ITZ loading (65% versus 94%), due to the larger stabilizer amount used. The ITZ nanoplex also exhibits superior amorphous state stability, attributed to the ITZ molecular mobility restriction by electrostatic complexation with dextran sulfate. The higher stability, however, is obtained at the expense of slower supersaturation generation, which is maintained over a prolonged period, compared to the nano-ITZ. The present results signify the importance of selecting the optimal amorphization strategy, in addition to formulating the excipient stabilizers, to produce amorphous drug nanoparticles having the desired characteristics.

Evaluation of various dissolution media for predicting in vivo performance of class I and II drugs.

PubMed

Galia, E; Nicolaides, E; Hörter, D; Löbenberg, R; Reppas, C; Dressman, J B

1998-05-01

In this paper we seek to verify the differences in dissolution behavior between class I and class II drugs and to evaluate the suitability of two new physiologically based media, of Simulated Gastric Fluid (SGF) and of milk for their ability to forecast trends in the in vivo performance of class II compounds and their formulations. Dissolution behavior of two class I drugs, i.e. acetaminophen and metoprolol, and of three class II drugs, i.e. danazol, mefenamic acid and ketoconazole, was studied with USP Apparatus 2 in water, SGF, milk, Simulated Intestinal Fluid without pancreatin (SIFsp) and in two media simulating the small intestinal contents in the fed (FeSSIF) and fasted (FaSSIF) states, respectively. Class I powders dissolved rapidly in all media tested. Acetaminophen dissolution in milk was slow from one tablet formulation, in all other cases dissolution was more than 85% complete in 15 minutes. The dissolution rate of metoprolol was shown to be dependent on formulation and manufacturing method, and one of the three tablet formulations did not meet compendial specifications (80%/30 minutes). Dissolution behavior of class II drugs was greatly affected by choice of medium. Dissolution from a capsule formulation of danazol proved to be dependent on the concentration of solubilizing agents, with a the 30-fold increase in percentage dissolved within 90 minutes upon changing from aqueous media without surfactants to FaSSIF. Use of FeSSIF or milk as the dissolution medium resulted in an even greater increase in percentage dissolved, 100 and 180-fold respectively. Dissolution of the weak acid mefenamic acid from a capsule formulation is dependent on both pH and bile salt concentration, which leads to an offset between increased bile salt concentration and lower pH in the fed state compared to the fasted state medium. The weak base ketoconazole showed complete dissolution from a tablet formulation in Simulated Gastric Fluid without pepsin (SGFsp) within 30 minutes, 70% dissolution in 2 hours under fed state simulated upper jejunal conditions but only 6% dissolution in 2 hours under fasted state conditions. As predicted, dissolution of class II drugs proved to be in general much more dependent on the medium than class I drugs. With the array of compendial and physiological media available, it should be possible to design a suitable set of tests to predict the in vivo dissolution of both class I and II drugs from immediate release formulations.

SC lipid model membranes designed for studying impact of ceramide species on drug diffusion and permeation--part II: diffusion and permeation of model drugs.

PubMed

Ochalek, M; Podhaisky, H; Ruettinger, H-H; Wohlrab, J; Neubert, R H H

2012-10-01

The barrier function of two quaternary stratum corneum (SC) lipid model membranes, which were previously characterized with regard to the lipid organization, was investigated based on diffusion studies of model drugs with varying lipophilicities. Diffusion experiments of a hydrophilic drug, urea, and more lipophilic drugs than urea (i.e. caffeine, diclofenac sodium) were conducted using Franz-type diffusion cells. The amount of permeated drug was analyzed using either HPLC or CE technique. The subjects of interest in the present study were the investigation of the influence of physicochemical properties of model drugs on their diffusion and permeation through SC lipid model membranes, as well as the study of the impact of the constituents of these artificial systems (particularly ceramide species) on their barrier properties. The diffusion through both SC lipid model membranes and the human SC of the most hydrophilic model drug, urea, was faster than the permeation of the more lipophilic drugs. The slowest rate of permeation through SC lipid systems occurred in the case of caffeine. The composition of SC lipid model membranes has a significant impact on their barrier function. Model drugs diffused and permeated faster through Membrane II (presence of Cer [EOS]). In terms of the barrier properties, Membrane II is much more similar to the human SC than Membrane I. Copyright © 2012 Elsevier B.V. All rights reserved.

Structure of the Angiotensin Receptor Revealed by Serial Femtosecond Crystallography

DOE PAGES

Zhang, Haitao; Unal, Hamiyet; Gati, Cornelius; ...

2015-05-07

We report that angiotensin II type 1 receptor (AT 1R) is a G protein-coupled receptor that serves as a primary regulator for blood pressure maintenance. Although several anti-hypertensive drugs have been developed as AT 1R blockers (ARBs), the structural basis for AT 1R ligand-binding and regulation has remained elusive, mostly due to the difficulties of growing high quality crystals for structure determination using synchrotron radiation. By applying the recently developed method of serial femtosecond crystallography at an X-ray free-electron laser, we successfully determined the room-temperature crystal structure of the human AT 1R in complex with its selective antagonist ZD7155 atmore » 2.9 Å resolution. The AT 1R-ZD7155 complex structure revealed key structural features ofAT 1R and critical interactions for ZD7155 binding. Finally, docking simulations of the clinically used ARBs into the AT 1R structure further elucidated both the common and distinct binding modes for these anti-hypertensive drugs. Our results thereby provide fundamental insights into AT 1R structure-function relationship and structure-based drug design.« less

Optimization of non-linear gradient in hydrophobic interaction chromatography for the analytical characterization of antibody-drug conjugates.

PubMed

Bobály, Balázs; Randazzo, Giuseppe Marco; Rudaz, Serge; Guillarme, Davy; Fekete, Szabolcs

2017-01-20

The goal of this work was to evaluate the potential of non-linear gradients in hydrophobic interaction chromatography (HIC), to improve the separation between the different homologous species (drug-to-antibody, DAR) of commercial antibody-drug conjugates (ADC). The selectivities between Brentuximab Vedotin species were measured using three different gradient profiles, namely linear, power function based and logarithmic ones. The logarithmic gradient provides the most equidistant retention distribution for the DAR species and offers the best overall separation of cysteine linked ADC in HIC. Another important advantage of the logarithmic gradient, is its peak focusing effect for the DAR0 species, which is particularly useful to improve the quantitation limit of DAR0. Finally, the logarithmic behavior of DAR species of ADC in HIC was modelled using two different approaches, based on i) the linear solvent strength theory (LSS) and two scouting linear gradients and ii) a new derived equation and two logarithmic scouting gradients. In both cases, the retention predictions were excellent and systematically below 3% compared to the experimental values. Copyright © 2016 Elsevier B.V. All rights reserved.

Structure of the Angiotensin Receptor Revealed by Serial Femtosecond Crystallography

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

Zhang, Haitao; Unal, Hamiyet; Gati, Cornelius

We report that angiotensin II type 1 receptor (AT 1R) is a G protein-coupled receptor that serves as a primary regulator for blood pressure maintenance. Although several anti-hypertensive drugs have been developed as AT 1R blockers (ARBs), the structural basis for AT 1R ligand-binding and regulation has remained elusive, mostly due to the difficulties of growing high quality crystals for structure determination using synchrotron radiation. By applying the recently developed method of serial femtosecond crystallography at an X-ray free-electron laser, we successfully determined the room-temperature crystal structure of the human AT 1R in complex with its selective antagonist ZD7155 atmore » 2.9 Å resolution. The AT 1R-ZD7155 complex structure revealed key structural features ofAT 1R and critical interactions for ZD7155 binding. Finally, docking simulations of the clinically used ARBs into the AT 1R structure further elucidated both the common and distinct binding modes for these anti-hypertensive drugs. Our results thereby provide fundamental insights into AT 1R structure-function relationship and structure-based drug design.« less

Pharmacological interactions of anti-inflammatory-analgesics in odontology.

PubMed

Gómez-Moreno, Gerardo; Guardia, Javier; Cutando, Antonio; Calvo-Guirado, José Luis

2009-02-01

In this second article we describe the more interesting pharmacological interactions in dental practice based on the prescription of analgesic narcotics, paracetamol and non-selective non-steroid anti-inflammatory drugs (NSAI) (which inhibit cyclooxigenase 1 -COX 1- and cyclooxigenase 2 -COX 2-) and selective NSAIs (COX 2 inhibitors). The importance of preventing the appearance of these pharmacological interactions is because these are medicaments prescribed daily in odontology for moderate pain treatment and inflammation in the oral cavity. Paracetamol can interact with warfarin and therefore care should be taken with chronic alcoholic patients. All NSAIs reduce renal blood flow and consequently are capable of reducing the efficacy of medicaments used for treating arterial hypertension, which act via a renal mechanism. Especial attention should be taken considering the risk of interaction between the antagonists of AT1 receptors of angiostensin II (ARAII) and the NSAIs.

Evaluation of new gastro-intestinal prokinetic (ENGIP-II) study.

PubMed

Walwaikar, Pradeep P; Kulkarni, Sujay S; Bargaje, Rahul S

2005-12-01

Non-ulcer dyspepsia is a common clinical disorder characterised by reduced gastric motility. Safety concerns have restricted use of currently available prokinetic drugs. Itopride is a new safer prokinetic drug with dopamine D2 antagonism and acetylcholinesterase inhibitory actions. The ENGIP-II study was conducted to investigate the efficacy, and safety of itopride in patients of non-ulcer dyspepsia. There were significant reductions in upper abdominal pain, heartburn frequency, gastro-oesophageal regurgitation, nausea, bloating, early satiety after meals at day 3 only; whereas significant improvements were noted in belching, anorexia at day 6 and in vomiting at day 9. Thus, ENGIP-II study shows that itopride was well tolerated patients and appears to be the drug of choice in patients with non-ulcer dyspepsia.

Electrochemistry-mass spectrometry for in-vitro determination of selected chemotherapeutics and their electrochemical products in comparison to in-vivo approach.

PubMed

Szultka-Mlynska, Malgorzata; Buszewski, Boguslaw

2016-11-01

Chemotherapeutics are among the most frequently prescribed medications in modern medicine. They are widely prescribed; however, problems with organisms developing resistance to these drugs means that their efficacy may be lost, so care should be taken to avoid unnecessary prescription. It is therefore of great interest to study the detailed metabolism of these biologically active compounds. This study aimed at developing an efficient analytical protocol for the determination of in-vitro electrochemical products of selected antibiotic drugs (amoxicillin, cefotaxime, fluconazole, linezolid, metronidazole and moxifloxacin). Combination of electrochemistry (EC) and mass spectrometry (MS) was applied for the in-vitro determination of the studied antibiotics and their electrochemical products. To identify the structure of the detected electrochemical products, MS/MS experiments were performed. This was one of the first applications of the EC system for generation of electrochemical products produced from antibiotic drugs. Adjustment of appropriate conditions and such parameters as the potential value, mobile phase (pH), working electrode and temperature had significant influence on electrochemical simulations and the creation of selected derivatives. Consequently, several working electrodes were evaluated for this purpose. In most of the studied cases, mainly two types of products were observed. One corresponded to an increase in mass by 14Da, which can be explained by a process consisting of oxidation (+16 m/z) and dehydrogenation (-2 m/z); The second in turn showed mass reduction by 14Da, which can be attributed to the loss of -CH2 as a result of N-demethylation. The performed experiments consisted of two stages: electrochemical oxidation of the analyzed samples (phase I of metabolic transformation), and addition of glutathione (GSH) for follow-up reactions (phase II conjunction). The electrochemical results were compared to in-vivo experiments by analyzing urine samples from patients after antibiotic drugs have been administered.. Overall, the comparison of electrochemistry to in-vivo experiments shows the high potential of EC-MS as a fast analytical tool in the prediction of electrochemical conversion that could be applied to therapeutic drug monitoring and pharmacokinetic studies as well. Copyright © 2016 Elsevier B.V. All rights reserved.

Differentiation in the angiotensin II receptor 1 blocker class on autonomic function.

PubMed

Krum, H

2001-09-01

Autonomic function is disordered in cardiovascular disease states such as chronic heart failure (CHF) and hypertension. Interactions between the renin-angiotensin-aldosterone system (RAAS) and the sympathetic nervous system (SNS) may potentially occur at a number of sites. These include central sites (eg, rostral ventrolateral medulla), at the level of baroreflex control, and at the sympathetic prejunctional angiotensin II receptor 1 (AT(1)) receptor, which is facilitatory for norepinephrine release from the sympathetic nerve terminal. Therefore, drugs that block the RAAS may be expected to improve autonomic dysfunction in cardiovascular disease states. In order to test the hypothesis that RAAS inhibition directly reduces SNS activity, a pithed rat model of sympathetic stimulation has been established. In this model, an increase in frequency of stimulation results in a pressor response that is sympathetically mediated and highly reproducible. This pressor response is enhanced in the presence of angiotensin II and is reduced in the presence of nonselective AIIRAs that block both AT(1) and AT(2) receptor subtypes (eg, saralasin). AT(1)-selective antagonists have also been studied in this model, at pharmacologically relevant doses. In one such study, only the AT(1) blocker eprosartan reduced sympathetically stimulated increases in blood pressure, whereas comparable doses of losartan, valsartan, and irbesartan did not. The reason(s) for the differences between eprosartan and other agents of this class on sympathetic modulation are not clear, but may relate to the chemical structure of the drug (a non- biphenyl tetrazole structure that is chemically distinct from the structure of other AIIRAs), receptor binding characteristics (competitive), or unique effects on presynaptic AT(1) receptors.

A new promising simultaneous approach for attenuating type II diabetes mellitus induced neuropathic pain in rats: iNOS inhibition and neuroregeneration.

PubMed

Ahlawat, Abhilasha; Sharma, Saurabh

2018-01-05

In view of the pathologic basis for the treatment of diabetic neuropathy, it is important to enhance nerve regeneration as well as prevent nerve degeneration. So, in the present study, we have investigated the effect of S-Methylisothiourea Sulfate (selective iNOS inhibitor) and Citicoline, alone and in combination, on Type II diabetes mellitus induced neuropathic pain in wistar rats. Type II diabetes was induced by providing high fat diet and low dose of Streptozotocin for 35 days in rats. Type II diabetes mellitus was assessed in terms of increased glucose, triglycerides, cholesterol, LDL levels, glucose tolerance and decrease in HDL levels. Neuropathy as the complication of type II diabetes was assessed in terms of decreased nerve conduction velocity, mechanical and thermal hyperalgesia and cold allodynia. Oxidative stress was assessed in sciatic nerve and showed increase in LPO and nitrite levels whereas decrease was shown in GSH and catalase activity. Axonal degeneration marked by nerve fibre dearrangement and demyelination was observed in histopathological studies. SMT (iNOS inhibitor), Citicoline and low dose combination of both drugs significantly attenuates the diabetic neuropathic pain assessed in terms of parameters employed. Thus, it may be concluded that simultaneous administration of SMT and Citicoline may provide potential therapeutics for diabetic neuropathic pain. Copyright © 2017 Elsevier B.V. All rights reserved.

Designing of Protein Kinase C β-II Inhibitors against Diabetic complications: Structure Based Drug Design, Induced Fit docking and analysis of active site conformational changes

PubMed Central

Vijayakumar, Balakrishnan; Velmurugan, Devadasan

2012-01-01

Protein Kinase C β-II (PKC β-II) is an important enzyme in the development of diabetic complications like cardiomyopathy, retinopathy, neuropathy, nephropathy and angiopathy. PKC β-II is activated in vascular tissues during diabetic vascular abnormalities. Thus, PKC β-II is considered as a potent drug target and the crystal structure of the kinase domain of PKC β-II (PDB id: 2I0E) was used to design inhibitors using Structure-Based Drug Design (SBDD) approach. Sixty inhibitors structurally similar to Staurosporine were retrieved from PubChem Compound database and High Throughput Virtual screening (HTVs) was carried out with PKC β-II. Based on the HTVs results and the nature of active site residues of PKC β-II, Staurosporine inhibitors were designed using SBDD. Induced Fit Docking (IFD) studies were carried out between kinase domain of PKC β-II and the designed inhibitors. These IFD complexes showed favorable docking score, glide energy, glide emodel and hydrogen bond and hydrophobic interactions with the active site of PKC β-II. Binding free energy was calculated for IFD complexes using Prime MM-GBSA method. The conformational changes induced by the inhibitor at the active site of PKC β-II were observed for the back bone Cα atoms and side-chain chi angles. PASS prediction tool was used to analyze the biological activities for the designed inhibitors. The various physicochemical properties were calculated for the compounds. One of the designed inhibitors successively satisfied all the in silico parameters among the others and seems to be a potent inhibitor against PKC β-II. PMID:22829732

New treatments for the motor symptoms of Parkinson's disease.

PubMed

Vijverman, Anne-Catherine; Fox, Susan H

2014-11-01

Levodopa remains the most potent drug to treat motor symptoms in Parkinson's disease (PD); however, motor fluctuations and levodopa-induced dyskinesia that occur with long-term use restrict some of its therapeutic value. Despite these limitations, the medical treatment of PD strives for continuous relief of symptoms using different strategies throughout the course of the illness: increasing the half-life of levodopa, using 'levodopa-sparing agents' and adding non-dopaminergic drugs. New options to 'improve' delivery of levodopa are under investigation, including long-acting levodopa, nasal inhalation and continuous subcutaneous or intrajejunal administration of levodopa. Long-acting dopamine agonists were recently developed and are undergoing further comparative studies to investigate potential superiority over the immediate-release formulations. Non-dopaminergic drugs acting on adenosine receptors, cholinergic, adrenergic, serotoninergic and glutamatergic pathways are newly developed and many are being evaluated in Phase II and Phase III trials. This article focuses on promising novel therapeutic approaches for the management of PD motor symptoms and motor complications. We will provide an update since 2011 on new formulations of current drugs, new drugs with promising results in Phase II and Phase III clinical trials, old drugs with new possibilities and some new potential strategies that are currently in Phase I and II of development (study start date may precede 2011 but are included as study is still ongoing or full data have not yet been published). Negative Phase II and Phase III clinical trials published since 2011 will also be briefly mentioned.

Statins, the renin-angiotensin-aldosterone system and hypertension - a tale of another beneficial effect of statins.

PubMed

Drapala, Adrian; Sikora, Mariusz; Ufnal, Marcin

2014-09-01

Statins, a class of lipid lowering drugs, decrease mortality associated with cardiovascular events. As hypercholesterolemia is often accompanied by hypertension, a large number of patients receive therapy with statins and antihypertensive drugs which act via the renin-angiotensin-aldosterone system (RAAS). New guidelines published by the American Heart Association and American College of Cardiology on the treatment of dyslipidaemia and the reduction of atherosclerotic cardiovascular risk, which use a risk prediction algorithm based on risk factors such as hypertension but not low-density lipoprotein (LDL) level, may even further increase the number of patients receiving such concomitant therapy. In this paper we review studies on an interaction between statins, the RAAS and antihypertensive drugs acting via the RAAS. Accumulating evidence suggests that the combination of statins and drugs affecting the RAAS exerts a synergistic effect on the circulatory system. For example, statins may lower arterial blood pressure and augment the effect of antihypertensive drugs acting via the RAAS. Statins may interact with the RAAS in a number of ways i.e. to decrease the expression of receptors for angiotensin II (Ang II), inhibit the Ang II-dependent intracellular signalling, reduce the RAAS-dependent oxidative stress and inflammation as well as inhibit the synthesis of Ang II and aldosterone. Although statins given either alone or together with antihypertensive drugs acting via the RAAS may lower arterial blood pressure, further research is needed to evaluate the mechanisms and their therapeutic significance. © The Author(s) 2014.

Polymer brush hexadecyltrimethylammonium bromide (CTAB) modified poly (propylene-g-styrene sulphonic acid) fiber (ZB-1): CTAB/ZB-1 as a promising strategy for improving the dissolution and physical stability of poorly water-soluble drugs.

PubMed

Cao, Jinxu; Yang, Baixue; Wang, Yumei; Wei, Chen; Wang, Hongyu; Li, Sanming

2017-11-01

The feasibility of polymer brush as drug delivery vehicle was demonstrated with the goal of improving the dissolution and physical stability of poorly water-soluble drugs. Polymer brush CTAB/ZB-1 was synthesized by electrostatic interaction using a physical modification method with anionic poly (propylene-g-styrene sulphonic acid) fiber (ZB-1) as the substrate and cationic hexadecyltrimethylammonium bromide (CTAB) as the modifier. The polymer brush structure of CTAB/ZB-1 was validated by atomic force microscopy (AFM) and the channels of brush provided the drug loading sites. Flurbiprofen (FP), a BCS class II representative drug, was selected as the model poorly water-soluble drug to be loaded into this polymer brush. Then the drug loading and release were systematically investigated. Besides, the transformation from crystalline FP to amorphous state was observed by differential scanning calorimeter (DSC). In vitro dissolution in pure water and pH1.2 HCl media with/without 0.1% sodium dodecyl sulfate (SDS) was tested. Moreover, the optimal formulations (namely carrier/drug ratios) were determined. The results demonstrated prominent improvement of dissolution when FP was released from CTAB/ZB-1. After a long time storage, FP remained amorphous in CTAB/ZB-1 according to DSC determinations and performed an approximately equivalent dissolution compared with fresh samples, suggesting the advantage of CTAB/ZB-1 as carrier in enhancing the physical stability of drugs. The study introduced the versatile easily formulated polymer brush CTAB/ZB-1 and demonstrated the potential of polymer brush as an alternative approach for improving the dissolution and physical stability of poorly water-soluble drugs. Copyright © 2017 Elsevier B.V. All rights reserved.

Non-dopaminergic treatments for motor control in Parkinson's disease.

PubMed

Fox, Susan H

2013-09-01

The pathological processes underlying Parkinson's disease (PD) involve more than dopamine cell loss within the midbrain. These non-dopaminergic neurotransmitters include noradrenergic, serotonergic, glutamatergic, and cholinergic systems within cortical, brainstem and basal ganglia regions. Several non-dopaminergic treatments are now in clinical use to treat motor symptoms of PD, or are being evaluated as potential therapies. Agents for symptomatic monotherapy and as adjunct to dopaminergic therapies for motor symptoms include adenosine A2A antagonists and the mixed monoamine-B inhibitor (MAO-BI) and glutamate release agent safinamide. The largest area of potential use for non-dopaminergic drugs is as add-on therapy for motor fluctuations. Thus adenosine A2A antagonists, safinamide, and the antiepileptic agent zonisamide can extend the duration of action of levodopa. To reduce levodopa-induced dyskinesia, drugs that target overactive glutamatergic neurotransmission can be used, and include the non-selective N-methyl D-aspartate antagonist amantadine. More recently, selective metabotropic glutamate receptor (mGluR₅) antagonists are being evaluated in phase II randomized controlled trials. Serotonergic agents acting as 5-HT2A/2C antagonists, such as the atypical antipsychotic clozapine, may also reduce dyskinesia. 5-HT1A agonists theoretically can reduce dyskinesia, but in practice, may also worsen PD motor symptoms, and so clinical applicability has not yet been shown. Noradrenergic α2A antagonism using fipamezole can potentially reduce dyskinesia. Several non-dopaminergic agents have also been investigated to reduce non-levodopa-responsive motor symptoms such as gait and tremor. Thus the cholinesterase inhibitor donepezil showed mild benefit in gait, while the predominantly noradrenergic re-uptake inhibitor methylphenidate had conflicting results in advanced PD subjects. Tremor in PD may respond to muscarinic M4 cholinergic antagonists (anticholinergics), but tolerability is often poor. Alternatives include β-adrenergic antagonists such as propranolol. Other options include 5-HT2A antagonists, and drugs that have mixed binding properties involving serotonin and acetylcholine, such as clozapine and the antidepressant mirtazapine, can be effective in reducing PD tremor. Many other non-dopaminergic agents are in preclinical and phase I/II early stages of study, and the reader is directed to recent reviews. While levodopa remains the most effective agent to treat motor symptoms in PD, the overall approach to using non-dopaminergic drugs in PD is to reduce reliance on levodopa and to target non-levodopa-responsive symptoms.

A guide to benzodiazepine selection. Part II: Clinical aspects.

PubMed

Teboul, E; Chouinard, G

1991-02-01

To suit the specific needs of various clinical situations, selection of an appropriate benzodiazepine derivative should be based on consideration of their different pharmacokinetic and pharmacodynamic properties. Benzodiazepine derivatives that are rapidly eliminated produce the most pronounced rebound and withdrawal syndromes. Benzodiazepines that are slowly absorbed and slowly eliminated are most appropriate for the anxious patient, since these derivatives produce a gradual and sustained anxiolytic effect. Rapidly absorbed and slowly eliminated benzodiazepines are usually more appropriate for patients with sleep disturbances, since the rapid absorption induces sleep and the slower elimination rate may induce less tolerance to the sedative effect. Rational selection of a benzodiazepine for the elderly and for the suspected drug abuser is more problematic. The relevant pharmacokinetic and clinical considerations for these users are discussed. Certain derivatives may possess pharmacodynamic properties not shared by the entire benzodiazepine class; empirical studies have suggested the existence of anti-panic properties for alprazolam and clonazepam, antidepressant properties for alprazolam, and anti-manic properties for clonazepam and possibly lorazepam.

Effect of Neem oil and Haridra on non-healing wounds.

PubMed

Singh, Anjali; Singh, Anil Kumar; Narayan, G; Singh, Teja B; Shukla, Vijay Kumar

2014-01-01

In Ayurveda, Vrana (wound) has stated as tissue destruction and discoloration of viable tissue due to various etiology. In Sushruta Samhita, Sushruta described Vrana as a main subject. Most commonly Vrana can be classified into Shuddha and Dushta Vrana (chronic wound/nonhealing ulcers). Among the various drugs mentioned for Dushta Vrana, two of them, Neem (Azadirechta indica A. Juss) oil and Haridra (Curcuma longa Linn.) powder are selected for their wide spectrum action on wound. To compare the effect of Neem oil and Haridra in the treatment of chronic non-healing wounds. Total 60 patients of wounds with more than 6 weeks duration were enrolled and alternatively allocated to Group I (topical application of Neem oil), Group II (Haridra powder capsules, 1 g 3 times orally) and Group III (both drugs). Duration of treatment was considered until complete healing of the wound, whereas 4(th) and 8(th) week were considered for assessment of 50% healing. Wound size was measured and recorded at weekly intervals. Wound biopsy was repeated after 4 weeks for assessment of angiogenesis and deoxyribonucleic acid (DNA) analysis. After 8 weeks of treatment, 50% wound healing was observed in 43.80% patients of Group I, 18.20% patients of Group II, and 70.00% patients of Group III. Microscopic angiogenesis grading system scores and DNA concentration showed highly significant effect of combined use of both drugs when compared before and after results of treatment (P < 0.001). Topical use of Neem oil and oral use of Haridra powder capsule used in combination were found effective for chronic non-healing wounds.

Biowaiver monograph for immediate-release solid oral dosage forms: fluconazole.

PubMed

Charoo, Naseem; Cristofoletti, Rodrigo; Graham, Alexandra; Lartey, Paul; Abrahamsson, Bertil; Groot, D W; Kopp, Sabine; Langguth, Peter; Polli, James; Shah, Vinod P; Dressman, Jennifer

2014-12-01

Literature data pertaining to the decision to allow a waiver of in vivo bioequivalence (BE) testing requirements for the approval of immediate release (IR) solid oral dosage forms containing fluconazole as the only active pharmaceutical ingredient (API) are reviewed. The decision is based on solubility, dissolution, permeability, therapeutic index, pharmacokinetic parameters, pharmacodynamic properties, and other relevant data. BE/bioavailability (BA) problems and drug-excipients interaction data were also reviewed and taken into consideration. According to the biopharmaceutics classification system (BCS), fluconazole in polymorphic forms II and III is a BCS class I drug and has a wide therapeutic index. BE of test formulations from many different manufacturers containing different excipients confirmed that the risk of bioinequivalence because of formulation and manufacturing factors is low. It was inferred that risk can be further reduced if in vitro studies are performed according to biowaiver guidelines. Thus, it is concluded that a biowaiver can be recommended for fluconazole IR dosage forms if (a) fluconazole is present as polymorphic form II or III or any other form/mixture showing high solubility, (b) the selection of excipients be limited to those found in IR drug products approved in International Conference on Harmonisation (ICH) countries for the same dosage form and used in their usual amounts, and (c) both the test and comparator dosage form are very rapidly dissolving, or, rapidly dissolving throughout the shelf life with similar dissolution profiles at pH 1.2, 4.5, and 6.8. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.

A Pharmacometric Approach to Substitute for a Conventional Dose-Finding Study in Rare Diseases: Example of Phase III Dose Selection for Emicizumab in Hemophilia A.

PubMed

Yoneyama, Koichiro; Schmitt, Christophe; Kotani, Naoki; Levy, Gallia G; Kasai, Ryu; Iida, Satofumi; Shima, Midori; Kawanishi, Takehiko

2017-12-06

Emicizumab (ACE910) is a bispecific antibody mimicking the cofactor function of activated coagulation factor VIII. In phase I-I/II studies, emicizumab reduced the bleeding frequency in patients with severe hemophilia A, regardless of the presence of factor VIII inhibitors, at once-weekly subcutaneous doses of 0.3, 1, and 3 mg/kg. Using the phase I-I/II study data, population pharmacokinetic and repeated time-to-event (RTTE) modeling were performed to quantitatively characterize the relationship between the pharmacokinetics of emicizumab and reduction in bleeding frequency. Simulations were then performed to identify the minimal exposure expected to achieve zero bleeding events for 1 year in at least 50% of patients and to select the dosing regimens to be tested in phase III studies. The RTTE model adequately predicted the bleeding onset over time as a function of plasma emicizumab concentration. Simulations suggested that plasma emicizumab concentrations of ≥  45 μg/mL should result in zero bleeding events for 1 year in at least 50% of patients. This efficacious exposure provided the basis for selecting previously untested dosing regimens of 1.5 mg/kg once weekly, 3 mg/kg every 2 weeks, and 6 mg/kg every 4 weeks for phase III studies. A pharmacometric approach guided the phase III dose selection of emicizumab in hemophilia A, without conducting a conventional dose-finding study. Phase III studies with the selected dosing regimens are currently ongoing. This case study indicates that a pharmacometric approach can substitute for a conventional dose-finding study in rare diseases and will streamline the drug development process.

Limonene enhances the in vitro and in vivo permeation of trimetazidine across a membrane-controlled transdermal therapeutic system.

PubMed

Krishnaiah, Yellela S; Al-Saidan, Saleh M

2008-01-01

The objective of the study was to design membrane-controlled transdermal therapeutic system (TTS) for trimetazidine. The optimization of (i) concentration of ethanol-water solvent system, (ii) HPMC concentration of drug reservoir and (iii) limonene concentration in 2% w/v HPMC gel was done based on the in vitro permeation of trimetazidine across excised rat epidermis. A limonene-based membrane-controlled TTS of trimetazidine was fabricated and evaluated for its in vivo drug release in rabbit model. The in vitro permeation of trimetazidine from water, ethanol and selected concentrations (25, 50 and 75% v/v) of ethanol-water co-solvent systems showed that 50% v/v of ethanol-water solvent system provided an optimal transdermal flux of 233.1+/-3.8 microg/cm(2.)h. The flux of the drug decreased to 194.1+/-7.4 microg/cm(2.)h on adding 2% w/v of HPMC to ethanolic (50% v/v ethanol-water) solution of trimetazidine. However, on adding selected concentrations of limonene (0, 2, 4, 6 and 8% w/v) to 2% w/v HPMC gel drug reservoir, the flux of the drug increased to 365.5+/-7.1 microg/cm(2.)h. Based on these results, 2% w/v HPMC gel drug reservoir containing 6% w/v of limonene was chosen as an optimal formulation for studying the influence of rate-controlling EVA2825 membrane and adhesive-coated EVA2825 membrane. The flux of the drug across EVA2825 membrane (mean thickness 31.2 microm) decreased to 285.8+/-2.2 microg/cm(2.)h indicating that the chosen membrane was effective as rate-controlling membrane. On applying an adhesive coat (mean thickness 10.2 microm) to EVA2825 membrane, the drug flux further decreased to 212.4+/-2.6 microg/cm(2.)h. However, the flux of the drug across adhesive-coated EVA2825 membrane-rat epidermis composite was 185.9+/-2.9 microg/cm(2.)h, which is about 2-times higher than the desired flux. The fabricated limonene-based TTS patch of trimetazidine showed a mean steady state plasma concentration of 71.5 ng/mL for about 14 h with minimal fluctuation when tested in rabbits. It was concluded from the investigation that the limonene-based TTS patch of trimetazidine provided constant drug delivery across the skin in rabbit model.

Recovering actives in multi-antitarget and target design of analogs of the myosin II inhibitor blebbistatin

NASA Astrophysics Data System (ADS)

Roman, Bart I.; Guedes, Rita C.; Stevens, Christian V.; García-Sosa, Alfonso T.

2018-05-01

In multitarget drug design, it is critical to identify active and inactive compounds against a variety of targets and antitargets. Multitarget strategies thus test the limits of available technology, be that in screening large databases of compounds versus a large number of targets, or in using in silico methods for understanding and reliably predicting these pharmacological outcomes. In this paper, we have evaluated the potential of several in silico approaches to predict the target, antitarget and physicochemical profile of (S)-blebbistatin, the best-known myosin II ATPase inhibitor, and a series of analogs thereof. Standard and augmented structure-based design techniques could not recover the observed activity profiles. A ligand-based method using molecular fingerprints was, however, able to select actives for myosin II inhibition. Using further ligand- and structure-based methods, we also evaluated toxicity through androgen receptor binding, affinity for an array of antitargets and the ADME profile (including assay-interfering compounds) of the series. In conclusion, in the search for (S)-blebbistatin analogs, the dissimilarity distance of molecular fingerprints to known actives and the computed antitarget and physicochemical profile of the molecules can be used for compound design for molecules with potential as tools for modulating myosin II and motility-related diseases.

76 FR 62447 - Importer of Controlled Substances; Notice of Registration

Federal Register 2010, 2011, 2012, 2013, 2014

2011-10-07

... narcotic raw material are not appropriate. With regard to all non-Narcotic Raw Material drugs on this...-phenethyl-4-piperidine (8333)... II Phenylacetone (8501) II Opium, raw (9600) II Poppy Straw Concentrate...

21 CFR 520.1100 - Griseofulvin.

Code of Federal Regulations, 2010 CFR

2010-04-01

... Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS § 520.1100 Griseofulvin. (a... animal is free of infection. (ii) Indications for use. For treatment of fungal infections of the skin...

21 CFR 520.1100 - Griseofulvin.

Code of Federal Regulations, 2014 CFR

2014-04-01

... Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS § 520.1100 Griseofulvin. (a... animal is free of infection. (ii) Indications for use. For treatment of fungal infections of the skin...

21 CFR 520.1100 - Griseofulvin.

Code of Federal Regulations, 2011 CFR

2011-04-01

... Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS § 520.1100 Griseofulvin. (a... animal is free of infection. (ii) Indications for use. For treatment of fungal infections of the skin...

21 CFR 520.1100 - Griseofulvin.

Code of Federal Regulations, 2013 CFR

2013-04-01

... Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS § 520.1100 Griseofulvin. (a... animal is free of infection. (ii) Indications for use. For treatment of fungal infections of the skin...

Prescription drug coverage and effects on drug expenditures among elderly Medicare beneficiaries.

PubMed

Huh, Soonim; Rice, Thomas; Ettner, Susan L

2008-06-01

To identify determinants of drug coverage among elderly Medicare beneficiaries and to investigate the impact of drug coverage on drug expenditures with and without taking selection bias into account. The primary data were from the 2000 Medicare Current Beneficiary Survey (MCBS) Cost and Use file, linked to other data sources at the county or state-level that provided instrumental variables. Community-dwelling elderly Medicare beneficiaries who completed the survey were included in the study (N=7,525). A probit regression to predict the probability of having drug coverage and the effects of drug coverage on drug expenditures was estimated by a two-part model, assuming no correlation across equations. In addition, the discrete factor model estimated choice of drug coverage and expenditures for prescription drugs simultaneously to control for self-selection into drug coverage, allowing for correlation of error terms across equations. Findings indicated that unobservable characteristics leading elderly Medicare beneficiaries to purchase drug coverage also lead them to have higher drug expenditures on conditional use (i.e., adverse selection), while the same unobservable factors do not influence their decisions whether to use any drugs. After controlling for potential selection bias, the probability of any drug use among persons with drug coverage use was 4.5 percent higher than among those without, and drug coverage led to an increase in drug expenditures of $308 among those who used prescription drugs. Given significant adverse selection into drug coverage before the implementation of the Medicare Prescription Drug Improvement and Modernization Act, it is essential that selection effects be monitored as beneficiaries choose whether or not to enroll in this voluntary program.

Phase II trial suggests new drug can shrink tumors in advanced ovarian cancer | Center for Cancer Research

Cancer.gov

In an ongoing phase II trial led by Jung-Min Lee, M.D., an Investigator in CCR’s Women’s Malignancies Branch, using the drug prexasertib led to decreases in tumor size in patients with advanced ovarian cancer, known as high-grade serious ovarian carcinoma, who currently have limited treatment options. Read more…

40 CFR 799.4360 - Tributyl phosphate.

Code of Federal Regulations, 2011 CFR

2011-07-01

... provisions also apply: (i) Animal selection. Testing shall be performed in laboratory rats. (ii) Duration of... apply: (i) Animal selection. Testing shall be performed in laboratory rats. (ii) Duration of testing...) Animal selection. Testing shall be performed in laboratory rats. (ii) Duration of testing. Animals shall...

Dynamics of human protein kinase Aurora A linked to drug selectivity

DOE PAGES

Pitsawong, Warintra; Buosi, Vanessa; Otten, Renee; ...

2018-06-14

Protein kinases are major drug targets, but the development of highly-selective inhibitors has been challenging due to the similarity of their active sites. The observation of distinct structural states of the fully-conserved Asp-Phe-Gly (DFG) loop has put the concept of conformational selection for the DFG-state at the center of kinase drug discovery. Recently, it was shown that Gleevec selectivity for the Tyr-kinases Abl was instead rooted in conformational changes after drug binding. Here, we investigate whether protein dynamics after binding is a more general paradigm for drug selectivity by characterizing the binding of several approved drugs to the Ser/Thr-kinase Auroramore » A. Using a combination of biophysical techniques, we propose a universal drug-binding mechanism, that rationalizes selectivity, affinity and long on-target residence time for kinase inhibitors. These new concepts, where protein dynamics in the drug-bound state plays the crucial role, can be applied to inhibitor design of targets outside the kinome.« less

Dynamics of human protein kinase Aurora A linked to drug selectivity

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

Pitsawong, Warintra; Buosi, Vanessa; Otten, Renee

Protein kinases are major drug targets, but the development of highly-selective inhibitors has been challenging due to the similarity of their active sites. The observation of distinct structural states of the fully-conserved Asp-Phe-Gly (DFG) loop has put the concept of conformational selection for the DFG-state at the center of kinase drug discovery. Recently, it was shown that Gleevec selectivity for the Tyr-kinases Abl was instead rooted in conformational changes after drug binding. Here, we investigate whether protein dynamics after binding is a more general paradigm for drug selectivity by characterizing the binding of several approved drugs to the Ser/Thr-kinase Auroramore » A. Using a combination of biophysical techniques, we propose a universal drug-binding mechanism, that rationalizes selectivity, affinity and long on-target residence time for kinase inhibitors. These new concepts, where protein dynamics in the drug-bound state plays the crucial role, can be applied to inhibitor design of targets outside the kinome.« less

Contrasting evolutionary histories of MHC class I and class II loci in grouse—Effects of selection and gene conversion

USGS Publications Warehouse

Minias, Piotr; Bateson, Zachary W.; Whittingham, Linda A.; Johnson, Jeff A.; Oyler-McCance, Sara J.; Dunn, Peter O.

2016-01-01

Genes of the major histocompatibility complex (MHC) encode receptor molecules that are responsible for recognition of intracellular and extracellular pathogens (class I and class II genes, respectively) in vertebrates. Given the different roles of class I and II MHC genes, one might expect the strength of selection to differ between these two classes. Different selective pressures may also promote different rates of gene conversion at each class. Despite these predictions, surprisingly few studies have looked at differences between class I and II genes in terms of both selection and gene conversion. Here, we investigated the molecular evolution of MHC class I and II genes in five closely related species of prairie grouse (Centrocercus and Tympanuchus) that possess one class I and two class II loci. We found striking differences in the strength of balancing selection acting on MHC class I versus class II genes. More than half of the putative antigen-binding sites (ABS) of class II were under positive or episodic diversifying selection, compared with only 10% at class I. We also found that gene conversion had a stronger role in shaping the evolution of MHC class II than class I. Overall, the combination of strong positive (balancing) selection and frequent gene conversion has maintained higher diversity of MHC class II than class I in prairie grouse. This is one of the first studies clearly demonstrating that macroevolutionary mechanisms can act differently on genes involved in the immune response against intracellular and extracellular pathogens.

Contrasting evolutionary histories of MHC class I and class II loci in grouse—effects of selection and gene conversion

PubMed Central

Minias, P; Bateson, Z W; Whittingham, L A; Johnson, J A; Oyler-McCance, S; Dunn, P O

2016-01-01

Genes of the major histocompatibility complex (MHC) encode receptor molecules that are responsible for recognition of intracellular and extracellular pathogens (class I and class II genes, respectively) in vertebrates. Given the different roles of class I and II MHC genes, one might expect the strength of selection to differ between these two classes. Different selective pressures may also promote different rates of gene conversion at each class. Despite these predictions, surprisingly few studies have looked at differences between class I and II genes in terms of both selection and gene conversion. Here, we investigated the molecular evolution of MHC class I and II genes in five closely related species of prairie grouse (Centrocercus and Tympanuchus) that possess one class I and two class II loci. We found striking differences in the strength of balancing selection acting on MHC class I versus class II genes. More than half of the putative antigen-binding sites (ABS) of class II were under positive or episodic diversifying selection, compared with only 10% at class I. We also found that gene conversion had a stronger role in shaping the evolution of MHC class II than class I. Overall, the combination of strong positive (balancing) selection and frequent gene conversion has maintained higher diversity of MHC class II than class I in prairie grouse. This is one of the first studies clearly demonstrating that macroevolutionary mechanisms can act differently on genes involved in the immune response against intracellular and extracellular pathogens. PMID:26860199

Natural variation in a single amino acid substitution underlies physiological responses to topoisomerase II poisons.

PubMed

Zdraljevic, Stefan; Strand, Christine; Seidel, Hannah S; Cook, Daniel E; Doench, John G; Andersen, Erik C

2017-07-01

Many chemotherapeutic drugs are differentially effective from one patient to the next. Understanding the causes of this variability is a critical step towards the development of personalized treatments and improvements to existing medications. Here, we investigate sensitivity to a group of anti-neoplastic drugs that target topoisomerase II using the model organism Caenorhabditis elegans. We show that wild strains of C. elegans vary in their sensitivity to these drugs, and we use an unbiased genetic approach to demonstrate that this natural variation is explained by a methionine-to-glutamine substitution in topoisomerase II (TOP-2). The presence of a non-polar methionine at this residue increases hydrophobic interactions between TOP-2 and its poison etoposide, as compared to a polar glutamine. We hypothesize that this stabilizing interaction results in increased genomic instability in strains that contain a methionine residue. The residue affected by this substitution is conserved from yeast to humans and is one of the few differences between the two human topoisomerase II isoforms (methionine in hTOPIIα and glutamine in hTOPIIβ). We go on to show that this amino acid difference between the two human topoisomerase isoforms influences cytotoxicity of topoisomerase II poisons in human cell lines. These results explain why hTOPIIα and hTOPIIβ are differentially affected by various poisons and demonstrate the utility of C. elegans in understanding the genetics of drug responses.

Intrinsic Thermodynamics and Structure Correlation of Benzenesulfonamides with a Pyrimidine Moiety Binding to Carbonic Anhydrases I, II, VII, XII, and XIII

PubMed Central

Kišonaitė, Miglė; Zubrienė, Asta; Čapkauskaitė, Edita; Smirnov, Alexey; Smirnovienė, Joana; Kairys, Visvaldas; Michailovienė, Vilma; Manakova, Elena; Gražulis, Saulius; Matulis, Daumantas

2014-01-01

The early stage of drug discovery is often based on selecting the highest affinity lead compound. To this end the structural and energetic characterization of the binding reaction is important. The binding energetics can be resolved into enthalpic and entropic contributions to the binding Gibbs free energy. Most compound binding reactions are coupled to the absorption or release of protons by the protein or the compound. A distinction between the observed and intrinsic parameters of the binding energetics requires the dissection of the protonation/deprotonation processes. Since only the intrinsic parameters can be correlated with molecular structural perturbations associated with complex formation, it is these parameters that are required for rational drug design. Carbonic anhydrase (CA) isoforms are important therapeutic targets to treat a range of disorders including glaucoma, obesity, epilepsy, and cancer. For effective treatment isoform-specific inhibitors are needed. In this work we investigated the binding and protonation energetics of sixteen [(2-pyrimidinylthio)acetyl]benzenesulfonamide CA inhibitors using isothermal titration calorimetry and fluorescent thermal shift assay. The compounds were built by combining four sulfonamide headgroups with four tailgroups yielding 16 compounds. Their intrinsic binding thermodynamics showed the limitations of the functional group energetic additivity approach used in fragment-based drug design, especially at the level of enthalpies and entropies of binding. Combined with high resolution crystal structural data correlations were drawn between the chemical functional groups on selected inhibitors and intrinsic thermodynamic parameters of CA-inhibitor complex formation. PMID:25493428

21 CFR 520.2475 - Toceranib.

Code of Federal Regulations, 2010 CFR

2010-04-01

... Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS § 520.2475 Toceranib. (a) Specifications...) Indications for use. For the treatment of Patnaik grade II or III, recurrent, cutaneous mast cell tumors with...

21 CFR 520.1195 - Ivermectin liquid.

Code of Federal Regulations, 2012 CFR

2012-04-01

... and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS § 520.1195 Ivermectin liquid. (a... oral drench. (ii) Indications for use. For treatment and control of: (A) Large Strongyles (adults...

18 CFR 1316.7 - Drug-free workplace.

Code of Federal Regulations, 2010 CFR

2010-04-01

... available drug counseling, rehabilitation, and employee assistance programs; and (iv) The penalties that may... prohibition; (2) Establish a drug-free awareness program to inform such employees about— (i) The dangers of... termination; or (ii) Require such employee to satisfactorily participate in a drug abuse assistance or...

Single-center evaluation of the single-dose pharmacokinetics of the angiotensin II receptor antagonist azilsartan medoxomil in renal impairment.

PubMed

Preston, Richard A; Karim, Aziz; Dudkowski, Caroline; Zhao, Zhen; Garg, Dyal; Lenz, Oliver; Sica, Domenic A

2013-05-01

Azilsartan medoxomil (AZL-M) is a potent angiotensin II receptor blocker that decreases blood pressure in a dose-dependent manner. It is a pro-drug and not detected in blood after oral administration because of rapid hydrolysis to the active moiety, azilsartan (AZL). AZL undergoes further metabolism to the major metabolite M-II and minor metabolites. The objective of this study was to determine the effect of renal impairment on the pharmacokinetics of AZL and its major metabolite. This was a single-center, open-label, phase I parallel-group study which examined the single-dose (40-mg) pharmacokinetics of AZL and M-II in 24 subjects with mild, moderate, or severe renal impairment or end-stage renal disease requiring hemodialysis (n = 6 per group), respectively, and healthy matched subjects (n = 24). Renal impairment/disease did not cause clinically meaningful increases in exposure to AZL. M-II exposure was higher in all renally impaired subjects and highest in those with severe impairment (approx fivefold higher vs. control). M-II is pharmacologically inactive; increased exposure was not considered important in dose selection for AZL-M in subjects with renal impairment. Hemodialysis did not significantly remove AZL or M-II. Renal impairment had no clinically meaningful effect on the plasma protein binding of AZL or M-II. Single doses of AZL-M 40 mg were well tolerated in all subject groups. Based on the pharmacokinetic and tolerability findings, no dose adjustment of AZL-M is required for subjects with any degree of renal impairment, including end-stage renal disease.

77 FR 24984 - Importer of Controlled Substances; Notice of Application; Rhodes Technologies

Federal Register 2010, 2011, 2012, 2013, 2014

2012-04-26

.... Comments and requests for hearings on applications to import narcotic raw material are not appropriate. 72... schedule II: Drug Schedule Opium, Raw (9600) II Poppy Straw Concentrate (9670) II The company plans to...

The Next Generation of Platinum Drugs: Targeted Pt(II) Agents, Nanoparticle Delivery, and Pt(IV) Prodrugs

PubMed Central

Johnstone, Timothy C.; Suntharalingam, Kogularamanan; Lippard, Stephen J.

2016-01-01

The platinum drugs, cisplatin, carboplatin, and oxaliplatin, prevail in the treatment of cancer,, but new platinum agents have been very slow to enter the clinic. Recently, however, there has been a surge of activity, based on a great deal of mechanistic information, aimed at developing non-classical platinum complexes that operate via mechanisms of action distinct from those of the approved drugs. The use of nanodelivery devices has also grown and many different strategies have been explored to incorporate platinum warheads into nanomedicine constructs. In this review, we discuss these efforts to create the next generation of platinum anticancer drugs. The introduction provides the reader with a brief overview of the use, development, and mechanism of action of the approved platinum drugs to provide the context in which more recent research has flourished. We then describe approaches that explore non-classical platinum(II) complexes with trans geometry and with a monofunctional coordination mode, polynuclear platinum(II) compounds, platinum(IV) prodrugs, dual-treat agents, and photoactivatable platinum(IV) complexes. Nanodelivery particles designed to deliver platinum(IV) complexes will also be discussed, including carbon nanotubes, carbon nanoparticles, gold nanoparticles, quantum dots, upconversion nanoparticles, and polymeric micelles. Additional nanoformulations including supramolecular self-assembled structures, proteins, peptides, metal-organic frameworks, and coordination polymers will then be described. Finally, the significant clinical progress made by nanoparticle formulations of platinum(II) agents will be reviewed. We anticipate that such a synthesis of disparate research efforts will not only help to generate new drug development ideas and strategies, but also reflect our optimism that the next generation of platinum cancer drugs is about to arrive. PMID:26865551

Spectroscopic characterization of furosemide binding to human carbonic anhydrase II.

PubMed

Ranjbar, Samira; Ghobadi, Sirous; Khodarahmi, Reza; Nemati, Houshang

2012-05-01

This study reports the interaction between furosemide and human carbonic anhydrase II (hCA II) using fluorescence, UV-vis and circular dichroism (CD) spectroscopy. Fluorescence data indicated that furosemide quenches the intrinsic fluorescence of the enzyme via a static mechanism and hydrogen bonding and van der Walls interactions play the major role in the drug binding. The binding average distance between furosemide and hCA II was estimated on the basis of the theory of Förster energy transfer. Decrease of protein surface hydrophobicity was also documented upon furosemide binding. Chemical modification of hCA II using N-bromosuccinimide indicated decrease of the number of accessible tryptophans in the presence of furosemide. CD results suggested the occurance of some alterations in α-helical content as well as tertiary structure of hCA II upon drug binding. Copyright © 2012 Elsevier B.V. All rights reserved.

Synthesis, characterization, antimicrobial activity and DFT studies of 2-(pyrimidin-2-ylamino)naphthalene-1,4-dione and its Mn(II), Co(II), Ni(II) and Zn(II) complexes

NASA Astrophysics Data System (ADS)

Chioma, Festus; Ekennia, Anthony C.; Ibeji, Collins U.; Okafor, Sunday N.; Onwudiwe, Damian C.; Osowole, Aderoju A.; Ujam, Oguejiofo T.

2018-07-01

A pyrimidine-based ligand, 2-(pyrimidin-2-ylamino)naphthalene-1,4-dione (L), has been synthesized by the reaction of 2-aminopyrimidine with 2-hydroxy-1,4-napthoquinone. Reaction of the ligand with Ni(II), Co(II), Mn(II) and Zn(II) acetate gave the corresponding metal complexes which were characterized by spectroscopic techniques, (infrared, electronic), elemental analysis, room-temperature magnetometry, conductance measurements and thermogravimetry-differential scanning calorimetry (TG-DSC) analyses. The room-temperature magnetic data and electronic spectral measurements of the complexes gave evidence of 4-coordinate square planar/tetrahedral geometry. The thermal analyses values obtained indicated the monohydrate complexes. The antimicrobial screening of the compounds showed mild to very good results. The Mn(II) complex showed the best result within in the range of 11.5-29 mm. The electronic, structural and spectroscopic properties of the complexes were further discussed using density functional theory. Molecular docking studies showed significant binding affinity with the drug targets and the metal complexes have potentials to be used as drugs.

Phytochemicals as Anticancer and Chemopreventive Topoisomerase II Poisons

PubMed Central

Ketron, Adam C.

2013-01-01

Phytochemicals are a rich source of anticancer drugs and chemopreventive agents. Several of these chemicals appear to exert at least some of their effects through interactions with topoisomerase II, an essential enzyme that regulates DNA supercoiling and removes knots and tangles from the genome. Topoisomerase II-active phytochemicals function by stabilizing covalent protein-cleaved DNA complexes that are intermediates in the catalytic cycle of the enzyme. As a result, these compounds convert topoisomerase II to a cellular toxin that fragments the genome. Because of their mode of action, they are referred to as topoisomerase II poisons as opposed to catalytic inhibitors. The first sections of this article discuss DNA topology, the catalytic cycle of topoisomerase II, and the two mechanisms (interfacial vs. covalent) by which different classes of topoisomerase II poisons alter enzyme activity. Subsequent sections discuss the effects of several phytochemicals on the type II enzyme, including demethyl-epipodophyllotoxins (semisynthetic anticancer drugs) as well as flavones, flavonols, isoflavones, catechins, isothiocyanates, and curcumin (dietary chemopreventive agents). Finally, the leukemogenic potential of topoisomerase II-targeted phytochemicals is described. PMID:24678287

Combinations of three or four HIV virostatics applied in short sequences which differ from each other by drug rotation. Preliminary results of the viral loads and CD4 numbers.

PubMed

Mathé, G; Morette, C; Hallard, M; Blanquet, D

1997-01-01

This paper presents the evolution during its follow-up of a virostatic combination study of the type I-II trial conducted on ten AIDS-related complex (ARC) or acquired immunodeficiency syndrome (AIDS) patients [1, 9, respectively]. Its concept is based on the following original notions: a) it is not the number of the virostatics applied to each patient at any phase which determines their effect; it is the number of affected virus targets which determines the effect. Thus, the so called "tritherapies", imposed by the "AIDS Command" to thousands of patients selected at random, to be compared to the same number of subjects receiving only "bi" or "monotherapies", might be beginning to face failure because they attack only two targets: retro-transcriptase and HIV1 protease. Having discovered, owing to our experimental screening, original HIV1 virostatics, acriflavine (ACF) and several ellipticine analogues among which we have used methyl-hydroxy-ellipticine (MHE), we are able to attack two virus targets unaffected by classical virostatics: ACF attacks DNA, from its integrated double branched stage to the provirus one, and MHE inhibits topoisomerase II. We experimentally combined these two agents with AZT, which inhibits retro-transcriptase, thus we realized a combination affecting three targets. This three agent combination was able to eradicate Friend's virus from infected mice. Clinically, combinations of three drugs affecting four targets (as they are selected among the ten virostatics available today) give a stronger result than three drug combinations affecting only three targets, because they were selected from the five virostatics which were the only ones available at the beginning of the present study. Five patients out of five who received the combinations of four virostatics chosen among the ten currently available (thus affecting four targets) from the beginning of their treatment to the present have all reduced their viral load (VL) and maintained it below the detectable level (< 200 RNA copies/mL then 20 copies/mL); b) as the toxicities of virostatics and as HIV1 resistances may happen as soon as 12 weeks of treatment, the combinations have been, in our study, applied in shorter (3 week) sequences, differing from each other due to drug rotation; c) neither toxicity nor resistance occurred; d) curiously, the CD4 numbers, even when they increased rapidly, has never attained their normal count, and their curve may be a Gombertzian one. This CD4 restoration limitation can be due to persisting virus, as indicated in some patients by small peaks which may appear on some VL plateaus, though they disappear without treatment change.

77 FR 64142 - Importer of Controlled Substances, Notice of Application, Noramco, Inc.

Federal Register 2010, 2011, 2012, 2013, 2014

2012-10-18

... following basic classes of controlled substances: Drug Schedule Phenylacetone (8501) II Opium, raw (9600) II Poppy Straw Concentrate (9670) II Tapentadol (9780) II The company plans to import raw Opium (9600) and... substance. Comments and requests for hearings on applications to import narcotic raw material are not...

Characterising and comparing drug-dispensing practices at animal health outlets in the Rift Valley, Kenya: an exploratory analysis (part II).

PubMed

Higham, L E; Ongeri, W; Asena, K; Thrusfield, M V

2016-12-01

A mixed-method study was conducted in the Rift Valley of Kenya to characterise drug-dispensing practices amongst staff at animal health outlets and to explore perceptions of veterinary medicines amongst pastoralists and farmers. Forty structured questionnaires were administered to staff at animal health outlets, including franchise outlets of 'Sidai Africa Ltd.', and two focus group discussions were facilitated to explore the perceptions of local animal health services by a Maasai pastoralist group and a dairy farmer cooperative. Differences were detected in the characteristics of Sidai outlets, agrovets, pharmacies and dukas. A greater proportion of Sidai outlet staff selected drugs based on principles of responsible drug use than staff at other types of outlet, and technical qualifications and training were associated with responsible drug use. Across all outlet types, staff knowledge and training gaps were identified, including in the correct administration of medicines. The majority of drug sales are accompanied by verbal advice to farmers. Members of the Maasai pastoralist group were concerned about accidental self-medication, withdrawal periods, drug residues and the misuse of drugs due to a lack of quality information and advice. The dairy farmer group raised similar concerns, reporting under-dosing as a common mistake amongst farmers. This study concludes that current knowledge, attitudes and practices of many service providers and livestock owners in the sale, purchase and use of veterinary medicines present risks of drug misuse and therefore the emergence of antimicrobial resistance. There is a clear demand from livestock keepers for accessible, affordable and quality animal health services and products in Kenya, and animal health practitioners have the potential to provide increased support to livestock-based livelihoods and act as stewards of our existing portfolio of animal and human medicines.

Drug-drug interaction and doping: Effect of non-prohibited drugs on the urinary excretion profile of methandienone.

PubMed

Mazzarino, Monica; Khevenhüller-Metsch, Franziska L; Fiacco, Ilaria; Parr, Maria Kristina; de la Torre, Xavier; Botrè, Francesco

2018-05-15

The potential consequences of drug-drug interactions on the excretion profile of the anabolic androgenic steroid methandienone (17β-hydroxy-17α-methylandrosta-1,4-dien-3-one) are discussed here. More specifically, we have evaluated by in vitro and in vivo experiments the effects of seven non-prohibited drugs (fluconazole, ketoconazole, itraconazole, miconazole, fluoxetine, paroxetine and nefazodone) on the main metabolic pathways of methandienone. These are selected among those most commonly used by the athletes. The in vitro assays were based on the use of human liver microsomes, specific recombinant enzyme isoforms of cytochrome P450 and uridine 5'-diphospho-glucuronosyl-transferase. The in vivo study was performed by analyzing urines collected after the oral administration of methandienone with and without the co-administration of ketoconazole. Methandienone and its metabolites were determined by liquid chromatography-mass spectrometry-based techniques after sample pre-treatment including an enzymatic hydrolysis step (performed only for the investigation on phase II metabolism) and liquid/liquid extraction with t-butyl methyl-ether. The results from the in vitro experiments showed that the formation of the hydroxylated and dehydrogenated metabolites was significantly reduced in the presence of itraconazole, ketoconazole, miconazole and nefazodone, whereas the production of the 18-nor-hydroxylated metabolites and glucuronidation reactions was reduced significantly only in the presence of ketoconazole and miconazole. The analysis of the post-administration samples confirmed the in vitro observations, validating the hypothesis that drug-drug interaction may cause significant alterations in the metabolic profile of banned drugs, making their detection during doping control tests more challenging. This article is protected by copyright. All rights reserved.

Selective adsorption of Pb(II) from aqueous solution using porous biosilica extracted from marine diatom biomass: Properties and mechanism

NASA Astrophysics Data System (ADS)

Qi, Yarong; Wang, Jingfeng; Wang, Xin; Cheng, Jay Jiayang; Wen, Zhiyou

2017-02-01

Biosilica with a surface area of 143 m2 g-1 derived from marine diatoms was prepared using an easy two-step method involving washing with dilute acid and baking. The extracted biosilica was used to remove divalent lead ions, i.e., Pb(II), from aqueous solution. The effects on Pb(II) adsorption of initial pH, shaking speed, and adsorbent loading were investigated. The adsorption of Pb(II) in the presence of other ions was also investigated. The biosilica showed a high adsorption capacity with high selectivity for Pb(II). The experimental maximum adsorption capacity was 108.2-120.4 mg g-1 at an adsorbent loading of 1 g L-1. The adsorption process was best described by the Langmuir model. The adsorbent selectively adsorbed Pb(II) from binary ion systems in the presence of Cu(II), Cd(II), Ni(II), and Ag(I). The results of this study show that biosilica extracted from fresh marine diatoms is a more efficient and selective adsorbent for Pb(II) than other inorganic adsorbents.

The role of validated analytical methods in JECFA drug assessments and evaluation for recommending MRLs.

PubMed

Boison, Joe O

2016-05-01

The Joint Food and Agriculture Organization and World Health Organization (FAO/WHO) Expert Committee on Food Additives (JECFA) is one of three Codex committees tasked with applying risk analysis and relying on independent scientific advice provided by expert bodies organized by FAO/WHO when developing standards. While not officially part of the Codex Alimentarius Commission structure, JECFA provides independent scientific advice to the Commission and its specialist committees such as the Codex Committee on Residues of Veterinary Drugs in Foods (CCRVDF) in setting maximum residue limits (MRLs) for veterinary drugs. Codex methods of analysis (Types I, II, III, and IV) are defined in the Codex Procedural Manual as are criteria to be used for selecting methods of analysis. However, if a method is to be used under a single laboratory condition to support regulatory work, it must be validated according to an internationally recognized protocol and the use of the method must be embedded in a quality assurance system in compliance with ISO/IEC 17025:2005. This paper examines the attributes of the methods used to generate residue depletion data for drug registration and/or licensing and for supporting regulatory enforcement initiatives that experts consider to be useful and appropriate in their assessment of methods of analysis. Copyright © 2016 Her Majesty the Queen in Right of Canada. Drug Testing and Analysis © 2016 John Wiley & Sons, Ltd. © 2016 Her Majesty the Queen in Right of Canada. Drug Testing and Analysis © 2016 John Wiley & Sons, Ltd.

Microfibrous Solid Dispersions of Poorly Water-Soluble Drugs Produced via Centrifugal Spinning: Unexpected Dissolution Behavior on Recrystallization.

PubMed

Marano, Stefania; Barker, Susan A; Raimi-Abraham, Bahijja T; Missaghi, Shahrzad; Rajabi-Siahboomi, Ali; Aliev, Abil E; Craig, Duncan Q M

2017-05-01

Temperature-controlled, solvent-free centrifugal spinning may be used as a means of rapid production of amorphous solid dispersions in the form of drug-loaded sucrose microfibers. However, due to the high content of amorphous sucrose in the formulations, such microfibers may be highly hygroscopic and unstable on storage. In this study, we explore both the effects of water uptake of the microfibers and the consequences of deliberate recrystallization for the associated dissolution profiles. The stability of sucrose microfibers loaded with three selected BCS class II model drugs (itraconazole (ITZ), olanzapine (OLZ), and piroxicam (PRX)) was investigated under four different relative humidity conditions (11, 33, 53, and 75% RH) at 25 °C for 8 months, particularly focusing on the effect of the highest level of moisture (75% RH) on the morphology, size, drug distribution, physical state, and dissolution performance of microfibers. While all samples were stable at 11% RH, at 33% RH the ITZ-sucrose system showed greater resistance against devitrification compared to the OLZ- and PRX-sucrose systems. For all three samples, the freshly prepared microfibers showed enhanced dissolution and supersaturation compared to the drug alone and physical mixes; surprisingly, the dissolution advantage was largely maintained or even enhanced (in the case of ITZ) following the moisture-induced recrystallization under 75% RH. Therefore, this study suggests that the moisture-induced recrystallization process may result in considerable dissolution enhancement compared to the drug alone, while overcoming the physical stability risks associated with the amorphous state.

Drugs in the Workplace: Research and Evaluation Data. Volume II. Research Monograph 100.

ERIC Educational Resources Information Center

Gust, Steven W., Ed.; And Others

This monograph presents 14 articles on the topics of the nature and extent of drug use by the workforce; drug use and job performance indicators; and drug free workplace program research. These articles are included: (1) Research on Drugs and the Workplace: Introduction and Summary (Steven Gust, Dennis Crouch, J. Michael Walsh); (2) Drug Use…

21 CFR 316.1 - Scope of this part.

Code of Federal Regulations, 2011 CFR

2011-04-01

... drugs for rare diseases or conditions, including biological products and antibiotics. This part sets... for investigations of drugs for rare diseases or conditions; (ii) Requests for designation of a drug for a rare disease or condition; and (iii) Requests for gaining exclusive approval for a drug product...

21 CFR 316.1 - Scope of this part.

Code of Federal Regulations, 2013 CFR

2013-04-01

... drugs for rare diseases or conditions, including biological products and antibiotics. This part sets... for investigations of drugs for rare diseases or conditions; (ii) Requests for designation of a drug for a rare disease or condition; and (iii) Requests for gaining exclusive approval for a drug product...

21 CFR 316.1 - Scope of this part.

Code of Federal Regulations, 2012 CFR

2012-04-01

... drugs for rare diseases or conditions, including biological products and antibiotics. This part sets... for investigations of drugs for rare diseases or conditions; (ii) Requests for designation of a drug for a rare disease or condition; and (iii) Requests for gaining exclusive approval for a drug product...

21 CFR 316.1 - Scope of this part.

Code of Federal Regulations, 2010 CFR

2010-04-01

... drugs for rare diseases or conditions, including biological products and antibiotics. This part sets... for investigations of drugs for rare diseases or conditions; (ii) Requests for designation of a drug for a rare disease or condition; and (iii) Requests for gaining exclusive approval for a drug product...

42 CFR 2.12 - Applicability.

Code of Federal Regulations, 2014 CFR

2014-10-01

... ALCOHOL AND DRUG ABUSE PATIENT RECORDS General Provisions § 2.12 Applicability. (a) General—(1... identification by another person; and (ii) Is drug abuse information obtained by a federally assisted drug abuse... assisted alcohol or drug abuse program after that date as part of an ongoing treatment episode which...

42 CFR 2.12 - Applicability.

Code of Federal Regulations, 2012 CFR

2012-10-01

... ALCOHOL AND DRUG ABUSE PATIENT RECORDS General Provisions § 2.12 Applicability. (a) General—(1... identification by another person; and (ii) Is drug abuse information obtained by a federally assisted drug abuse... assisted alcohol or drug abuse program after that date as part of an ongoing treatment episode which...

42 CFR 2.12 - Applicability.

Code of Federal Regulations, 2011 CFR

2011-10-01

... ALCOHOL AND DRUG ABUSE PATIENT RECORDS General Provisions § 2.12 Applicability. (a) General—(1... identification by another person; and (ii) Is drug abuse information obtained by a federally assisted drug abuse... assisted alcohol or drug abuse program after that date as part of an ongoing treatment episode which...

42 CFR 2.12 - Applicability.

Code of Federal Regulations, 2010 CFR

2010-10-01

... ALCOHOL AND DRUG ABUSE PATIENT RECORDS General Provisions § 2.12 Applicability. (a) General—(1... identification by another person; and (ii) Is drug abuse information obtained by a federally assisted drug abuse... assisted alcohol or drug abuse program after that date as part of an ongoing treatment episode which...

42 CFR 2.12 - Applicability.

Code of Federal Regulations, 2013 CFR

2013-10-01

... ALCOHOL AND DRUG ABUSE PATIENT RECORDS General Provisions § 2.12 Applicability. (a) General—(1... identification by another person; and (ii) Is drug abuse information obtained by a federally assisted drug abuse... assisted alcohol or drug abuse program after that date as part of an ongoing treatment episode which...

EPILEPSY SURGERY IN DRUG RESISTANT TEMPORAL LOBE EPILEPSY ASSOCIATED WITH NEURONAL ANTIBODIES

PubMed Central

Carreño, Mar; Bien, Christian; Asadi-Pooya, Ali A.; Sperling, Michael; Marusic, Petr.; Elisak, Martin; Pimentel, Jose; Wehner, Tim; Mohanraj, Rajiv; Uranga, Juan; Gómez-Ibáñez, Asier; Villanueva, Vicente; Gil, Francisco; Donaire, Antonio; Bargalló, Nuria; Rumià, Jordi; Roldán, Pedro; Setoain, Xavier; Pintor, Luis; Boget, Teresa; Bailles, Eva; Falip, Mercè; Aparicio, Javier; Dalmau, Josep; Graus, Francesc

2017-01-01

We assessed the outcome of patients with drug resistant epilepsy and neuronal antibodies who underwent epilepsy surgery. Retrospective study, information collected with a questionnaire sent to epilepsy surgery centers. Thirteen patients identified, with antibodies to GAD (8), Ma2 (2), Hu (1), LGI1 (1) or CASPR2 (1). Mean age at seizure onset: 23 years. Five patients had an encephalitic phase. Three had testicular tumors and five had autoimmune diseases. All had drug resistant temporal lobe epilepsy (median: 20 seizures/month). MRI showed unilateral temporal lobe abnormalities (mainly hippocampal sclerosis) in 9 patients, bilateral abnormalities in 3, and was normal in 1. Surgical procedures included anteromesial temporal lobectomy (10 patients), selective amygdalohippocampectomy (1), temporal pole resection (1) and radiofrequency ablation of mesial structures (1). Perivascular lymphocytic infiltrates were seen in 7/12 patients. One year outcome available in all patients, at 3 years in 9. At last visit 5/13 patients (38.5%) (with Ma2, Hu, LGI1, and 2 GAD antibodies) were in Engel`s classes I or II. Epilepsy surgery may be an option for patients with drug resistant seizures associated with neuronal antibodies. Outcome seems to be worse than that expected in other etiologies, even in the presence of unilateral HS. Intracranial EEG may be required in some patients. PMID:28043058

Investigational drugs to treat methicillin-resistant Staphylococcus aureus

PubMed Central

Vuong, Cuong; Yeh, Anthony J; Cheung, Gordon YC; Otto, Michael

2016-01-01

Introduction Staphylococcus aureus remains one of the leading causes of morbidity and mortality worldwide. This is to a large extent due to antibiotic-resistant strains, in particular methicillin-resistant S. aureus (MRSA). While the toll of invasive MRSA infections appears to decrease in U.S. hospitals, the rate of community-associated MRSA infections remains constant and there is a surge of MRSA in many other countries. This situation calls for continuing if not increased efforts to find novel strategies to combat MRSA infections. Areas covered This review will provide an overview of current investigational antibiotics in clinical development (up to phase II), and of therapeutic antibodies and alternative drugs against S. aureus in preclinical and clinical development, including a short description of the mechanism of action and a presentation of microbiological and clinical data. Expert opinion Increased recent antibiotic development efforts and results from pathogenesis research have led to several new antibiotics and alternative drugs, as well as a more informed selection of targets for vaccination efforts against MRSA. This developing portfolio of novel anti-staphylococcal drugs will hopefully provide us with additional and more efficient ways to combat MRSA infections in the near future and prevent us from running out of treatment options, even if new resistances arise. PMID:26536498

Cellulose-lanthanum hydroxide nanocomposite as a selective marker for detection of toxic copper

PubMed Central

2014-01-01

In this current report, a simple, reliable, and rapid method based on modifying the cellulose surface by doping it with different percentages of lanthanum hydroxide (i.e., 1% La(OH)3-cellulose (LC), 5% La(OH)3-cellulose (LC2), and 10% La(OH)3-cellulose (LC3)) was proposed as a selective marker for detection of copper (Cu(II)) in aqueous medium. Surface properties of the newly modified cellulose phases were confirmed by Fourier transform infrared spectroscopy, field emission scanning electron microscope, energy dispersive X-ray spectroscopy, X-ray diffraction, and X-ray photoelectron spectroscopic analysis. The effect of pH on the adsorption of modified cellulose phases for Cu(II) was evaluated, and LC3 was found to be the most selective for Cu(II) at pH 6.0. Other parameters, influencing the maximum uptake of Cu(II) on LC3, were also investigated for a deeper mechanistic understanding of the adsorption phenomena. Results showed that the adsorption capacity for Cu(II) was improved by 211% on the LC3 phase as compared to diethylaminoethyl cellulose phase after only 2 h contact time. Adsorption isotherm data established that the adsorption process nature was monolayer with a homogeneous adsorbent surface. Results displayed that the adsorption of Cu(II) onto the LC3 phase obeyed a pseudo-second-order kinetic model. Selectivity studies toward eight metal ions, i.e., Cd(II), Co(II), Cr(III), Cr(VI), Cu(II), Fe(III), Ni(II), and Zn(II), were further performed at the optimized pH value. Based on the selectivity study, it was found that Cu(II) is highly selective toward the LC3 phase. Moreover, the efficiency of the proposed method was supported by implementing it to real environmental water samples with adequate results. PMID:25258599

Effect of Simvastatin, Coenzyme Q10, Resveratrol, Acetylcysteine and Acetylcarnitine on Mitochondrial Respiration.

PubMed

Fišar, Z; Hroudová, J; Singh, N; Kopřivová, A; Macečková, D

2016-01-01

Some therapeutic and/or adverse effects of drugs may be related to their effects on mitochondrial function. The effects of simvastatin, resveratrol, coenzyme Q10, acetylcysteine, and acetylcarnitine on Complex I-, Complex II-, or Complex IV-linked respiratory rate were determined in isolated brain mitochondria. The protective effects of these biologically active compounds on the calcium-induced decrease of the respiratory rate were also studied. We observed a significant inhibitory effect of simvastatin on mitochondrial respiration (IC50 = 24.0 μM for Complex I-linked respiration, IC50 = 31.3 μM for Complex II-linked respiration, and IC50 = 42.9 μM for Complex IV-linked respiration); the inhibitory effect of resveratrol was found at very high concentrations (IC50 = 162 μM for Complex I-linked respiration, IC50 = 564 μM for Complex II-linked respiration, and IC50 = 1454 μM for Complex IV-linked respiration). Concentrations required for effective simvastatin- or resveratrol-induced inhibition of mitochondrial respiration were found much higher than concentrations achieved under standard dosing of these drugs. Acetylcysteine and acetylcarnitine did not affect the oxygen consumption rate of mitochondria. Coenzyme Q10 induced an increase of Complex I-linked respiration. The increase of free calcium ions induced partial inhibition of the Complex I+II-linked mitochondrial respiration, and all tested drugs counteracted this inhibition. None of the tested drugs showed mitochondrial toxicity (characterized by respiratory rate inhibition) at drug concentrations achieved at therapeutic drug intake. Resveratrol, simvastatin, and acetylcarnitine had the greatest neuroprotective potential (characterized by protective effects against calcium-induced reduction of the respiratory rate).

Recent Advances in Understanding of Kinetic Interplay Between Phase II Metabolism and Efflux Transport.

PubMed

Wang, Shuai; Xing, Huijie; Zhao, Mengjing; Lu, Danyi; Li, Zhijie; Dong, Dong; Wu, Baojian

2016-01-01

Mechanistic understanding of the metabolism-transport interplay assumes great importance in pharmaceutical fields because the knowledge can help to interpret drug/xenobiotic metabolism and disposition studies as well as the drug-drug interactions in vivo. About 10 years ago, it started to recognize that cellular phase II metabolism is strongly influenced by the excretion (efflux transport) of generated metabolites, a kinetic phenomenon termed "phase II metabolism-transport interplay". This interplay is believed to have significant effects on the pharmacokinetics (bioavailability) of drugs/chemicals undergoing phase II metabolism. In this article, we review the studies investigating the phase II metabolism-transport interplay using cell models, perfused rat intestine, and intact rats. The potential confounding factors in exploring such interplay is also summarized. Moreover, the mechanism underlying the phase II metabolism-transport interplay is discussed. Various studies with engineered cells and rodents have demonstrated that there is an interaction (interplay) between phase II enzymes and efflux transporters. This type of interplay mainly refers to the dependence of phase II (conjugative) metabolism on the activities of efflux transporters. In general, inhibiting efflux transporters or decreasing their expression causes the reductions in metabolite excretion, apparent excretion clearance (CLapp) and total metabolism (fmet), as well as an increase in the intracellular level of metabolite (Ci). The deconjugation mediated by hydrolase (acting as a "bridge") is essential for the interplay to play out based on pharmacokinetic modeling/simulations, cell and animal studies. The hydrolases bridge the two processes (i.e., metabolite formation and excretion) and enable the interplay thereof (a bridging effect). Without the bridge, metabolite formation is independent on its downstream process excretion, thus impact of metabolite excretion on its formation is impossible. Deconjugation (mediated by hydrolases) plays an essential role in the conjugation-transport interplay. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

The selective beta 1-blocking agent metoprolol compared with antithyroid drug and thyroxine as preoperative treatment of patients with hyperthyroidism. Results from a prospective, randomized study.

PubMed Central

Adlerberth, A; Stenström, G; Hasselgren, P O

1987-01-01

Despite the increasing use of beta-blocking agents alone as preoperative treatment of patients with hyperthyroidism, there are no controlled clinical studies in which this regimen has been compared with a more conventional preoperative treatment. Thirty patients with newly diagnosed and untreated hyperthyroidism were randomized to preoperative treatment with methimazole in combination with thyroxine (Group I) or the beta 1-blocking agent metoprolol (Group II). Metoprolol was used since it has been demonstrated that the beneficial effect of beta-blockade in hyperthyroidism is mainly due to beta 1-blockade. The preoperative, intraoperative, and postoperative courses in the two groups were compared, and patients were followed up for 1 year after thyroidectomy. At the time of diagnosis, serum concentration of triiodothyronine (T3) was 6.1 +/- 0.59 nmol/L in Group I and 5.7 +/- 0.66 nmol/L in Group II (reference interval 1.5-3.0 nmol/L). Clinical improvement during preoperative treatment was similar in the two groups of patients, but serum T3 was normalized only in Group I. The median length of preoperative treatment was 12 weeks in Group I and 5 weeks in Group II (p less than 0.01). There were no serious adverse effects of the drugs during preoperative preparation in either treatment group. Operating time, consistency and vascularity of the thyroid gland, and intraoperative blood loss were similar in the two groups. No anesthesiologic or cardiovascular complications occurred during operation in either group. One patient in Group I (7%) and three patients in Group II (20%) had clinical signs of hyperthyroid function during the first postoperative day. These symptoms were abolished by the administration of small doses of metoprolol, and no case of thyroid storm occurred. Postoperative hypocalcemia or recurrent laryngeal nerve paralysis did not occur in either group. During the first postoperative year, hypothyroidism developed in two patients in Group I (13%) and in six patients in Group II (40%). No patient had recurrent hyperthyroidism. The results suggest that metoprolol can be used as sole preoperative treatment of patients with hyperthyroidism without serious intra- or postoperative complications. Although the data indicate that the risk of postoperative hypothyroidism is higher after preoperative treatment with metoprolol than with an antithyroid drug, a longer follow-up period than 1 year is needed to draw conclusions regarding late results. PMID:3545108

Advising depression patients to reduce alcohol and drug use: factors associated with provider intervention in outpatient psychiatry.

PubMed

Satre, Derek D; Leibowitz, Amy S; Mertens, Jennifer R; Weisner, Constance

2014-01-01

Mental health clinicians have an important opportunity to help depression patients reduce co-occurring alcohol and drug use. This study examined demographic and clinical patient characteristics and service factors associated with receiving a recommendation to reduce alcohol and drug use from providers in a university-based outpatient psychiatry clinic. The sample consisted of 97 participants ages 18 and older who reported hazardous drinking (≥3 drinks/occasion), illegal drug use (primarily cannabis) or misuse of prescription drugs, and who scored ≥15 on the Beck Depression Inventory-II (BDI-II). Participants were interviewed at intake and 6 months. At 6-month telephone interview, 30% of participants reported that a clinic provider had recommended that they reduce alcohol or drug use. In logistic regression, factors associated with receiving advice to reduce use included greater number of drinks consumed in the 30 days prior to intake (p = .035); and greater depression severity on the BDI-II (p = .096) and hazardous drinking at 6 months (p = .05). While participants with greater alcohol intake and depression symptom severity were more likely to receive advice to reduce use, the low overall rate of recommendation to reduce use highlights the need to improve alcohol and drug use intervention among depression patients, and potentially to address alcohol and drug training and treatment implementation issues among mental health providers. © American Academy of Addiction Psychiatry.

Therapeutic cancer vaccines

PubMed Central

Melief, Cornelis J.M.; van Hall, Thorbald; Arens, Ramon; Ossendorp, Ferry; van der Burg, Sjoerd H.

2015-01-01

The clinical benefit of therapeutic cancer vaccines has been established. Whereas regression of lesions was shown for premalignant lesions caused by HPV, clinical benefit in cancer patients was mostly noted as prolonged survival. Suboptimal vaccine design and an immunosuppressive cancer microenvironment are the root causes of the lack of cancer eradication. Effective cancer vaccines deliver concentrated antigen to both HLA class I and II molecules of DCs, promoting both CD4 and CD8 T cell responses. Optimal vaccine platforms include DNA and RNA vaccines and synthetic long peptides. Antigens of choice include mutant sequences, selected cancer testis antigens, and viral antigens. Drugs or physical treatments can mitigate the immunosuppressive cancer microenvironment and include chemotherapeutics, radiation, indoleamine 2,3-dioxygenase (IDO) inhibitors, inhibitors of T cell checkpoints, agonists of selected TNF receptor family members, and inhibitors of undesirable cytokines. The specificity of therapeutic vaccination combined with such immunomodulation offers an attractive avenue for the development of future cancer therapies. PMID:26214521

Aptamer-Mediated Codelivery of Doxorubicin and NF-κB Decoy Enhances Chemosensitivity of Pancreatic Tumor Cells

PubMed Central

Porciani, David; Tedeschi, Lorena; Marchetti, Laura; Citti, Lorenzo; Piazza, Vincenzo; Beltram, Fabio; Signore, Giovanni

2015-01-01

Aptamers able to bind efficiently cell-surface receptors differentially expressed in tumor and in healthy cells are emerging as powerful tools to perform targeted anticancer therapy. Here, we present a novel oligonucleotide chimera, composed by an RNA aptamer and a DNA decoy. Our assembly is able to (i) target tumor cells via an antitransferrin receptor RNA aptamer and (ii) perform selective codelivery of a chemotherapeutic drug (Doxorubicin) and of an inhibitor of a cell-survival factor, the nuclear factor κB decoy oligonucleotide. Both payloads are released under conditions found in endolysosomal compartments (low pH and reductive environment). Targeting and cytotoxicity of the oligonucleotidic chimera were assessed by confocal microscopy, cell viability, and Western blot analysis. These data indicated that the nuclear factor κB decoy does inhibit nuclear factor κB activity and ultimately leads to an increased therapeutic efficacy of Doxorubicin selectively in tumor cells. PMID:25919089

Traditional beliefs and practices among Mexican American immigrants with type II diabetes: A case study.

PubMed

Lemley, Megan; Spies, Lori A

2015-04-01

To describe selected common health beliefs and practices among Mexican American immigrants with type II diabetes. Selected clinical trials, qualitative studies, and systematic reviews. The Hispanic folk illness belief susto refers to an episode of severe fright, and Mexican American immigrants hold varying views on its relation to diabetes. Culturally and in the research, susto has also been linked with depression. Sabila (aloe vera) and nopal (prickly pear cactus) are herbal remedies that have had widespread, longstanding use in Mexican culture and while this is not the gold standard of research, it does provide ample evidence and a strong cultural belief that these therapies work. There is some evidence in the literature to support their efficacy as glucose-lowering agents, but lack of Food and Drug Administration (FDA) regulation, potential side effects, and a dearth of rigorous clinical trials preclude aloe vera and nopal from being recommended therapy. Awareness about susto beliefs, commonly used herbal remedies, and development of culturally sensitive communication skills are essential for nurse practitioners to effectively assist patients in this population achieve their glycemic goals. Research on the effects of nopal and aloe vera on diabetes is needed to guide clinical decisions. ©2014 American Association of Nurse Practitioners.

21 CFR 314.55 - Pediatric use information.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 5 2014-04-01 2014-04-01 false Pediatric use information. 314.55 Section 314.55 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS... to be used in a substantial number of pediatric patients; (ii) Necessary studies are impossible or...

21 CFR 316.1 - Scope of this part.

Code of Federal Regulations, 2014 CFR

2014-04-01

... drugs for rare diseases or conditions, including biological products and antibiotics. This part sets... for investigations of drugs for rare diseases or conditions; (ii) Requests for designation of a drug for a rare disease or condition; and (iii) Requests for gaining exclusive approval for a drug for a...

21 CFR 1313.14 - Distribution of import declaration.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 9 2011-04-01 2011-04-01 false Distribution of import declaration. 1313.14 Section 1313.14 Food and Drugs DRUG ENFORCEMENT ADMINISTRATION, DEPARTMENT OF JUSTICE IMPORTATION AND... forms for List II chemical must be retained for two years. (b) Copy 2 is the Drug Enforcement...

21 CFR 1313.23 - Distribution of export declaration.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 9 2011-04-01 2011-04-01 false Distribution of export declaration. 1313.23 Section 1313.23 Food and Drugs DRUG ENFORCEMENT ADMINISTRATION, DEPARTMENT OF JUSTICE IMPORTATION AND...; declaration forms for list II chemical must be retained for two years. (b) Copy 2 is the Drug Enforcement...

21 CFR 884.2800 - Computerized Labor Monitoring System.

Code of Federal Regulations, 2010 CFR

2010-04-01

...: “Guidance for Industry and Food and Drug Administration Staff; Class II Special Controls Guidance Document... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Computerized Labor Monitoring System. 884.2800 Section 884.2800 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES...

21 CFR 1313.14 - Distribution of import declaration.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 9 2010-04-01 2010-04-01 false Distribution of import declaration. 1313.14 Section 1313.14 Food and Drugs DRUG ENFORCEMENT ADMINISTRATION, DEPARTMENT OF JUSTICE IMPORTATION AND... forms for List II chemical must be retained for two years. (b) Copy 2 is the Drug Enforcement...

21 CFR 884.5460 - Scented or scented deodorized menstrual tampon.

Code of Federal Regulations, 2010 CFR

2010-04-01

... menstrual tampons treated with added antimicrobial agents or other drugs. (b) Classification. Class II... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Scented or scented deodorized menstrual tampon. 884.5460 Section 884.5460 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN...

Drug Distribution into Peripheral Nerve.

PubMed

Liu, Houfu; Chen, Yan; Huang, Liang; Sun, Xueying; Fu, Tingting; Wu, Shengqian; Zhu, Xiaoyan; Zhen, Wei; Liu, Jihong; Lu, Gang; Cai, Wei; Yang, Ting; Zhang, Wandong; Yu, Xiaohong; Wan, Zehong; Wang, Jianfei; Summerfield, Scott G; Dong, Kelly; Terstappen, Georg C

2018-05-01

Little is known about the impact of the blood-nerve barrier (BNB) on drug distribution into peripheral nerves. In this study, we examined the peripheral nerve penetration in rats of 11 small-molecule drugs possessing diverse physicochemical and transport properties and ProTx-II, a tarantula venom peptide with molecular mass of 3826 Daltons. Each drug was administered as constant rate intravenous infusion for 6 hours (small molecules) or 24 hours (ProTx-II). Blood and tissues including brain, spinal cord, sciatic nerve, and dorsal root ganglion (DRG) were collected for drug concentration measurements. Unbound fractions of a set of compounds were determined by equilibrium dialysis method in rat blood, brains, spinal cords, sciatic nerves, and DRG. We also investigated the influence of N -[4-[2-(6,7-dimethoxy-3,4-dihydro-1 H -isoquinolin-2-yl)ethyl]phenyl]-5-methoxy-9-oxo-10 H -acridine-4-carboxamide (GF120918), a P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) inhibitor, on the peripheral nerve and central nervous system (CNS) tissue penetration of imatinib. We found that: 1) the unbound fraction in brain tissue homogenate highly correlates with that in the spinal cord, sciatic nerve, and DRG for a set of compounds and thus provides a good surrogate for spinal cord and peripheral nerve tissues, 2) small-molecule drugs investigated can penetrate the DRG and sciatic nerve, 3) P-gp and BCRP have a limited impact on the distribution of small-molecule drugs into peripheral nerves, and 4) DRG is permeable to ProTx-II, but its distribution into sciatic nerve and CNS tissues is restricted. These results demonstrate that small-molecule drugs investigated can penetrate peripheral nerve tissues, and P-gp/BCRP may not be a limiting factor at the BNB. Biologics as large as ProTx-II can access the DRG but not sciatic nerve and CNS tissues. Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics.

77 FR 31388 - Importer of Controlled Substances; Notice of Application; Noramco, Inc.

Federal Register 2010, 2011, 2012, 2013, 2014

2012-05-25

... material are not appropriate. 72 FR 3417 (2007). In regard to the non-narcotic raw material, any bulk... following basic classes of controlled substances: Drug Schedule Phenylacetone (8501) II Opium, raw (9600) II Poppy Straw Concentrate (9670) II Tapentadol (9780) II The company plans to import the raw Opium (9600...

75 FR 65658 - Importer of Controlled Substances; Notice of Application

Federal Register 2010, 2011, 2012, 2013, 2014

2010-10-26

... basic classes of controlled substances listed in schedule II: Drug Schedule Raw Opium (9600) II Concentrate of Poppy Straw (9670) II Tapentadol (9780) II The company plans to import the Raw Opium (9600) and... Technologies, 72 FR 3417 (2007), comments and requests for hearings on applications to import narcotic raw...

Pharmacophore Hybridization To Discover Novel Topoisomerase II Poisons with Promising Antiproliferative Activity.

PubMed

Ortega, Jose Antonio; Riccardi, Laura; Minniti, Elirosa; Borgogno, Marco; Arencibia, Jose M; Greco, Maria L; Minarini, Anna; Sissi, Claudia; De Vivo, Marco

2018-02-08

We used a pharmacophore hybridization strategy to combine key structural elements of merbarone and etoposide and generated new type II topoisomerase (topoII) poisons. This first set of hybrid topoII poisons shows promising antiproliferative activity on human cancer cells, endorsing their further exploration for anticancer drug discovery.

The Kinetic Mechanism for Cytochrome P450 Metabolism of Type II Binding Compounds: Evidence Supporting Direct Reduction

PubMed Central

Pearson, Joshua; Dahal, Upendra P.; Rock, Daniel; Peng, Chi-Chi; Schenk, James O.; Joswig-Jones, Carolyn; Jones, Jeffrey P.

2011-01-01

The metabolic stability of a drug is an important property that should be optimized during drug design and development. Nitrogen incorporation is hypothesized to increase the stability by coordination of nitrogen to the heme iron of cytochrome P450, a binding mode that is referred to as type II binding. However, we noticed that the type II binding compound 1 has less metabolic stability at subsaturating conditions than a closely related type I binding compound 3. Three kinetic models will be presented for type II binder metabolism; 1) Dead-end type II binding, 2) a rapid equilibrium between type I and II binding modes before reduction, and 3) a direct reduction of the type II coordinated heme. Data will be presented on reduction rates of iron, the off rates of substrate (using surface plasmon resonance) and the catalytic rate constants. These data argue against the dead-end, and rapid equilibrium models, leaving the direct reduction kinetic mechanism for metabolism of the type II binding compound 1. PMID:21530484

Formulation and in vitro and in vivo characterization of a phenytoin self-emulsifying drug delivery system (SEDDS).

PubMed

Atef, Eman; Belmonte, Albert A

2008-11-15

The aim of this study is to develop and characterize a self-emulsifying drug delivery system (SEDDS) of phenytoin, and to compare its relative bioavailability to a commercially available suspension. Four phenytoin SEDDS were prepared and evaluated. Following emulsification, the optimized formula was selected to have the smallest mean particle size and the highest absolute zeta potential, which should yield the formation of a stable emulsion. Its dissolution characteristics were superior to the other SEDDS formulas. In vivo and in vitro tests were run to compare the optimized formula, SEDDS II, to a commercially available Dilantin suspension. The in vitro dissolution indicated a significant improvement in phenytoin release characteristics. The in vivo study using male rats showed a clear enhancement in phenytoin oral absorption from SEDDS compared to Dilantin suspension. The area under the curve AUC((-10min-->10h)) of phenytoin after SEDDS administration increased by 2.3 times compared to Dilantin (p<0.05), and the rate of absorption of phenytoin was significantly faster from the SEDDS. The concentration after 30min (C(30min)) of SEDDS administration was 4.9 times higher than C(30min) after Dilantin administration (p<0.05). A sustained effect of phenytoin in plasma was also observed. After 12 weeks storage, SEDDS II was found to be chemically and physically stable under stressed conditions.

Assessment of dual life stage antiplasmodial activity of british seaweeds.

PubMed

Spavieri, Jasmine; Allmendinger, Andrea; Kaiser, Marcel; Itoe, Maurice Ayamba; Blunden, Gerald; Mota, Maria M; Tasdemir, Deniz

2013-10-22

Terrestrial plants have proven to be a prolific producer of clinically effective antimalarial drugs, but the antimalarial potential of seaweeds has been little explored. The main aim of this study was to assess the in vitro chemotherapeutical and prophylactic potential of the extracts of twenty-three seaweeds collected from the south coast of England against blood stage (BS) and liver stage (LS) Plasmodium parasites. The majority (14) of the extracts were active against BS of P. falciparum, with brown seaweeds Cystoseira tamariscifolia, C. baccata and the green seaweed Ulva lactuca being the most active (IC(50)s around 3 μg/mL). The extracts generally had high selectivity indices (>10). Eight seaweed extracts inhibited the growth of LS parasites of P. berghei without any obvious effect on the viability of the human hepatoma (Huh7) cells, and the highest potential was exerted by U. lactuca and red seaweeds Ceramium virgatum and Halopitys incurvus (IC50 values 14.9 to 28.8 μg/mL). The LS-active extracts inhibited one or more key enzymes of the malarial type-II fatty acid biosynthesis (FAS-II) pathway, a drug target specific for LS. Except for the red seaweed Halopitys incurvus, all LS-active extracts showed dual activity versus both malarial intracellular stage parasites. This is the first report of LS antiplasmodial activity and dual stage inhibitory potential of seaweeds.

Assessment of Dual Life Stage Antiplasmodial Activity of British Seaweeds

PubMed Central

Spavieri, Jasmine; Allmendinger, Andrea; Kaiser, Marcel; Itoe, Maurice Ayamba; Blunden, Gerald; Mota, Maria M.; Tasdemir, Deniz

2013-01-01

Terrestrial plants have proven to be a prolific producer of clinically effective antimalarial drugs, but the antimalarial potential of seaweeds has been little explored. The main aim of this study was to assess the in vitro chemotherapeutical and prophylactic potential of the extracts of twenty-three seaweeds collected from the south coast of England against blood stage (BS) and liver stage (LS) Plasmodium parasites. The majority (14) of the extracts were active against BS of P. falciparum, with brown seaweeds Cystoseira tamariscifolia, C. baccata and the green seaweed Ulva lactuca being the most active (IC50s around 3 μg/mL). The extracts generally had high selectivity indices (>10). Eight seaweed extracts inhibited the growth of LS parasites of P. berghei without any obvious effect on the viability of the human hepatoma (Huh7) cells, and the highest potential was exerted by U. lactuca and red seaweeds Ceramium virgatum and Halopitys incurvus (IC50 values 14.9 to 28.8 μg/mL). The LS-active extracts inhibited one or more key enzymes of the malarial type-II fatty acid biosynthesis (FAS-II) pathway, a drug target specific for LS. Except for the red seaweed Halopitys incurvus, all LS-active extracts showed dual activity versus both malarial intracellular stage parasites. This is the first report of LS antiplasmodial activity and dual stage inhibitory potential of seaweeds. PMID:24152562

Evaluation of early efficacy endpoints for proof-of-concept trials.

PubMed

Chen, Cong; Sun, Linda; Li, Chih-Lin

2013-03-11

A Phase II proof-of-concept (POC) trial usually uses an early efficacy endpoint other than a clinical endpoint as the primary endpoint. Because of the advancement in bioscience and technology, which has yielded a number of new surrogate biomarkers, drug developers often have more candidate endpoints to choose from than they can handle. As a result, selection of endpoint and its effect size as well as choice of type I/II error rates are often at the center of heated debates in design of POC trials. While optimization of the trade-off between benefit and cost is the implicit objective in such a decision-making process, it is seldom explicitly accounted for in practice. In this research note, motivated by real examples from the oncology field, we provide practical measures for evaluation of early efficacy endpoints (E4) for POC trials. We further provide optimal design strategies for POC trials that include optimal Go-No Go decision criteria for initiation of Phase III and optimal resource allocation strategies for conducting multiple POC trials in a portfolio under fixed resources. Although oncology is used for illustration purpose, the same idea developed in this research note also applies to similar situations in other therapeutic areas or in early-stage drug development in that a Go-No Go decision has to rely on limited data from an early efficacy endpoint and cost-effectiveness is the main concern.

Fluorescence Spectroscopic Studies on the Complexation of Antidiabetic Drugs with Glycosylated Serum Albumin

NASA Astrophysics Data System (ADS)

Seedher, N.; Kanojia, M.

2013-11-01

Glycosylation decreases the association constant values and hence the binding affinity of human serum albumin (HSA) for the antidiabetic drugs under study. The percentage of HAS-bound drug at physiological temperature was only about 21-38 % as compared to 46-74 % for non-glycosylated HSA. Thus the percentage of free drug available for an antihyperglycemic effect was about double (62-79 %) compared to the values for non-glycosylated HSA. Much higher free drug concentrations available for pharmacological effect can lead to the risk of hypoglycemia. Hydrophobic interactions were predominantly involved in the binding. In the binding of gliclazide, hydrogen bonding and electrostatic interactions were involved. Site specificity for glycosylated HSA was the same as that for non-glycosylated HSA; gliclazide and repaglinide bind only at site II whereas glimepiride and glipizide bind at both sites I and II. Glycosylation, however, caused conformational changes in albumin, and the binding region within site II was different for glycosylated and non-glycosylated albumin. Stern-Volmer analysis also indicated the conformational changes in albumin as a result of glycosylation and showed that the dynamic quenching mechanism was valid for fluorescence of both glycosylated and non-glycosylated HSA.

Microencapsulation of Drugs: New Cancer Therapies and Improved Drug Delivery Derived from Micro Gravity Research

NASA Technical Reports Server (NTRS)

Morrison, Dennis R.; Haddad, Ruwaida S.

2003-01-01

Experiments on the ISS include encapsulation of several different anti-cancer drugs, magnetic triggering particles, and encapsulation of genetically engineered DNA. Eight experiments, using the MEPS-II apparatus, were conducted to study the limitations of the fluid shear and g-dependent forces. These studies included: 1) formation of anti-tumor microcapsules containing drugs for "Chemoembolization" of vascularized tumors, 2) formation of microcapsules containing a photo-activated drug which can be used for Photo Dynamic Therapy of solid tumors by activation with near infrared light (630 nm), 3) coencapsulation of magnetic trigger particles and anti-tumor drugs, and 4) encapsulation of plasmid DNA. The Microencapsulation Electrostatic Processing System (MEPS-II) is an automated apparatus modified for use in the ISS Express Rack. The process brings together two immiscible liquids, restricting fluid shear to permitting surface tension forces to predominate at the interface of the fluids. Microcapsules were recovered from all 8 experiments and are currently being analyzed for size distribution and drug content. Six NASA Patents have issued from the space research and several more are pending. The preliminary results from the Increment 5 - UF-2 experiments have provided new insight into the best formulations and conditions required to produce microcapsules of different drugs, esp. special capsules containing diagnostic imaging materials and triggered release particles. Co-encapsulation of multiple drugs and Photodynamic Therapy (PDT) drugs has enabled new engineering strategies for production of microcapsules on Earth designed for direct delivery into cancer tissues. Other microcapsules have now been made for treatment of deep tissue infections, clotting disorders, and to provide delivery of genetic engineered materials for potential gene therapy approaches. The MEPS-II apparatus remains in the ISS awaiting microencapsulation experiments to be conducted in micro-g, and returned to Earth for analysis.

A phase II study tests a new drug for patients with advanced thyroid cancer | Center for Cancer Research

Cancer.gov

A phase II trial of CUDC-907, a new drug that may be able to shrink thyroid tumors that have spread or gotten worse, is being tested in metastatic or advanced thyroid cancer.  Currently, there is no standard or effective treatment for the most aggressive types of thyroid cancer such as anaplastic and poorly differentiated thyroid cancer.  Learn more...

Use of alcohol and drugs by employees in selected business areas in Norway: a study using oral fluid testing and questionnaires.

PubMed

Edvardsen, Hilde Marie Erøy; Moan, Inger Synnøve; Christophersen, Asbjørg S; Gjerde, Hallvard

2015-01-01

Alcohol or drug use and associated hangover may reduce workplace safety and productivity and also cause sickness absence. The aims of this study were to examine (i) the use of alcohol and drugs, and (ii) reduced efficiency at work and absence due to such use among employees. Forty-four companies were invited; half of them agreed to participate. Employees filled in a questionnaire and provided a sample of oral fluid, which was analysed for alcohol, 12 psychoactive medicinal drugs and 6 illicit drugs. Participation was voluntary and anonymous. Two thousand four hundred thirty-seven employees in eight business areas agreed to participate (92 % of those invited). By combining questionnaires and oral fluid testing, we found that 5.2 % had used psychoactive medication during the last couple of days, 1.4 % had used illicit drugs, 17.0 % had used alcohol during the last 24 h but only one person (0.04 %) was positive for alcohol in oral fluid. About 25 % reported reduced efficiency at work, and 5 % reported absence from work due to alcohol use during the past 12 months. The use of illicit drugs and binge drinking resulting in reduced efficiency and absence was most common among restaurant and bar workers and more common among men than women, whereas use of psychoactive medication was most common among healthcare, transportation and storage workers. Impairment at work due to alcohol or drugs was rare, whereas reduced efficiency due to drinking was reported by a fairly large proportion. There were marked differences between some business areas, and across gender.

Improved quality-by-design compliant methodology for method development in reversed-phase liquid chromatography.

PubMed

Debrus, Benjamin; Guillarme, Davy; Rudaz, Serge

2013-10-01

A complete strategy dedicated to quality-by-design (QbD) compliant method development using design of experiments (DOE), multiple linear regressions responses modelling and Monte Carlo simulations for error propagation was evaluated for liquid chromatography (LC). The proposed approach includes four main steps: (i) the initial screening of column chemistry, mobile phase pH and organic modifier, (ii) the selectivity optimization through changes in gradient time and mobile phase temperature, (iii) the adaptation of column geometry to reach sufficient resolution, and (iv) the robust resolution optimization and identification of the method design space. This procedure was employed to obtain a complex chromatographic separation of 15 antipsychotic basic drugs, widely prescribed. To fully automate and expedite the QbD method development procedure, short columns packed with sub-2 μm particles were employed, together with a UHPLC system possessing columns and solvents selection valves. Through this example, the possibilities of the proposed QbD method development workflow were exposed and the different steps of the automated strategy were critically discussed. A baseline separation of the mixture of antipsychotic drugs was achieved with an analysis time of less than 15 min and the robustness of the method was demonstrated simultaneously with the method development phase. Copyright © 2013 Elsevier B.V. All rights reserved.

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.

The enhancement of oxidative DNA damage by anti-diabetic metformin, buformin, and phenformin, via nitrogen-centered radicals.

PubMed

Ohnishi, Shiho; Mizutani, Hideki; Kawanishi, Shosuke

2016-08-01

Metformin (N,N-dimethylbiguanide), buformin (1-butylbiguanide), and phenformin (1-phenethylbiguanide) are anti-diabetic biguanide drugs, expected to having anti-cancer effect. The mechanism of anti-cancer effect by these drugs is not completely understood. In this study, we demonstrated that these drugs dramatically enhanced oxidative DNA damage under oxidative condition. Metformin, buformin, and phenformin enhanced generation of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) in isolated DNA reacted with hydrogen peroxide (H2O2) and Cu(II), although these drugs did not form 8-oxodG in the absence of H2O2 or Cu(II). An electron paramagnetic resonance (EPR) study, utilizing alpha-(4-pyridyl-1-oxide)-N-tert-butylnitrone and 3,3,5,5-tetramethyl-1-pyrroline-N-oxide as spin trapping agents, showed that nitrogen-centered radicals were generated from biguanides in the presence of Cu(II) and H2O2, and that these radicals were decreased by the addition of DNA. These results suggest that biguanides enhance Cu(II)/H2O2-mediated 8-oxodG generation via nitrogen-centered radical formation. The enhancing effect on oxidative DNA damage may play a role on anti-cancer activity.

Inhibition and oxygen activation in copper amine oxidases.

PubMed

Shepard, Eric M; Dooley, David M

2015-05-19

Copper-containing amine oxidases (CuAOs) use both copper and 2,4,5-trihydroxyphenylalanine quinone (TPQ) to catalyze the oxidative deamination of primary amines. The CuAO active site is highly conserved and comprised of TPQ and a mononuclear type II copper center that exhibits five-coordinate, distorted square pyramidal coordination geometry with histidine ligands and equatorially and axially bound water in the oxidized, resting state. The active site is buried within the protein, and CuAOs from various sources display remarkable diversity with respect to the composition of the active site channel and cofactor accessibility. Structural and mechanistic factors that influence substrate preference and inhibitor sensitivity and selectivity have been defined. This Account summarizes the strategies used to design selective CuAO inhibitors based on active site channel characteristics, leading to either enhanced steric fits or the trapping of reactive electrophilic products. These findings provide a framework to support the future development of candidate molecules aimed at minimizing the negative side effects associated with drugs containing amine functionalities. This is vital given the existence of human diamine oxidase and vascular adhesion protein-1, which have distinct amine substrate preferences and are associated with different metabolic processes. Inhibition of these enzymes by antifungal or antiprotozoal agents, as well as classic monoamine oxidase (MAO) inhibitors, may contribute to the adverse side effects associated with drug treatment. These observations provide a rationale for the limited clinical value associated with certain amine-containing pharmaceuticals and emphasize the need for more selective AO inhibitors. This Account also discusses the novel roles of copper and TPQ in the chemistry of O2 activation and substrate oxidation. Reduced CuAOs exist in a redox equilibrium between the Cu(II)-TPQAMQ (aminoquinol) and Cu(I)-TPQSQ (semiquinone). Elucidating the roles of Cu(I), TPQSQ, and TPQAMQ in O2 activation, for example, distinguishing inner-sphere versus outer-sphere electron transfer mechanisms, has been actively investigated since the discovery of TPQSQ in 1991 and has only recently been clarified. Kinetics and spectroscopic studies encompassing metal substitution, stopped-flow and temperature-jump relaxation methods, and oxygen kinetic isotope experiments have provided strong support for an inner-sphere electron transfer step from Cu(I) to O2. Data for two enzymes support a mechanism wherein O2 prebinds to a three-coordinate Cu(I) site, yielding a [Cu(II)(η(1)-O2(-1))](+) intermediate, with H2O2 generated from ensuing rate-determining proton coupled electron transfer from TPQSQ. While kinetics data from the cobalt-substituted yeast enzyme indicated that O2 is reduced through an outer-sphere process involving TPQAMQ, new findings with a bacterial CuAO demonstrate that both the Cu(II) and Co(II) forms of the enzyme operate via parallel mechanisms involving metal-superoxide intermediates. Structural observations of a coordinated TPQSQ-Cu(I) complex in two CuAOs supports previous indications that Cu(II)/(I) ligand substitution chemistry may be mechanistically relevant. Substantial evidence indicates that rapid and reversible inner-sphere reduction of O2 at a three-coordinate Cu(I) site occurs, but the existence of a coordinated semiquinone in some AOs suggests that, in these enzymes, an outer-sphere reaction between O2 and TPQSQ may also be possible, since this is expected to be energetically favorable compared with outer-sphere electron transfer from TPQAMQ to O2.

A review of channel selection algorithms for EEG signal processing

NASA Astrophysics Data System (ADS)

Alotaiby, Turky; El-Samie, Fathi E. Abd; Alshebeili, Saleh A.; Ahmad, Ishtiaq

2015-12-01

Digital processing of electroencephalography (EEG) signals has now been popularly used in a wide variety of applications such as seizure detection/prediction, motor imagery classification, mental task classification, emotion classification, sleep state classification, and drug effects diagnosis. With the large number of EEG channels acquired, it has become apparent that efficient channel selection algorithms are needed with varying importance from one application to another. The main purpose of the channel selection process is threefold: (i) to reduce the computational complexity of any processing task performed on EEG signals by selecting the relevant channels and hence extracting the features of major importance, (ii) to reduce the amount of overfitting that may arise due to the utilization of unnecessary channels, for the purpose of improving the performance, and (iii) to reduce the setup time in some applications. Signal processing tools such as time-domain analysis, power spectral estimation, and wavelet transform have been used for feature extraction and hence for channel selection in most of channel selection algorithms. In addition, different evaluation approaches such as filtering, wrapper, embedded, hybrid, and human-based techniques have been widely used for the evaluation of the selected subset of channels. In this paper, we survey the recent developments in the field of EEG channel selection methods along with their applications and classify these methods according to the evaluation approach.

Therapeutic strategies for metabolic diseases: Small-molecule diacylglycerol acyltransferase (DGAT) inhibitors.

PubMed

Naik, Ravi; Obiang-Obounou, Brice W; Kim, Minkyoung; Choi, Yongseok; Lee, Hyun Sun; Lee, Kyeong

2014-11-01

Metabolic diseases such as atherogenic dyslipidemia, hepatic steatosis, obesity, and type II diabetes are emerging as major global health problems. Acyl-CoA:diacylglycerol acyltransferase (DGAT) is responsible for catalyzing the final reaction in the glycerol phosphate pathway of triglycerol synthesis. It has two isoforms, DGAT-1 and DGAT-2, which are widely expressed and present in white adipose tissue. DGAT-1 is most highly expressed in the small intestine, whereas DGAT-2 is primarily expressed in the liver. Therefore, the selective inhibition of DGAT-1 has become an attractive target with growing potential for the treatment of obesity and type II diabetes. Furthermore, DGAT-2 has been suggested as a new target for the treatment of DGAT-2-related liver diseases including hepatic steatosis, hepatic injury, and fibrosis. In view the discovery of drugs that target DGAT, herein we attempt to provide insight into the scope and further reasons for optimization of DGAT inhibitors. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Tripeptidyl Peptidase II Is Required for c-MYC-Induced Centriole Overduplication and a Novel Therapeutic Target in c-MYC-Associated Neoplasms.

PubMed

Duensing, Stefan; Darr, Sebastian; Cuevas, Rolando; Melquiot, Nadja; Brickner, Anthony G; Duensing, Anette; Münger, Karl

2010-09-01

Centrosome aberrations are frequently detected in c-MYC-associated human malignancies. Here, we show that c-MYC-induced centrosome and centriole overduplication critically depend on the protease tripeptidyl peptidase II (TPPII). We found that TPPII localizes to centrosomes and that overexpression of TPPII, similar to c-MYC, can disrupt centriole duplication control and cause centriole multiplication, a process during which maternal centrioles nucleate the formation of more than a single daughter centriole. We report that inactivation of TPPII using chemical inhibitors or siRNA-mediated protein knockdown effectively reduced c-MYC-induced centriole overduplication. Remarkably, the potent and selective TPPII inhibitor butabindide not only potently suppressed centriole aberrations but also caused significant cell death and growth suppression in aggressive human Burkitt lymphoma cells with c-MYC overexpression. Taken together, these results highlight the role of TPPII in c-MYC-induced centriole overduplication and encourage further studies to explore TPPII as a novel antineoplastic drug target.

Tripeptidyl Peptidase II Is Required for c-MYC–Induced Centriole Overduplication and a Novel Therapeutic Target in c-MYC–Associated Neoplasms

PubMed Central

Duensing, Stefan; Darr, Sebastian; Cuevas, Rolando; Melquiot, Nadja; Brickner, Anthony G.; Duensing, Anette; Münger, Karl

2010-01-01

Centrosome aberrations are frequently detected in c-MYC–associated human malignancies. Here, we show that c-MYC–induced centrosome and centriole overduplication critically depend on the protease tripeptidyl peptidase II (TPPII). We found that TPPII localizes to centrosomes and that overexpression of TPPII, similar to c-MYC, can disrupt centriole duplication control and cause centriole multiplication, a process during which maternal centrioles nucleate the formation of more than a single daughter centriole. We report that inactivation of TPPII using chemical inhibitors or siRNA-mediated protein knockdown effectively reduced c-MYC–induced centriole overduplication. Remarkably, the potent and selective TPPII inhibitor butabindide not only potently suppressed centriole aberrations but also caused significant cell death and growth suppression in aggressive human Burkitt lymphoma cells with c-MYC overexpression. Taken together, these results highlight the role of TPPII in c-MYC–induced centriole overduplication and encourage further studies to explore TPPII as a novel antineoplastic drug target. PMID:21647238

Completeness assessment of type II active pharmaceutical ingredient drug master files under generic drug user fee amendment: review metrics and common incomplete items.

PubMed

Zhang, Huyi; Li, Haitao; Song, Wei; Shen, Diandian; Skanchy, David; Shen, Kun; Lionberger, Robert A; Rosencrance, Susan M; Yu, Lawrence X

2014-09-01

Under the Generic Drug User Fee Amendments (GDUFA) of 2012, Type II active pharmaceutical ingredient (API) drug master files (DMFs) must pay a user fee and pass a Completeness Assessment (CA) before they can be referenced in an Abbreviated New Drug Application (ANDA), ANDA amendment, or ANDA prior approval supplement (PAS). During the first year of GDUFA implementation, from October 1, 2012 to September 30, 2013, approximately 1,500 Type II API DMFs received at least one cycle of CA review and more than 1,100 Type II DMFs were deemed complete and published on FDA's "Available for Reference List". The data from CA reviews were analyzed for factors that influenced the CA review process and metrics, as well as the areas of DMF submissions which most frequently led to an incomplete CA status. The metrics analysis revealed that electronic DMFs appear to improve the completeness of submission and shorten both the review and response times. Utilizing the CA checklist to compile and proactively update the DMFs improves the chance for the DMFs to pass the CA in the first cycle. However, given that the majority of DMFs require at least two cycles of CA before being deemed complete, it is recommended that DMF fees are paid 6 months in advance of the ANDA submissions in order to avoid negatively impacting the filling status of the ANDAs.

Identification of a better Homo sapiens Class II HDAC inhibitor through binding energy calculations and descriptor analysis

PubMed Central

2010-01-01

Human papillomaviruses (HPVs) are the most common on sexually transmitted viruses in the world. HPVs are responsible for a large spectrum of deseases, both benign and malignant. The certain types of HPV are involved in the development of cervical cancer. In attemps to find additional drugs in the treatment of cervical cancer, inhibitors of the histone deacetylases (HDAC) have received much attention due to their low cytotoxic profiles and the E6/E7 oncogene function of human papilomavirus can be completely by passed by HDAC inhibition. The histone deacetylase inhibitors can induce growth arrest, differentiation and apoptosis of cancer cells. HDAC class I and class II are considered the main targets for cancer. Therefore, the six HDACs class II was modeled and about two inhibitors (SAHA and TSA) were docked using AutoDock4.2, to each of the inhibitor in order to identify the pharmacological properties. Based on the results of docking, SAHA and TSA were able to bind with zinc ion in HDACs models as a drug target. SAHA was satisfied almost all the properties i.e., binding affinity, the Drug-Likeness value and Drug Score with 70% oral bioavailability and the carbonyl group of these compound fits well into the active site of the target where the zinc is present. Hence, SAHA could be developed as potential inhibitors of class II HDACs and valuable cervical cancer drug candidate. PMID:21106123

Diuretics: from classical carbonic anhydrase inhibitors to novel applications of the sulfonamides.

PubMed

Supuran, Claudiu T

2008-01-01

The widely clinically used benzothiadiazines and high ceiling diuretics, such as hydrochlorothiazide, hydroflumethiazide, quinethazone, metolazone, chlorthalidone, indapamide, furosemide and bumetanide, contain SO(2)NH(2) moieties acting as an effective zinc-binding function in carbonic anhydrases (CAs, EC 4.2.1.1) inhibitors. These drugs were launched in a period when only isoform CA II was known and considered physiologically/pharmacologically relevant. Although acting as moderate-weak inhibitors of CA II, all these drugs considerably inhibit other CA isozymes known nowadays to be involved in critical physiologic processes, among the 16 CAs present in vertebrates. Some low nanomolar (or even subnanomolar) inhibitors against such isoforms were recently detected, such as metholazone against CA VII, XII and XIII, chlorthalidone against CA VB, VII, IX, XII and XIII, indapamide against CA VII, IX, XII and XIII, furosemide against CA I, II and XIV, and bumethanide against CA IX and XII. The X-ray crystal structure of the CA II-indapamide adduct was also reported recently, revealing interesting aspects useful for the drug design of CA inhibitors. It has also been proposed that the recently observed beneficial effect of indapamide for the treatment of patients with hypertension and type 2 diabetes might be due to its potent inhibition of CA isoforms present in kidneys and blood vessels, which would thus explain both the blood pressure lowering effects as well as organ-protective activity of the drug. Thus, these old drugs may be useful as leads for new applications.

Identification of phase I and II metabolites of the new designer drug α-pyrrolidinohexiophenone (α-PHP) in human urine by liquid chromatography quadrupole time-of-flight mass spectrometry (LC-QTOF-MS).

PubMed

Paul, Michael; Bleicher, Sergej; Guber, Susanne; Ippisch, Josef; Polettini, Aldo; Schultis, Wolfgang

2015-11-01

Pyrrolidinophenones represent one emerging class of newly encountered drugs of abuse, also known as 'new psychoactive substances', with stimulating psychoactive effects. In this work, we report on the detection of the new designer drug α-pyrrolidinohexiophenone (α-PHP) and its phase I and II metabolites in a human urine sample of a drug abuser. Determination and structural elucidation of these metabolites have been achieved by liquid chromatography electrospray ionisation quadrupole time-of-flight mass spectrometry (LC-ESI-QTOF-MS). By tentative identification, the exact and approximate structures of 19 phase I metabolites and nine phase II glucuronides were elucidated. Major metabolic pathways revealed the reduction of the ß-keto moieties to their corresponding alcohols, didesalkylation of the pyrrolidine ring, hydroxylation and oxidation of the aliphatic side chain leading to n-hydroxy, aldehyde and carboxylate metabolites, and oxidation of the pyrrolidine ring to its lactam followed by ring cleavage and additional hydroxylation, reduction and oxidation steps and combinations thereof. The most abundant phase II metabolites were glucuronidated ß-keto-reduced alcohols. Besides the great number of metabolites detected in this sample, α-PHP is still one of the most abundant ions together with its ß-keto-reduced alcoholic dihydro metabolite. Monitoring of these metabolites in clinical and forensic toxicology may unambiguously prove the abuse of the new designer drug α-PHP. Copyright © 2015 John Wiley & Sons, Ltd.

Identification of a better Homo sapiens Class II HDAC inhibitor through binding energy calculations and descriptor analysis.

PubMed

Tambunan, Usman Sumo Friend; Wulandari, Evi Kristin

2010-10-15

Human papillomaviruses (HPVs) are the most common on sexually transmitted viruses in the world. HPVs are responsible for a large spectrum of deseases, both benign and malignant. The certain types of HPV are involved in the development of cervical cancer. In attemps to find additional drugs in the treatment of cervical cancer, inhibitors of the histone deacetylases (HDAC) have received much attention due to their low cytotoxic profiles and the E6/E7 oncogene function of human papilomavirus can be completely by passed by HDAC inhibition. The histone deacetylase inhibitors can induce growth arrest, differentiation and apoptosis of cancer cells. HDAC class I and class II are considered the main targets for cancer. Therefore, the six HDACs class II was modeled and about two inhibitors (SAHA and TSA) were docked using AutoDock4.2, to each of the inhibitor in order to identify the pharmacological properties. Based on the results of docking, SAHA and TSA were able to bind with zinc ion in HDACs models as a drug target. SAHA was satisfied almost all the properties i.e., binding affinity, the Drug-Likeness value and Drug Score with 70% oral bioavailability and the carbonyl group of these compound fits well into the active site of the target where the zinc is present. Hence, SAHA could be developed as potential inhibitors of class II HDACs and valuable cervical cancer drug candidate.

[Treatment options for nystagmus].

PubMed

Tegetmeyer, H

2015-02-01

The goal of treatment for nystagmus is to reduce or to abolish the typical symptoms associated with nystagmus. These are (i) reduction of visual acuity (and amblyopia in infantile nystagmus), (ii) abnormal head posture (with possible secondary changes of cervical spine) and (iii) oscillopsia (often connected with vertigo and disorders of gait and orientation). Treatment strategies include pharmacological treatment, surgical therapy and optical devices. Choice of treatment depends on the type of nystagmus and its characteristics. The following surgical procedures were successfully used as treatment of selected symptoms: (i) unilateral recess-resect surgery of the dominant eye in infantile esotropia with latent nystagmus for the relief of abnormal head posture, (ii) Kestenbaum operation of both eyes in infantile nystagmus syndrome with excentric null zone and abnormal head posture, (iii) recess-resect surgery to produce artificial exophoria in infantile nystagmus syndrome. PHARMACOLOGICAL TREATMENT: Depending on the pathophysiology of different types of nystagmus, several drugs were effective in clinical application (off-label use): (i) gabapentin (non-selective GABAergic and anti-glutamatergic effect): up to 2400 mg/d in infantile nystagmus, acquired pendular nystagmus and oculopalatal tremor, (ii) nemantine (anti-glutamatergic effect): dosage up to 40 mg/d in infantile nystagmus, also in acquired pendular nystagmus and oculopalatal tremor, (iii) baclofen (GABA-B-receptor agonist): 3 × 5-10 mg/d in periodic alternating nystagmus and in upbeat nystagmus, (iv) 4-aminopyridine (non-selective blocker of voltage-gated potassium channels): 3 × 5 mg/d or 1-2 × 10 mg Fampridin in downbeat nystagmus and upbeat nystagmus, (v) acetazolamide (carbonic anhydrase inhibitor): in hereditary episodic ataxia type 2. OPTICAL DEVICES: (i) Contact lenses are used in infantile nystagmus in order to overcome negative effects of eye glasses in abnormal head posture, lateral gaze, and higher refractive errors, (ii) spectacle prisms are useful to induce an artificial exophoria (base-out prisms) or to shift an excentric null zone (base in direction of head posture) of infantile nystagmus with abnormal head posture, (iii) low vision aids may be necessary and should be prescribed according to magnification requirements. Georg Thieme Verlag KG Stuttgart · New York.

Synthesis and Biological Evaluation of Ru(II) and Pt(II) Complexes Bearing Carboxyl Groups as Potential Anticancer Targeted Drugs.

PubMed

Martínez, Ma Ángeles; Carranza, M Pilar; Massaguer, Anna; Santos, Lucia; Organero, Juan A; Aliende, Cristina; de Llorens, Rafael; Ng-Choi, Iteng; Feliu, Lidia; Planas, Marta; Rodríguez, Ana M; Manzano, Blanca R; Espino, Gustavo; Jalón, Félix A

2017-11-20

The synthesis and characterization of Pt(II) (1 and 2) and Ru(II) arene (3 and 4) or polypyridine (5 and 6) complexes is described. With the aim of having a functional group to form bioconjugates, one uncoordinated carboxyl group has been introduced in all complexes. Some of the complexes were selected for their potential in photodynamic therapy (PDT). The molecular structures of complexes 2 and 5, as well as that of the sodium salt of the 4'-(4-carboxyphenyl)-2,2':6',2″-terpyridine ligand (cptpy), were determined by X-ray diffraction. Different techniques were used to evaluate the binding capacity to model DNA molecules, and MTT cytotoxicity assays were performed against four cell lines. Compounds 3, 4, and 5 showed little tendency to bind to DNA and exhibited poor biological activity. Compound 2 behaves as bonded to DNA probably through a covalent interaction, although its cytotoxicity was very low. Compound 1 and possibly 6, both of which contain a cptpy ligand, were able to intercalate with DNA, but toxicity was not observed for 6. However, compound 1 was active in all cell lines tested. Clonogenic assays and apoptosis induction studies were also performed on the PC-3 line for 1. The photodynamic behavior for complexes 1, 5, and 6 indicated that their nuclease activity was enhanced after irradiation at λ = 447 nm. The cell viability was significantly reduced only in the case of 5. The different behavior in the absence or presence of light makes complex 5 a potential prodrug of interest in PDT. Molecular docking studies followed by molecular dynamics simulations for 1 and the counterpart without the carboxyl group confirmed the experimental data that pointed to an intercalation mechanism. The cytotoxicity of 1 and the potential of 5 in PDT make them good candidates for subsequent conjugation, through the carboxyl group, to "selected peptides" which could facilitate the selective vectorization of the complex toward receptors that are overexpressed in neoplastic cell lines.

77 FR 16262 - Importer of Controlled Substances, Notice of Registration; Johnson Matthey, Inc., Pharmaceutical...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-03-20

... substances: Drug Schedule Coca Leaves (9040) II Thebaine (9333) II Opium, raw (9600) II Noroxymorphone (9668... raw materials, to be used in the manufacture of bulk controlled substances, for distribution to its customers. In regard [[Page 16263

Selective attention and drug related attention bias in methadone maintenance patients.

PubMed

Nejati, Majid; Nejati, Vahid; Mohammadi, Mohammad Reza

2011-01-01

One of the main problems of the drug abusers is drug related attention bias, which causes craving, and as a result drive the drug abusers to take narcotics. Methadone is used as a maintenance treatment for drug abusers. The purpose of this study is evaluation of the effect of Methadone maintenance therapy (MMT) on selective attention and drug related attention bias. This study investigated drug cue-related attention bias and selective attention in 16 methadone-maintained patients before and 45 days after methadone therapy period. Stroop color-word test and addiction Stroop test were used as measurement methods. Results show less reaction time and higher accuracy in Color-Word Stroop Test after MMT and less delay for addict related word in addiction Stroop test. It is concluded that methadone can improve selective attention capability and reduce drug related attention bias.

76 FR 81979 - Manufacturer of Controlled Substances; Notice of Registration

Federal Register 2010, 2011, 2012, 2013, 2014

2011-12-29

... DEPARTMENT OF JUSTICE Drug Enforcement Administration Manufacturer of Controlled Substances... Cordova, California 95670, made application to the Drug Enforcement Administration (DEA) as a bulk manufacturer of the following basic classes of controlled substances: Drug Schedule Thebaine (9333) II Poppy...

77 FR 5848 - Manufacturer of Controlled Substances; Notice of Registration

Federal Register 2010, 2011, 2012, 2013, 2014

2012-02-06

... DEPARTMENT OF JUSTICE Drug Enforcement Administration Manufacturer of Controlled Substances... 12194, Research Triangle, North Carolina 27709, made application by renewal to the Drug Enforcement... substances: Drug Schedule Marihuana (7360) I Cocaine (9041) II The Institute will manufacture marihuana, and...

21 CFR 522.311 - Cefovecin.

Code of Federal Regulations, 2013 CFR

2013-04-01

... FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS IMPLANTATION OR INJECTABLE DOSAGE FORM NEW ANIMAL DRUGS § 522.311 Cefovecin. (a... not complete. (ii) Indications for use. For the treatment of skin infections (secondary superficial...

21 CFR 522.311 - Cefovecin.

Code of Federal Regulations, 2011 CFR

2011-04-01

... FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS IMPLANTATION OR INJECTABLE DOSAGE FORM NEW ANIMAL DRUGS § 522.311 Cefovecin. (a... not complete. (ii) Indications for use. For the treatment of skin infections (secondary superficial...

21 CFR 522.311 - Cefovecin.

Code of Federal Regulations, 2014 CFR

2014-04-01

... FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS IMPLANTATION OR INJECTABLE DOSAGE FORM NEW ANIMAL DRUGS § 522.311 Cefovecin. (a... not complete. (ii) Indications for use. For the treatment of skin infections (secondary superficial...

21 CFR 522.311 - Cefovecin.

Code of Federal Regulations, 2012 CFR

2012-04-01

... FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS IMPLANTATION OR INJECTABLE DOSAGE FORM NEW ANIMAL DRUGS § 522.311 Cefovecin. (a... not complete. (ii) Indications for use. For the treatment of skin infections (secondary superficial...

28 CFR 2.219 - Maximum terms of imprisonment and supervised release.

Code of Federal Regulations, 2011 CFR

2011-07-01

... other than above (e.g., marijuana/hashish), or schedule III drugs 3 years 2 years. If schedule IV drugs... PCP 5 years 3 years. If schedule I or II drugs other than above (e.g., marijuana, hashish....g., marijuana, hashish), or schedule III or IV drugs 3 years 2 years. If schedule V drugs 3 years 1...

28 CFR 2.219 - Maximum terms of imprisonment and supervised release.

Code of Federal Regulations, 2013 CFR

2013-07-01

... other than above (e.g., marijuana/hashish), or schedule III drugs 3 years 2 years. If schedule IV drugs... PCP 5 years 3 years. If schedule I or II drugs other than above (e.g., marijuana, hashish....g., marijuana, hashish), or schedule III or IV drugs 3 years 2 years. If schedule V drugs 3 years 1...

28 CFR 2.219 - Maximum terms of imprisonment and supervised release.

Code of Federal Regulations, 2012 CFR

2012-07-01

... other than above (e.g., marijuana/hashish), or schedule III drugs 3 years 2 years. If schedule IV drugs... PCP 5 years 3 years. If schedule I or II drugs other than above (e.g., marijuana, hashish....g., marijuana, hashish), or schedule III or IV drugs 3 years 2 years. If schedule V drugs 3 years 1...

28 CFR 2.219 - Maximum terms of imprisonment and supervised release.

Code of Federal Regulations, 2014 CFR

2014-07-01

... other than above (e.g., marijuana/hashish), or schedule III drugs 3 years 2 years. If schedule IV drugs... PCP 5 years 3 years. If schedule I or II drugs other than above (e.g., marijuana, hashish....g., marijuana, hashish), or schedule III or IV drugs 3 years 2 years. If schedule V drugs 3 years 1...

28 CFR 2.219 - Maximum terms of imprisonment and supervised release.

Code of Federal Regulations, 2010 CFR

2010-07-01

... other than above (e.g., marijuana/hashish), or schedule III drugs 3 years 2 years. If schedule IV drugs... PCP 5 years 3 years. If schedule I or II drugs other than above (e.g., marijuana, hashish....g., marijuana, hashish), or schedule III or IV drugs 3 years 2 years. If schedule V drugs 3 years 1...

Structure-Based Rational Design of Novel Inhibitors Against Fructose-1,6-Bisphosphate Aldolase from Candida albicans.

PubMed

Han, Xinya; Zhu, Xiuyun; Hong, Zongqin; Wei, Lin; Ren, Yanliang; Wan, Fen; Zhu, Shuaihua; Peng, Hao; Guo, Li; Rao, Li; Feng, Lingling; Wan, Jian

2017-06-26

Class II fructose-1,6-bisphosphate aldolases (FBA-II) are attractive new targets for the discovery of drugs to combat invasive fungal infection, because they are absent in animals and higher plants. Although several FBA-II inhibitors have been reported, none of these inhibitors exhibit antifungal effect so far. In this study, several novel inhibitors of FBA-II from C. albicans (Ca-FBA-II) with potent antifungal effects were rationally designed by jointly using a specific protocols of molecular docking-based virtual screening, accurate binding-conformation evaluation strategy, synthesis and enzymatic assays. The enzymatic assays reveal that the compounds 3c, 3e-g, 3j and 3k exhibit high inhibitory activity against Ca-FBA-II (IC 50 < 10 μM), and the most potential inhibitor is 3g, with IC 50 value of 2.7 μM. Importantly, the compounds 3f, 3g, and 3l possess not only high inhibitions against Ca-FBA-II, but also moderate antifungal activities against C. glabrata (MIC 80 = 4-64 μg/mL). The compounds 3g, 3l, and 3k in combination with fluconazole (8 μg/mL) displayed significantly synergistic antifungal activities (MIC 80 < 0.0625 μg/mL) against resistant Candida strains, which are resistant to azoles drugs. The probable binding modes between 3g and the active site of Ca-FBA-II have been proposed by using the DOX (docking, ONIOM, and XO) strategy. To our knowledge, no FBA-II inhibitors with antifungal activities against wild type and resistant strains from Candida were reported previously. The positive results suggest that the strategy adopted in this study are a promising method for the discovery of novel drugs against azole-resistant fungal pathogens in the future.

A prediction model of drug-induced ototoxicity developed by an optimal support vector machine (SVM) method.

PubMed

Zhou, Shu; Li, Guo-Bo; Huang, Lu-Yi; Xie, Huan-Zhang; Zhao, Ying-Lan; Chen, Yu-Zong; Li, Lin-Li; Yang, Sheng-Yong

2014-08-01

Drug-induced ototoxicity, as a toxic side effect, is an important issue needed to be considered in drug discovery. Nevertheless, current experimental methods used to evaluate drug-induced ototoxicity are often time-consuming and expensive, indicating that they are not suitable for a large-scale evaluation of drug-induced ototoxicity in the early stage of drug discovery. We thus, in this investigation, established an effective computational prediction model of drug-induced ototoxicity using an optimal support vector machine (SVM) method, GA-CG-SVM. Three GA-CG-SVM models were developed based on three training sets containing agents bearing different risk levels of drug-induced ototoxicity. For comparison, models based on naïve Bayesian (NB) and recursive partitioning (RP) methods were also used on the same training sets. Among all the prediction models, the GA-CG-SVM model II showed the best performance, which offered prediction accuracies of 85.33% and 83.05% for two independent test sets, respectively. Overall, the good performance of the GA-CG-SVM model II indicates that it could be used for the prediction of drug-induced ototoxicity in the early stage of drug discovery. Copyright © 2014 Elsevier Ltd. All rights reserved.

Neutron structure of human carbonic anhydrase II in complex with methazolamide: Mapping the solvent and hydrogen-bonding patterns of an effective clinical drug

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

Aggarwal, Mayank; Kovalevsky, Andrey Y.; Velazquez, Hector

Carbonic anhydrases (CAs; EC 4.2.1.1) catalyze the interconversion of CO 2 and HCO 3 –, and their inhibitors have long been used as diuretics and as a therapeutic treatment for many disorders such as glaucoma and epilepsy. Acetazolamide (AZM) and methazolamide (MZM, a methyl derivative of AZM) are two of the classical CA inhibitory drugs that have been used clinically for decades. The jointly refined X-ray/neutron structure of MZM in complex with human CA isoform II (hCA II) has been determined to a resolution of 2.2 Å with an R cryst of ~16.0%. Presented in this article, along with onlymore » the second neutron structure of a clinical drug-bound hCA, is an in-depth structural comparison and analyses of differences in hydrogen-bonding network, water-molecule orientation and solvent displacement that take place upon the binding of AZM and MZM in the active site of hCA II. Even though MZM is slightly more hydrophobic and displaces more waters than AZM, the overall binding affinity ( K i) for both of the drugs against hCA II is similar (~10 n M). The plausible reasons behind this finding have also been discussed using molecular dynamics and X-ray crystal structures of hCA II–MZM determined at cryotemperature and room temperature. Furthermore, this study not only allows a direct comparison of the hydrogen bonding, protonation states and solvent orientation/displacement of AZM and MZM, but also shows the significant effect that the methyl derivative has on the solvent organization in the hCA II active site.« less

Neutron structure of human carbonic anhydrase II in complex with methazolamide: Mapping the solvent and hydrogen-bonding patterns of an effective clinical drug

DOE PAGES

Aggarwal, Mayank; Kovalevsky, Andrey Y.; Velazquez, Hector; ...

2016-07-22

Carbonic anhydrases (CAs; EC 4.2.1.1) catalyze the interconversion of CO 2 and HCO 3 –, and their inhibitors have long been used as diuretics and as a therapeutic treatment for many disorders such as glaucoma and epilepsy. Acetazolamide (AZM) and methazolamide (MZM, a methyl derivative of AZM) are two of the classical CA inhibitory drugs that have been used clinically for decades. The jointly refined X-ray/neutron structure of MZM in complex with human CA isoform II (hCA II) has been determined to a resolution of 2.2 Å with an R cryst of ~16.0%. Presented in this article, along with onlymore » the second neutron structure of a clinical drug-bound hCA, is an in-depth structural comparison and analyses of differences in hydrogen-bonding network, water-molecule orientation and solvent displacement that take place upon the binding of AZM and MZM in the active site of hCA II. Even though MZM is slightly more hydrophobic and displaces more waters than AZM, the overall binding affinity ( K i) for both of the drugs against hCA II is similar (~10 n M). The plausible reasons behind this finding have also been discussed using molecular dynamics and X-ray crystal structures of hCA II–MZM determined at cryotemperature and room temperature. Furthermore, this study not only allows a direct comparison of the hydrogen bonding, protonation states and solvent orientation/displacement of AZM and MZM, but also shows the significant effect that the methyl derivative has on the solvent organization in the hCA II active site.« less

Diversion and Illicit Sale of Extended Release Tapentadol in the United States

PubMed Central

Surratt, Hilary L.; Le Lait, Marie-Claire; Stivers, Yami; Bebarta, Vikhyat S.; Freifeld, Clark C.; Brownstein, John S.; Burke, John J.; Kurtz, Steven P.; Dasgupta, Nabarun

2016-01-01

Objective.  Prescription opioid analgesics are commonly prescribed for moderate to severe pain. An unintended consequence of prescribing opioid analgesics is the abuse and diversion of these medications. Tapentadol ER is a recently approved centrally acting analgesic with synergistic mechanisms of action: μ-opioid receptor agonism and inhibition of norepinephrine reuptake. We assessed the amount of diversion and related cost of obtaining tapentadol IR (Nucynta®) and tapentadol ER (Nucynta ER®) as well as other Schedule II opioid medications in street transactions in the United States using the Researched Abuse, Diversion and Addiction-Related Surveillance (RADARS®) System. Methods.  The Drug Diversion Program measures the number of cases opened by 260 drug diversion investigators in 49 states. StreetRxTM uses a crowd-sourcing Website to collect the prices paid for licit or illicit drugs. Results.  The population-based rates of diversion were 0.003 (tapentadol IR), 0.001 (tapentadol ER), and 1.495 (other Schedule II opioid tablets) reports per 100,000 population. The tapentadol ER rate was lower than the other Schedule II opioid tablets (P < 0.001) and tapentadol IR (P= 0.004). Diversion rates based on drug availability were 0.03 (tapentadol IR), 0.016 (tapentadol ER), and 0.172 (other Schedule II opioid tablets) per 1,000 prescriptions dispensed. The median street price per milligram was $0.18 (tapentadol IR), $0.10 (tapentadol ER), and $1.00 (other Schedule II opioid tablets). Discussion.  Our results indicate that tapentadol ER is rarely sold illicitly in the United States. When sold illicitly, tapentadol ER costs less than other Schedule II opioid products. PMID:26814267

Effects of polyamines on the DNA-reactive properties of dimeric mithramycin complexed with cobalt(II): implications for anticancer therapy.

PubMed

Hou, Ming-Hon; Lu, Wen-Je; Huang, Chun-Yu; Fan, Ruey-Jane; Yuann, Jeu-Ming P

2009-06-09

Few studies have examined the effects of polyamines on the action of DNA-binding anticancer drugs. Here, a Co(II)-mediated dimeric mithramycin (Mith) complex, (Mith)(2)-Co(II), was shown to be resistant to polyamine competition toward the divalent metal ion when compared to the Fe(II)-mediated drug complexes. Surface plasmon resonance experiments demonstrated that polyamines interfered with the binding capacity and association rates of (Mith)(2)-Co(II) binding to DNA duplexes, while the dissociation rates were not affected. Although (Mith)(2)-Co(II) exhibited the highest oxidative activity under physiological conditions (pH 7.3 and 37 degrees C), polyamines (spermine in particular) inhibited the DNA cleavage activity of the (Mith)(2)-Co(II) in a concentration-dependent manner. Depletion of intracellular polyamines by methylglyoxal bis(guanylhydrazone) (MGBG) enhanced the sensitivity of A549 lung cancer cells to (Mith)(2)-Co(II), most likely due to the decreased intracellular effect of polyamines on the action of (Mith)(2)-Co(II). Our study suggests a novel method for enhancing the anticancer activity of DNA-binding metalloantibiotics through polyamine depletion.

Extrahepatic ischemia-reperfusion injury reduces hepatic oxidative drug metabolism as determined by serial antipyrine clearance.

PubMed

Gurley, B J; Barone, G W; Yamashita, K; Polston, S; Estes, M; Harden, A

1997-01-01

All transplanted solid organs experience some degree of ischemia-reperfusion (I-R) injury. This I-R injury can contribute to graft dysfunction which stems in part from the acute phase response and a resultant host of cytokines. Recent evidence suggests that organs remote to the site of I-R injury can be affected by circulating cytokines originating from these I-R injuries. Since many of these acute phase cytokines inhibit hepatic cytochrome P-450 (CYP) enzymes, we chose to investigate whether extrahepatic I-R injuries could influence hepatic oxidative drug metabolism. Fifteen dogs were divided into three surgical groups: (I) sham I-R; (II) bilateral normothermic renal I-R; and (III) normothermic intestinal I-R. Antipyrine (AP) was selected as a model substrate and administered intravenously at a dose of 10 mg/kg. AP serum concentrations were determined by HPLC and cytokine activity (IL-1, IL-6, and TNFalpha) was measured via bioassay. Serial AP clearance and serum cytokine concentrations were determined 3 days prior to and at 4 hr, 24 hr, 3 days and 7 days after surgery. Hematology and blood chemistries were monitored throughout the study period. AP clearance was significantly reduced in groups II and III at 4 and 24 hrs post-l-R injury, while AP binding and apparent volume of distribution were unaffected. Peak levels of TNF and IL-6 activity occurred at 1 and 4 hours, respectively. IL-I activity was not detected in any group. AP clearance correlated strongly to circulating levels of IL-6 (r = -0.789, p = 0.0002). Our findings indicate that extrahepatic I-R injury can affect hepatic oxidative drug metabolism and this effect is mediated in part by circulating cytokines.

Selective targeting of alveolar type II respiratory epithelial cells by anti-surfactant protein-C antibody-conjugated lipoplexes

PubMed Central

Wu, Yun; Ma, Junyu; Woods, Parker S.; Chesarino, Nicholas M.; Liu, Chang; Lee, L. James; Nana-Sinkam, Serge P.; Davis, Ian C.

2015-01-01

Alveolar type II (ATII) respiratory epithelial cells are essential to normal lung function. They may be also central to the pathogenesis of diseases such as acute lung injury, pulmonary fibrosis, and pulmonary adenocarcinoma. Hence, ATII cells are important therapeutic targets. However, effective ATII cell-specific drug delivery in vivo requires carriers of an appropriate size, which can cross the hydrophobic alveolar surfactant film and polar aqueous layer overlying ATII cells, and be taken up without inducing ATII cell dysfunction, pulmonary inflammation, lung damage, or excessive systemic spread and side-effects. We have developed lipoplexes as a versatile nanoparticle carrier system for drug/RNA delivery. To optimize their pulmonary localization and ATII cell specificity, lipoplexes were conjugated to an antibody directed against the ATII cell-specific antigen surfactant protein-C (SP-C) then administered to C57BL/6 mice via the nares. Intranasally-administered, anti-SP-C-conjugated lipoplexes targeted mouse ATII cells with >70% specificity in vivo, were retained within ATII cells for at least 48 hours, and did not accumulate at significant levels in other lung cell types or viscera. 48 hours after treatment with anti-SP-C-conjugated lipoplexes containing the test microRNA miR-486, expression of mature miR-486 was approximately 4-fold higher in ATII cells than whole lung by qRT-PCR, and was undetectable in other viscera. Lipoplexes induced no weight loss, hypoxemia, lung dysfunction, pulmonary edema, or pulmonary inflammation over a 6-day period. These findings indicate that ATII cell-targeted lipoplexes exhibit all the desired characteristics of an effective drug delivery system for treatment of pulmonary diseases that result primarily from ATII cell dysfunction. PMID:25687308

Current use of anti-HIV drugs in AIDS.

PubMed

Clumeck, N

1993-07-01

Since 1987 major advances have been made in our understanding of the pathogenesis of infection and the possible inhibition of the HIV virus. Various drugs targeted to the different steps of viral replication have been selected, but drugs such as soluble CD4 or dextran derivatives aimed to inhibit or interfere with the GP120-CD4 attachment step have shown little or no clinical benefit. Protease inhibitors or interferons acting at the post-transcriptional level are currently under phase I to II investigation. The only group of compounds clinically active belong to the nucleosides analogues that act as DNA chain terminators and by inhibiting viral reverse transcriptase. Zidovudine (AZT), didanosine (ddI) and dideoxycytidine (ddC) have been extensively studied, and used on a large clinical scale. Stavudine (D4T), deoxyfluorothymidine (FLT) and 3'thiacytidine (3TC) are entering phase I-II studies. Being the first nucleoside analogue discovered and used since early 1985, zidovudine remains the gold standard of anti-HIV therapy. Zidovudine is indicated at a dosage varying between 500 and 1000 mg in patients with AIDS and ARC, in asymptomatic patients with CD4 < 200/mm3 and in asymptomatic patients with CD4 between 200 and 500 cells/mm3 with a rapid decrease of CD4 cell count or a positive P24 circulating antigen. There is as yet no consensus concerning patients with more than 500 cell/mm3. ddI and ddC are currently indicated for patients intolerant to AZT or in those who have not responded (clinically or biologically) to AZT. Emergence of resistance to AZT has been reported in 30 to 80% of patients at various stages of the disease and after six to nine months of therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Drug Discovery Targeting Serotonin G Protein-Coupled Receptors in the Treatment of Neuropsychiatric Disorders

NASA Astrophysics Data System (ADS)

Felsing, Daniel E.

Clinical data show that activation of 5-HT2C G protein-coupled receptors (GPCRs) can treat obesity (lorcaserin/BelviqRTM) and psychotic disorders (aripiprazole/Abilify.), including schizophrenia. 5-HT2C GPCRs are members of the 5-HT2 sub-family of 5-HT GPCRs, which include 5-HT2A, 5-HT2B, and 5-HT 2C GPCRs. 5-HT2C is structurally similar to 5-HT2A and 5-HT2B GPCRs, but activation of 5-HT2A and/or 5-HT 2B causes deleterious effects, including hallucinations and cardiac valvulopathy. Thus, there is a challenge to develop drugs that selectively activate only 5-HT2C. Prolonged activation of GPCRs by agonists reduces their function via a regulatory process called desensitization. This has clinical relevance, as 45% of drugs approved by the FDA target GPCRs, and agonist drugs (e.g., morphine) typically lose efficacy over time due to desensitization, which invites tolerance. Agonists that cause less desensitization may show extended clinical efficacy as well as a more acceptable clinical dose range. We hypothesized that structurally distinct agonists of the 5-HT2C receptor may cause varying degrees of desensitization by stabilizing unique 5-HT2C receptor conformations. Discovery of 5-HT2C agonists that exhibit minimal desensitization is therapeutically relevant for the pharmacotherapeutic treatment of chronic diseases such as obesity and psychotic disorders. The 5-HT7 receptor has recently been discovered as a druggable target, and selective activation of the 5-HT7 receptor has been shown to alleviate locomotor deficits in mouse models of Rett Syndrome. Additionally, buspirone has been shown to display therapeutically relevant affinity at 5-HT 1A and is currently in phase II clinical trials to treat stereotypy in children with autism. The 5-PAT chemical scaffold shows high affinity towards the 5-HT7 and 5-HT1A receptors. Modulations around the 5-phenyl moiety were able to improve selectivity in binding towards the 5-HT 7 receptor, whereas modulations of the alkyl chains bonded to the vital basic nitrogen modulated 5-HT1A selectivity. The lead candidate, (+)-o-F-5-PAT, was shown effective in attenuating three separate murine models of stereotypy and two models of drug-induced hyperlocomotion. Therefore, the 5-PAT chemical scaffold is a unique chemical scaffold enabling discrimination of therapeutic function of the 5-HT7 and 5-HT 1A receptors in vivo..

21 CFR 520.870 - Etodolac.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 6 2010-04-01 2010-04-01 false Etodolac. 520.870 Section 520.870 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS... (4.5 to 6.8 mg per pound) of body weight per day orally. (ii) Indications for use. For the management...

49 CFR 219.4 - Recognition of a foreign railroad's workplace testing program.

Code of Federal Regulations, 2013 CFR

2013-10-01

... (Continued) FEDERAL RAILROAD ADMINISTRATION, DEPARTMENT OF TRANSPORTATION CONTROL OF ALCOHOL AND DRUG USE... contains equivalents to subparts B, E, F, and G of this part: (i) Pre-employment drug testing; (ii) A policy dealing with co-worker and self-reporting of alcohol and drug abuse problems; (iii) Random drug...

49 CFR 219.4 - Recognition of a foreign railroad's workplace testing program.

Code of Federal Regulations, 2014 CFR

2014-10-01

... (Continued) FEDERAL RAILROAD ADMINISTRATION, DEPARTMENT OF TRANSPORTATION CONTROL OF ALCOHOL AND DRUG USE... contains equivalents to subparts B, E, F, and G of this part: (i) Pre-employment drug testing; (ii) A policy dealing with co-worker and self-reporting of alcohol and drug abuse problems; (iii) Random drug...

49 CFR 219.4 - Recognition of a foreign railroad's workplace testing program.

Code of Federal Regulations, 2011 CFR

2011-10-01

... (Continued) FEDERAL RAILROAD ADMINISTRATION, DEPARTMENT OF TRANSPORTATION CONTROL OF ALCOHOL AND DRUG USE... contains equivalents to subparts B, E, F, and G of this part: (i) Pre-employment drug testing; (ii) A policy dealing with co-worker and self-reporting of alcohol and drug abuse problems; (iii) Random drug...

49 CFR 219.4 - Recognition of a foreign railroad's workplace testing program.

Code of Federal Regulations, 2012 CFR

2012-10-01

... (Continued) FEDERAL RAILROAD ADMINISTRATION, DEPARTMENT OF TRANSPORTATION CONTROL OF ALCOHOL AND DRUG USE... contains equivalents to subparts B, E, F, and G of this part: (i) Pre-employment drug testing; (ii) A policy dealing with co-worker and self-reporting of alcohol and drug abuse problems; (iii) Random drug...

Bayesian dose selection design for a binary outcome using restricted response adaptive randomization.

PubMed

Meinzer, Caitlyn; Martin, Renee; Suarez, Jose I

2017-09-08

In phase II trials, the most efficacious dose is usually not known. Moreover, given limited resources, it is difficult to robustly identify a dose while also testing for a signal of efficacy that would support a phase III trial. Recent designs have sought to be more efficient by exploring multiple doses through the use of adaptive strategies. However, the added flexibility may potentially increase the risk of making incorrect assumptions and reduce the total amount of information available across the dose range as a function of imbalanced sample size. To balance these challenges, a novel placebo-controlled design is presented in which a restricted Bayesian response adaptive randomization (RAR) is used to allocate a majority of subjects to the optimal dose of active drug, defined as the dose with the lowest probability of poor outcome. However, the allocation between subjects who receive active drug or placebo is held constant to retain the maximum possible power for a hypothesis test of overall efficacy comparing the optimal dose to placebo. The design properties and optimization of the design are presented in the context of a phase II trial for subarachnoid hemorrhage. For a fixed total sample size, a trade-off exists between the ability to select the optimal dose and the probability of rejecting the null hypothesis. This relationship is modified by the allocation ratio between active and control subjects, the choice of RAR algorithm, and the number of subjects allocated to an initial fixed allocation period. While a responsive RAR algorithm improves the ability to select the correct dose, there is an increased risk of assigning more subjects to a worse arm as a function of ephemeral trends in the data. A subarachnoid treatment trial is used to illustrate how this design can be customized for specific objectives and available data. Bayesian adaptive designs are a flexible approach to addressing multiple questions surrounding the optimal dose for treatment efficacy within the context of limited resources. While the design is general enough to apply to many situations, future work is needed to address interim analyses and the incorporation of models for dose response.

Substance use in pregnancy.

PubMed

Wong, Suzanne; Ordean, Alice; Kahan, Meldon

2011-04-01

To improve awareness and knowledge of problematic substance use in pregnancy and to provide evidence-based recommendations for the management of this challenging clinical issue for all health care providers. This guideline reviews the use of screening tools, general approach to care, and recommendations for clinical management of problematic substance use in pregnancy. Evidence-based recommendations for screening and management of problematic substance use during pregnancy and lactation. Medline, PubMed, CINAHL, and The Cochrane Library were searched for articles published from 1950 using the following key words: substance-related disorders, mass screening, pregnancy complications, pregnancy, prenatal care, cocaine, cannabis, methadone, opioid, tobacco, nicotine, solvents, hallucinogens, and amphetamines. Results were initially restricted to systematic reviews and randomized control trials/controlled clinical trials. A subsequent search for observational studies was also conducted because there are few RCTs in this field of study. Articles were restricted to human studies published in English. Additional articles were located by hand searching through article reference lists. Searches were updated on a regular basis and incorporated in the guideline up to December 2009. Grey (unpublished) literature was also identified through searching the websites of health technology assessment and health technology assessment-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies. The quality of evidence was rated using the criteria described in the Report of the Canadian Task Force on the Preventive Health Care. Recommendations for practice were ranked according to the method described in that report (Table 1). This guideline is intended to increase the knowledge and comfort level of health care providers caring for pregnant women who have substance use disorders. Improved access to health care and assistance with appropriate addiction care leads to reduced health care costs and decreased maternal and neonatal morbidity and mortality. 1. All pregnant women and women of childbearing age should be screened periodically for alcohol, tobacco, and prescription and illicit drug use. (III-A) 2. When testing for substance use is clinically indicated, urine drug screening is the preferred method. (II-2A) Informed consent should be obtained from the woman before maternal drug toxicology testing is ordered. (III-B) 3. Policies and legal requirements with respect to drug testing of newborns may vary by jurisdiction, and caregivers should be familiar with the regulations in their region. (III-A) 4. Health care providers should employ a flexible approach to the care of women who have substance use problems, and they should encourage the use of all available community resources. (II-2B) 5. Women should be counselled about the risks of periconception, antepartum, and postpartum drug use. (III-B) 6. Smoking cessation counselling should be considered as a first-line intervention for pregnant smokers. (I-A) Nicotine replacement therapy and/or pharmacotherapy can be considered if counselling is not successful. (I-A) 7. Methadone maintenance treatment should be standard of care for opioid-dependent women during pregnancy. (II-IA) Other slow-release opioid preparations may be considered if methadone is not available. (II-2B) 8. Opioid detoxification should be reserved for selected women because of the high risk of relapse to opioids. (II-2B) 9. Opiate-dependent women should be informed that neonates exposed to heroin, prescription opioids, methadone, or buprenorphine during pregnancy are monitored closely for symptoms and signs of neonatal withdrawal (neonatal abstinence syndrome). (II-2B) Hospitals providing obstetric care should develop a protocol for assessment and management of neonates exposed to opiates during pregnancy. (III-B) 10. Antenatal planning for intrapartum and postpartum analgesia may be offered for all women in consultation with appropriate health care providers. (III-B) 11. The risks and benefits of breastfeeding should be weighed on an individual basis because methadone maintenance therapy is not a contraindication to breastfeeding. (II-3B).

EFFECT OF HYDROPHILIC AND HYDROPHOBIC POLYMER ON IN VITRO DISSOLUTION AND PERMEATION OF BISOPROLOL FUMARATE THROUGH TRANSDERMAL PATCH.

PubMed

Shabbir, Maryam; Ali, Sajid; Raza, Moosa; Sharif, Ali; Akhtar, Furoan Muhammad; Manan, Abdul; Fazli, Ali Raza; Younas, Neelofar; Manzoor, Iqra

2017-01-01

A matrix transdermal patch of bisoprolol fumarate was formulated with different concentrations of Eudragit RS 100 and Methocel E5 with PEG 400 as plasticizer by solvent evaporation technique. Tween 80 was added to the optimized patch to evaluate the effect of permeation enhancer at different concentration through the excised rabbit's skin. The patches were analyzed for weight variation, drug content, swelling index, erosion studies, moisture content, moisture uptake, water vapor transmission rate (WVTR) and water vapor permeability (WVP). In vitro dissolution test was carried out in USP dissolution apparatus V to select the optimized formulation. In vitr skin permeation studies were done in Franz diffusion cell using rabbit skin as a model membrane. The cumulative drug release and flux were determined to compare the result of test patches with a control patch. The greatest enhancement ratio (ER) was obtained in F03-PE with 30% Tween 80. F03-PE seemed to follow zero order kinetics with super case II mechanism of drug release. Statistical ANOVA suggested that there was a significant difference in formulations, steady flux and cumulative permeation rate at different Tween 80 concentrations.

77 FR 43861 - Importer of Controlled Substances; Notice Of Application; Cody Laboratories, Inc.

Federal Register 2010, 2011, 2012, 2013, 2014

2012-07-26

... basic class of any controlled substance in schedule I or II are, and will continue to be, required to... importer of the following basic classes of controlled substances: Drug Schedule Opium, Raw (9600) II Concentrate Poppy Straw (9670) II Tapentadol (9780) II The company plans to import narcotic raw materials for...

Amsacrine as a Topoisomerase II Poison: Importance of Drug-DNA Interactions†

PubMed Central

Ketron, Adam C.; Denny, William A.; Graves, David E.; Osheroff, Neil

2012-01-01

Amsacrine (m-AMSA) is an anticancer agent that displays activity against refractory acute leukemias as well as Hodgkin’s and non-Hodgkin’s lymphomas. The drug is comprised of an intercalative acridine moiety coupled to a 4’-amino-methanesulfon-m-anisidide head group. m-AMSA is historically significant in that it was the first drug demonstrated to function as a topoisomerase II poison. Although m-AMSA was designed as a DNA binding agent, the ability to intercalate does not appear to be the sole determinant of drug activity. Therefore, to more fully analyze structure-function relationships and the role of DNA binding in the action of m-AMSA, we analyzed a series of derivatives for the ability to enhance DNA cleavage mediated by human topoisomerase IIα and topoisomerase IIβ and to intercalate DNA. Results indicate that the 3’-methoxy (m-AMSA) positively affects drug function, potentially by restricting the rotation of the head group in a favorable orientation. Shifting the methoxy to the 2’-position (o-AMSA), which abrogates drug function, appears to increase rotational freedom of the head group and may impair interactions of the 1’-substituent or other portions of the head group within the ternary complex. Finally, the non-intercalative m-AMSA head group enhanced enzyme-mediated DNA cleavage when it was detached from the acridine moiety, albeit with 100-fold lower affinity. Taken together, our results suggest that much of the activity and specificity of m-AMSA as a topoisomerase II poison is embodied in the head group, while DNA intercalation is used primarily to increase the affinity of m-AMSA for the topoisomerase II-DNA cleavage complex. PMID:22304499

Synthesis and topoisomerase II inhibitory and cytotoxic activity of oxiranylmethoxy- and thiiranylmethoxy-chalcone derivatives.

PubMed

Na, Younghwa; Nam, Jung-Min

2011-01-01

In order to find potential anticancer drug candidate targeting topoisomerases enzyme, we have designed and synthesized oxiranylmethoxy- and thiiranylmethoxy-retrochalcone derivatives and evaluated their pharmacological activity including topoisomerases inhibitory and cytotoxic activity. Of the compounds prepared compound 25 showed comparable or better cytotoxic activity against cancer cell lines tested. Compound 25 inhibited MCF7 (IC(50): 0.49 ± 0.21 μM) and HCT15 (IC(50): 0.23 ± 0.02 μM) carcinoma cell growth more efficiently than references. In the topoisomerases inhibition test, all the compounds were inactive to topoisomerase I but moderate inhibitors to topoisomerase II enzyme. Especially, compound 25 inhibited topoisomerase II activity with comparable extent to etoposide at 100 μM concentrations. Correlation between cytotoxicity and topoisomerase II inhibitory activity implies that compound 25 can be a possible lead compound for anticancer drug impeding the topoisomerase II function. Copyright © 2010 Elsevier Ltd. All rights reserved.

Fungal Zinc Homeostasis - A Tug of War Between the Pathogen and Host.

PubMed

Walencik, Paulina K; Watly, Joanna; Rowinska-Zyrek, Magdalena

2016-01-01

In the last decade, drug resistant invasive mycoses have become significantly more common and new antifungal drugs and ways to specifically deliver them to the fungal cell are being looked for. One of the biggest obstacles in finding such comes from the fact that fungi share essential metabolic pathways with humans. One significant difference in the metabolism of those two cells that can be challenged when looking for possible selective therapeutics is the uptake of zinc, a nutrient crucial for the fungal survival and virulence. This work summarizes the recent advances in the biological inorganic chemistry of zinc metabolism in fungi. The regulation of zinc uptake, various types of its transmembrane transport, storage and the maintenance of intracellular zinc homeostasis is discussed in detail, with a special focus on the concept of a constant 'tug of war' over zinc between the fungus and its host, with the host trying to withhold essential Zn(II), and the fungus counteracting by producing high-affinity zinc binding molecules.

Poly(ortho esters)--from concept to reality.

PubMed

Heller, Jorge; Barr, John

2004-01-01

The development of poly(ortho esters) dates back to the early 1970s, and during that time, four distinct families were developed. These polymers can be prepared by a transesterification reaction or by the addition of polyols to diketene acetals, and it is the latter method that has proven to be preferred one. The latest polymer, now under intense development, incorporates a latent acid segment in the polymer backbone that takes advantage of the acid-labile nature of the ortho ester linkages and allows control over erosion rates. By use of diols having selected chain flexibility, polymers that range from hard, brittle materials to materials that have a gel-like consistency at room temperature can be obtained. Drug release from solid materials will be illustrated with 5-fluorouacil and bovine serum albumin, and drug release from gel-like materials will be illustrated with mepivacaine, now in Phase II clinical trials as a delivery system to treat post-operative pain. A brief summary of preclinical toxicology studies is also presented.

Discovery of the Highly Potent PI3K/mTOR Dual Inhibitor PF-04979064 through Structure-Based Drug Design

PubMed Central

2012-01-01

PI3K, AKT, and mTOR are key kinases from PI3K signaling pathway being extensively pursued to treat a variety of cancers in oncology. To search for a structurally differentiated back-up candidate to PF-04691502, which is currently in phase I/II clinical trials for treating solid tumors, a lead optimization effort was carried out with a tricyclic imidazo[1,5]naphthyridine series. Integration of structure-based drug design and physical properties-based optimization yielded a potent and selective PI3K/mTOR dual kinase inhibitor PF-04979064. This manuscript discusses the lead optimization for the tricyclic series, which both improved the in vitro potency and addressed a number of ADMET issues including high metabolic clearance mediated by both P450 and aldehyde oxidase (AO), poor permeability, and poor solubility. An empirical scaling tool was developed to predict human clearance from in vitro human liver S9 assay data for tricyclic derivatives that were AO substrates. PMID:24900568

Simultaneous Identification of Four "Legal High" Plant Species in a Multiplex PCR High-Resolution Melt Assay.

PubMed

Elkins, Kelly M; Perez, Anjelica C U; Quinn, Alicia A

2017-05-01

The international prevalence of "legal high" drugs necessitates the development of a method for their detection and identification. Herein, we describe the development and validation of a tetraplex multiplex real-time polymerase chain reaction (PCR) assay used to simultaneously identify morning glory, jimson weed, Hawaiian woodrose, and marijuana detected by high-resolution melt using LCGreen Plus ® . The PCR assay was evaluated based on the following: (i) specificity and selectivity-primers were tested on DNA extracted from 30 species and simulated forensic samples, (ii) sensitivity-serial dilutions of the target DNA were prepared, and (iii) reproducibility and reliability-sample replicates were tested and remelted on different days. The assay is ideal for cases in which inexpensive assays are needed to quickly detect and identify trace biological material present on drug paraphernalia that is too compromised for botanical microscopic identification and for which analysts are unfamiliar with the morphology of the emerging "legal high" species. © 2016 American Academy of Forensic Sciences.

Keep calm and have a good night: nurses' strategies to promote inpatients' sleep in the hospital environment.

PubMed

Salzmann-Erikson, Martin; Lagerqvist, Linda; Pousette, Sandra

2016-06-01

Patients in the hospital environment are suffering from disrupted sleep, which adversely affects their recovery process, health and well-being. The aim of this study was to explore nurses' experiences and their strategies to promote inpatients' sleep. An empirical qualitative design was applied. Eight nurses at a hospital in Sweden were purposefully selected to be included in semi-structured interviews. Burnard's method for inductively analysing interview transcripts was applied. The findings are presented in four categories: (i) prevention and planning as a sleep-promoting nursing strategy; (ii) adaptation of the environment as a sleep-promoting nursing strategy; (iii) use of drugs as a sleep-promoting nursing strategy; and (iv) caring conversation as a sleep-promoting nursing strategy. Using strategies to promote sleep is important as it affects the recovery of the patients. We argue for the use of simple strategies of sensory reduction as cost-effective sleep-promoting measures that also reduce the use of sedative drugs. © 2015 Nordic College of Caring Science.

HDAC2 deregulation in tumorigenesis is causally connected to repression of immune modulation and defense escape

PubMed Central

Conte, Mariarosaria; Dell'Aversana, Carmela; Benedetti, Rosaria; Petraglia, Francesca; Carissimo, Annamaria; Petrizzi, Valeria Belsito; D'Arco, Alfonso Maria; Abbondanza, Ciro; Nebbioso, Angela; Altucci, Lucia

2015-01-01

Histone deacetylase 2 (HDAC2) is overexpressed or mutated in several disorders such as hematological cancers, and plays a critical role in transcriptional regulation, cell cycle progression and developmental processes. Here, we performed comparative transcriptome analyses in acute myeloid leukemia to investigate the biological implications of HDAC2 silencing versus its enzymatic inhibition using epigenetic-based drug(s). By gene expression analysis of HDAC2-silenced vs wild-type cells, we found that HDAC2 has a specific role in leukemogenesis. Gene expression profiling of U937 cell line with or without treatment of the well-known HDAC inhibitor vorinostat (SAHA) identifies and characterizes several gene clusters where inhibition of HDAC2 ‘mimics’ its silencing, as well as those where HDAC2 is selectively and exclusively regulated by HDAC2 protein expression levels. These findings may represent an important tool for better understanding the mechanisms underpinning immune regulation, particularly in the study of major histocompatibility complex class II genes. PMID:25473896

Structure-activity relationships of phenothiazines and related drugs for inhibition of protein kinase C.

PubMed

Aftab, D T; Ballas, L M; Loomis, C R; Hait, W N

1991-11-01

Phenothiazines are known to inhibit the activity of protein kinase C. To identify structural features that determine inhibitory activity against the enzyme, we utilized a semiautomated assay [Anal. Biochem. 187:84-88 (1990)] to compare the potency of greater than 50 phenothiazines and related compounds. Potency was decreased by trifluoro substitution at position 2 on the phenothiazine nucleus and increased by quinoid structures on the nucleus. An alkyl bridge of at least three carbons connecting the terminal amine to the nucleus was required for activity. Primary amines and unsubstituted piperazines were the most potent amino side chains. We selected 7,8-dihydroxychlorpromazine (DHCP) (IC50 = 8.3 microM) and 2-chloro-9-(3-[1-piperazinyl]propylidene)thioxanthene (N751) (IC50 = 14 microM) for further study because of their potency and distinct structural features. Under standard (vesicle) assay conditions, DHCP was noncompetitive with respect to phosphatidylserine and a mixed-type inhibitor with respect to ATP. N751 was competitive with respect to phosphatidylserine and noncompetitive with respect to ATP. Using the mixed micelle assay, DHCP was a competitive inhibitor with respect to both phosphatidylserine and ATP. DHCP was selective for protein kinase C compared with cAMP-dependent protein kinase, calmodulin-dependent protein kinase type II, and casein kinase. N751 was more potent against protein kinase C compared with cAMP-dependent protein kinase and casein kinase but less potent against protein kinase C compared with calmodulin-dependent protein kinase type II. DHCP was analyzed for its ability to inhibit different isoenzymes of protein kinase C, and no significant isozyme selectivity was detected. These data provide important information for the rational design of more potent and selective inhibitors of protein kinase C.

[Drug supplies in primary care units at the Ministry of Health in Mexico].

PubMed

Gómez-Dantés, O; Garrido-Latorre, F; Tirado-Gómez, L L; Ramírez, D; Macías, C

2001-01-01

To identify the availability of some essential drugs (ED) at primary health care units of the Mexican Ministry of Health (SSA), using data from a research work conducted in 1996 and 1997. A random sample of the 18 sanitary jurisdictions of states participating in the Extension of Coverage Program (ECP) was drawn. All primary care units from selected jurisdictions were evaluated through an inspection visit, using a checklist that included 36 ED. In phase I of the analysis, the absolute number and proportion of units without a single item of any of the 36 drugs were calculated. In the units with available drugs, the median of the distribution was also calculated. In phase II, the medians according to the type of health unit and state was obtained. The statistic utilized for the comparison of the medians was the Scheffé test with one way variance analysis. In addition, the drugs were classified according to their therapeutic indication and the medians and proportion of available drugs were calculated. The differences in proportion were evaluated with the statistic chi 2. During the visits, on average, 18 of the 36 drugs included in the list of the study were found in the health units. The availability of antibiotics, antituberculosis drugs, and antimalarial drugs was particularly poor. In contrast, oral rehydration salts, family planning methods and vaccines were usually available. In general, the PAC3 states presented the best availability figures. The Ministry of Health of México will have to develop an enormous effort to overcome the obstacles related to the supply of essential drugs in primary health care units. Otherwise, all other efforts directed to meet the needs of the non-insured population will end up being useless, and enormous amounts of the already scarce resources of the health sector will be wasted since drugs are a vital component of the long chain of health care.

Banned -- Select: "a drug to alter the sex of the foetus".

PubMed

Unnikrishnan, P V

1993-04-01

In 1991, the Government of Gujarat State, India, banned the manufacture and sale of an Ayurvedic drug called Select. This was the first time an Ayurvedic product had ever been banned. The manufacturer claimed that if a pregnant woman took Select for 45 days after her last menstrual period, she would have a male fetus. Further, the manufacturer marketed the drug as a tool which would change the dowry system (i.e., it would reduce the number of girls in the population). Select's high cost did not deter the naive and trusting public in Gujarat and other states. Drug activists and consumer groups called for the ban and noted that the marketing claims were typical of the unethical behavior of the Ayurvedic market. These consumer groups brought the existence of Select to the attention of the government which admittedly cannot adequately monitor and control the drug market. Groups ranging from illegal smugglers to multinational giants use loopholes in the Drugs and Cosmetics Act and Excise Laws to license their drugs as Ayurvedic/Herbal, but most drugs are hazardous. Policy makers, physicians, nongovernmental and consumer groups, the media, and others should join together to rid India of this unethical practice. They should help the government to implement a rational policy for traditional systems of medicine and, once the policy has been developed to select an essential drug list of Ayurvedic drugs needed for national health programs; monitor and minimize misleading advertisements; screen all existing Ayurvedic drugs and drugs of other traditional medicine systems; and require thorough research on the relevance, usefulness, and safety of new patent drugs of other traditional medicine systems; and require thorough research on the relevance, usefulness, and safety of new patent drugs. The government should declare any products with more than 12% alcohol to be liquor.

21 CFR 884.1425 - Perineometer.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Perineometer. 884.1425 Section 884.1425 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES... correct, through exercise, uninary incontinence or sexual dysfunction. (b) Classification. Class II...

21 CFR 884.1425 - Perineometer.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Perineometer. 884.1425 Section 884.1425 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES... correct, through exercise, uninary incontinence or sexual dysfunction. (b) Classification. Class II...

21 CFR 884.1425 - Perineometer.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Perineometer. 884.1425 Section 884.1425 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES... correct, through exercise, uninary incontinence or sexual dysfunction. (b) Classification. Class II...

21 CFR 884.1425 - Perineometer.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Perineometer. 884.1425 Section 884.1425 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES... correct, through exercise, uninary incontinence or sexual dysfunction. (b) Classification. Class II...

21 CFR 884.1425 - Perineometer.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Perineometer. 884.1425 Section 884.1425 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES... correct, through exercise, uninary incontinence or sexual dysfunction. (b) Classification. Class II...

21 CFR 868.1900 - Diagnostic pulmonary-function interpretation calculator.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Diagnostic pulmonary-function interpretation calculator. 868.1900 Section 868.1900 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND... pulmonary-function values. (b) Classification. Class II (performance standards). ...

21 CFR 868.1900 - Diagnostic pulmonary-function interpretation calculator.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Diagnostic pulmonary-function interpretation calculator. 868.1900 Section 868.1900 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND... pulmonary-function values. (b) Classification. Class II (performance standards). ...

21 CFR 868.1620 - Halothane gas analyzer.

Code of Federal Regulations, 2010 CFR

2010-04-01

... infrared or ultraviolet radiation. (b) Classification. Class II (performance standards). ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Halothane gas analyzer. 868.1620 Section 868.1620 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED...

76 FR 7233 - Importer of Controlled Substances; Notice of Registration

Federal Register 2010, 2011, 2012, 2013, 2014

2011-02-09

... DEPARTMENT OF JUSTICE Drug Enforcement Administration Importer of Controlled Substances; Notice of..., made application by renewal to the Drug Enforcement Administration (DEA) to be registered as an importer of the following basic classes of controlled substances: Drug Schedule Methamphetamine (1105) II...

78 FR 52802 - Manufacturer of Controlled Substances; Notice of Registration: Navinta, LLC

Federal Register 2010, 2011, 2012, 2013, 2014

2013-08-26

... DEPARTMENT OF JUSTICE Drug Enforcement Administration Manufacturer of Controlled Substances..., made application to the Drug Enforcement Administration (DEA) to be registered as a bulk manufacturer of the following basic classes of controlled substances: Drug Schedule Pentobarbital (2270) II...

21 CFR 882.4560 - Stereotaxic instrument.

Code of Federal Regulations, 2012 CFR

2012-04-01

... part of the nervous system. (b) Classification. Class II (performance standards). ... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Stereotaxic instrument. 882.4560 Section 882.4560 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED...

21 CFR 882.4560 - Stereotaxic instrument.

Code of Federal Regulations, 2014 CFR

2014-04-01

... part of the nervous system. (b) Classification. Class II (performance standards). ... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Stereotaxic instrument. 882.4560 Section 882.4560 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED...

21 CFR 882.4560 - Stereotaxic instrument.

Code of Federal Regulations, 2013 CFR

2013-04-01

... part of the nervous system. (b) Classification. Class II (performance standards). ... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Stereotaxic instrument. 882.4560 Section 882.4560 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED...

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

PubMed

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

1997-04-01

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

EFFECT OF CADMIUM(II) ON FREE RADICALS IN DOPA-MELANIN TESTED BY EPR SPECTROSCOPY.

PubMed

Zdybel, Magdalena; Pilawa, Barbara; Chodurek, Ewa

2015-01-01

Electron paramagnetic resonance (EPR) spectroscopy may be applied to examine interactions of melanin with metal ions and drugs. In this work EPR method was used to examination of changes in free radical system of DOPA-melanin--the model eumelanin after complexing with diamagnetic cadmium(II) ions. Cadmium(II) may affect free radicals in melanin and drugs binding by this polymer, so the knowledge of modification of properties and free radical concentration in melanin is important to pharmacy. The effect of cadmium(II) in different concentrations on free radicals in DOPA-melanin was determined. EPR spectra of DOPA-melanin, and DOPA-melanin complexes with cadmium(II) were measured by an X-band (9.3 GHz) EPR spectrometer produced by Radiopan (Poznań, Poland) and the Rapid Scan Unit from Jagmar (Krak6w, Poland). The DOPA (3,4-dihydroxyphenylalanine) to metal ions molar ratios in the reaction mixtures were 2:1, 1:1, and 1: 2. High concentrations of o-semiquinone (g ~2.0040) free radicals (~10(21)-10(22) spin/g) characterize DOPA-melanin and its complexes with cadmium(II). Formation of melanin complexes with cadmium(II) increase free radical concentration in DOPA-melanin. The highest free radical concentration was obtained for DOPA-melanin-cadmium(II) (1:1) complexes. Broad EPR lines with linewidths: 0.37-0.73 mT, were measured. Linewidths increase after binding of cadmium(II) to melanin. Changes of integral intensities and linewidths with increasing microwave power indicate the homogeneous broadening of EPR lines, independently on the metal ion concentration. Slow spin-lattice relaxation processes existed in all the tested samples, their EPR lines saturated at low microwave powers. Cadmium(II) causes fastening of spin-lattice relaxation processes in DOPA-melanin. The EPR results bring to light the effect of cadmium(II) on free radicals in melanin, and probably as the consequence on drug binding to eumelanin.

Consumer perceptions of prescription drug websites: a pilot study.

PubMed

Wymer, Walter

2010-04-01

Consumer perceptions of the information content contained on prescription drug websites was of interest in this investigation. Twenty branded prescription drugs were selected because they were evaluated as being poor consumer choices for safety reasons or because better alternatives existed. Study participants visited each of 20 websites for the selected drugs, and then they answered a series of questions for each website, in order to evaluate each website's information content. Participants, without knowing the selected prescription drugs were selected because they were problematic, reported that the drug company information was complete, fully presenting benefit and risk information, without being false or misleading in any respect. Pricing information was generally not provided by drug companies. Alternative medicines, treatments, and behavioral approaches for dealing with an illness or health condition were generally not part of the information provided by drug companies. Public policy implications are also discussed.

Orthopedic devices; classification for the resorbable calcium salt bone void filler device. Final rule.

PubMed

2003-06-02

The Food and Drug Administration (FDA) is classifying the resorbable calcium salt bone void filler device intended to fill bony voids or gaps of the extremities, spine, and pelvis that are caused by trauma or surgery and are not intrinsic to the stability of the bony structure into class II (special controls). Elsewhere in this issue of the Federal Register, FDA is announcing the availability of a class II special controls guidance entitled "Class II Special Controls Guidance Document: Resorbable Calcium Salt Bone Void Filler Device; Guidance for Industry and FDA." This action is being undertaken based on new information submitted in a classification proposal from Wright Medical Technology under the Federal Food, Drug, and Cosmetic Act as amended by the Medical Device Amendments of 1976, the Safe Medical Devices Act of 1990, and the Food and Drug Administration Modernization Act of 1997.

Challenges of Antibacterial Discovery

PubMed Central

Silver, Lynn L.

2011-01-01

Summary: The discovery of novel small-molecule antibacterial drugs has been stalled for many years. The purpose of this review is to underscore and illustrate those scientific problems unique to the discovery and optimization of novel antibacterial agents that have adversely affected the output of the effort. The major challenges fall into two areas: (i) proper target selection, particularly the necessity of pursuing molecular targets that are not prone to rapid resistance development, and (ii) improvement of chemical libraries to overcome limitations of diversity, especially that which is necessary to overcome barriers to bacterial entry and proclivity to be effluxed, especially in Gram-negative organisms. Failure to address these problems has led to a great deal of misdirected effort. PMID:21233508

Geographic patterns of Plasmodium falciparum drug resistance distinguished by differential responses to amodiaquine and chloroquine

PubMed Central

Sá, Juliana Martha; Twu, Olivia; Hayton, Karen; Reyes, Sahily; Fay, Michael P.; Ringwald, Pascal; Wellems, Thomas E.

2009-01-01

Chloroquine (CQ) resistance (CQR) in Plasmodium falciparum originated from at least six foci in South America, Asia, and Oceania. Malaria parasites from these locations exhibit contrasting resistance phenotypes that are distinguished by point mutations and microsatellite polymorphisms in and near the CQR transporter gene, pfcrt, and the multidrug resistance transporter gene, pfmdr1. Amodiaquine (AQ), a 4-aminoquinoline related to CQ, is recommended and often used successfully against CQ-resistant P. falciparum in Africa, but it is largely ineffective across large regions of South America. The relationship of different pfcrt and pfmdr1 combinations to these drug-resistant phenotypes has been unclear. In two P. falciparum genetic crosses, particular pfcrt and pfmdr1 alleles from South America interact to yield greater levels of resistance to monodesethylamodiaquine (MDAQ; the active metabolite of AQ) than to CQ, whereas a pfcrt allele from Southeast Asia and Africa is linked to greater CQ than MDAQ resistance with all partner pfmdr1 alleles. These results, together with (i) available haplotype data from other parasites; (ii) evidence for an emerging focus of AQ resistance in Tanzania; and (iii) the persistence of 4-aminoquinoline-resistant parasites in South America, where CQ and AQ use is largely discontinued, suggest that different histories of drug use on the two continents have driven the selection of distinct suites of pfcrt and pfmdr1 mutations. Increasing use of AQ in Africa poses the threat of a selective sweep of highly AQ-resistant, CQ-resistant parasites with pfcrt and pfmdr1 mutations that are as advantaged and persistent as in South America. PMID:19884511

Development of an HPLC-UV Method for the Analysis of Drugs Used for Combined Hypertension Therapy in Pharmaceutical Preparations and Human Plasma.

PubMed

Kepekci Tekkeli, Serife Evrim

2013-01-01

A simple, rapid, and selective HPLC-UV method was developed for the determination of antihypertensive drug substances: amlodipine besilat (AML), olmesartan medoxomil (OLM), valsartan (VAL), and hydrochlorothiazide (HCT) in pharmaceuticals and plasma. These substances are mostly used as combinations. The combinations are found in various forms, especially in current pharmaceuticals as threesome components: OLM, AML, and HCT (combination I) and AML, VAL, and HCT (combination II). The separation was achieved by using an RP-CN column, and acetonitrile-methanol-10 mmol orthophosphoric acid pH 2.5 (7 : 13 : 80, v/v/v) was used as a mobile phase; the detector wavelength was set at 235 nm. The linear ranges were found as 0.1-18.5  μ g/mL, 0.4-25.6  μ g/mL, 0.3-15.5  μ g/mL, and 0.3-22  μ g/mL for AML, OLM, VAL, and HCT, respectively. In order to check the selectivity of the method for pharmaceutical preparations, forced degradation studies were carried out. According to the validation studies, the developed method was found to be reproducible and accurate as shown by RSD ≤6.1%, 5.7%, 6.9%, and 4.6% and relative mean error (RME) ≤10.6%, 5.8%, 6.5%, and 6.8% for AML, OLM, VAL, and HCT, respectively. Consequently, the method was applied to the analysis of tablets and plasma of the patients using drugs including those substances.

Meclofenamic acid selectively inhibits FTO demethylation of m6A over ALKBH5

PubMed Central

Huang, Yue; Yan, Jingli; Li, Qi; Li, Jiafei; Gong, Shouzhe; Zhou, Hu; Gan, Jianhua; Jiang, Hualiang; Jia, Gui-Fang; Luo, Cheng; Yang, Cai-Guang

2015-01-01

Two human demethylases, the fat mass and obesity-associated (FTO) enzyme and ALKBH5, oxidatively demethylate abundant N6-methyladenosine (m6A) residues in mRNA. Achieving a method for selective inhibition of FTO over ALKBH5 remains a challenge, however. Here, we have identified meclofenamic acid (MA) as a highly selective inhibitor of FTO. MA is a non-steroidal, anti-inflammatory drug that mechanistic studies indicate competes with FTO binding for the m6A-containing nucleic acid. The structure of FTO/MA has revealed much about the inhibitory function of FTO. Our newfound understanding, revealed herein, of the part of the nucleotide recognition lid (NRL) in FTO, for example, has helped elucidate the principles behind the selectivity of FTO over ALKBH5. Treatment of HeLa cells with the ethyl ester form of MA (MA2) has led to elevated levels of m6A modification in mRNA. Our collective results highlight the development of functional probes of the FTO enzyme that will (i) enable future biological studies and (ii) pave the way for the rational design of potent and specific inhibitors of FTO for use in medicine. PMID:25452335

California drug courts: outcomes, costs and promising practices: an overview of Phase II in a statewide study.

PubMed

Carey, Shannon M; Finigan, Michael; Crumpton, Dave; Waller, Mark

2006-11-01

The rapid expansion of drug courts in California and the state's uncertain fiscal climate highlighted the need for definitive cost information on drug court programs. This study focused on creating a research design that can be utilized for statewide and national cost-assessment of drug courts by conducting in-depth case studies of the costs and benefits in nine adult drug courts in California. A Transactional Institutional Costs Analysis (TICA) approach was used, allowing researchers to calculate costs based on every individual's transactions within the drug court or the traditional criminal justice system. This methodology also allows the calculation of costs and benefits by agency (e.g., Public Defender's office, court, District Attorney). Results in the nine sites showed that the majority of agencies save money in processing an offender though drug court. Overall, for these nine study sites, participation in drug court saved the state over 9 million dollars in criminal justice and treatment costs due to lower recidivism in drug court participants. Based on the lessons learned in Phases I and II, Phase III of this study focuses on the creation of a web-based drug court cost self-evaluation tool (DC-CSET) that drug courts can use to determine their own costs and benefits.

Molecular Preadaptation to Antimony Resistance in Leishmania donovani on the Indian Subcontinent

PubMed Central

Imamura, H.; Zander, D.; D’Haenens, E.; Maes, I.; Domagalska, M. A.; Clos, J.

2018-01-01

ABSTRACT Antimonials (Sb) were used for decades for chemotherapy of visceral leishmaniasis (VL). Now abandoned in the Indian subcontinent (ISC) because of Leishmania donovani resistance, this drug offers a unique model for understanding drug resistance dynamics. In a previous phylogenomic study, we found two distinct populations of L. donovani: the core group (CG) in the Gangetic plains and ISC1 in the Nepalese highlands. Sb resistance was only encountered within the CG, and a series of potential markers were identified. Here, we analyzed the development of resistance to trivalent antimonials (SbIII) upon experimental selection in ISC1 and CG strains. We observed that (i) baseline SbIII susceptibility of parasites was higher in ISC1 than in the CG, (ii) time to SbIII resistance was higher for ISC1 parasites than for CG strains, and (iii) untargeted genomic and metabolomic analyses revealed molecular changes along the selection process: these were more numerous in ISC1 than in the CG. Altogether these observations led to the hypothesis that CG parasites are preadapted to SbIII resistance. This hypothesis was experimentally confirmed by showing that only wild-type CG strains could survive a direct exposure to the maximal concentration of SbIII. The main driver of this preadaptation was shown to be MRPA, a gene involved in SbIII sequestration and amplified in an intrachromosomal amplicon in all CG strains characterized so far. This amplicon emerged around 1850 in the CG, well before the implementation of antimonials for VL chemotherapy, and we discuss here several hypotheses of selective pressure that could have accompanied its emergence. IMPORTANCE The “antibiotic resistance crisis” is a major challenge for scientists and medical professionals. This steady rise in drug-resistant pathogens also extends to parasitic diseases, with antimony being the first anti-Leishmania drug that fell in the Indian subcontinent (ISC). Leishmaniasis is a major but neglected infectious disease with limited therapeutic options. Therefore, understanding how parasites became resistant to antimonials is of commanding importance. In this study, we experimentally characterized the dynamics of this resistance acquisition and show for the first time that some Leishmania populations of the ISC were preadapted to antimony resistance, likely driven by environmental factors or by drugs used in the 19th century. PMID:29669889

Critical material attributes (CMAs) of strip films loaded with poorly water-soluble drug nanoparticles: I. Impact of plasticizer on film properties and dissolution

PubMed Central

Krull, Scott M.; Patel, Hardik V.; Li, Meng; Bilgili, Ecevit; Davé, Rajesh N.

2016-01-01

Recent studies have demonstrated polymer films to be a promising platform for delivery of poorly water-soluble drug particles. However, the impact of critical material attributes, for example plasticizer, on the properties of and drug release from such films has yet to be investigated. In response, this study focuses on the impact of plasticizer and plasticizer concentration on properties and dissolution rate of polymer films loaded with poorly water-soluble drug nanoparticles. Glycerin, triacetin, and polyethylene glycol were selected as film plasticizers. Griseofulvin was used as a model Biopharmaceutics Classification System class II drug and hydroxypropyl methylcellulose was used as a film-forming polymer. Griseofulvin nanoparticles were prepared via wet stirred media milling in aqueous suspension. A depression in film glass transition temperature was observed with increasing plasticizer concentration, along with a decrease in film tensile strength and an increase in film elongation, as is typical of plasticizers. However, the type and amount of plasticizer necessary to produce strong yet flexible films had no significant impact on the dissolution rate of the films, suggesting that film mechanical properties can be effectively manipulated with minimal impact on drug release. Griseofulvin nanoparticles were successfully recovered upon redispersion in water regardless of plasticizer or content, even after up to 6 months’ storage at 40 °C and 75% relative humidity, which contributed to similar consistency in dissolution rate after 6 months’ storage for all films. Good content uniformity (<4% R.S.D. for very small film sample size) was also maintained across all film formulations. PMID:27402100

Enhancement of oral bioavailability of anti-HIV drug rilpivirine HCl through nanosponge formulation.

PubMed

Zainuddin, Rana; Zaheer, Zahid; Sangshetti, Jaiprakash N; Momin, Mufassir

2017-12-01

To synthesize β cyclodextrin nanosponges using a novel and efficient microwave mediated method for enhancing bioavailability of Rilpivirine HCl (RLP). Belonging to BCS class II RLP has pH dependent solubility and poor oral bioavailability. However, a fatty meal enhances its absorption hence the therapy indicates that the dosage form be consumed with a meal. But then it becomes tedious and inconvenient to continue the therapy for years with having to face the associated gastric side effects such as nausea. Microwave synthesizer was used to mediate the poly-condensation reaction between β-cyclodextrin and cross-linker diphenylcarbonate. Critical parameters selected were polymer to cross-linker ratio, Watt power, reaction time and solvent volume. Characterization studies were performed using FTIR, DSC, SEM, 1 H-NMR and PXRD. Molecular modeling was applied to confirm the possibility of drug entrapment. In vitro drug dissolution followed by oral bioavailability studies was performed in Sprawley rats. Samples were analyzed using HPLC. Microwave synthesis yields para-crystalline, porous nanosponges (∼205 nm). Drug entrapment led to enhancement of solubility and a two-fold increase in drug dissolution (P < 0.001) following Higuchi release model. Enhanced oral bioavailability was observed in fasted Sprawley rats where C max and AUC 0-∞ increases significantly (C max of NS∼ 586 ± 5.91 ng/mL; plain RLP ∼310 ± 5. 74 ng/mL). The approach offers a comfortable dosing zone for AIDs patients, negating the requirement of consuming the formulation in a fed state due to enhancement in drugs' oral bioavailability.

Role of estrogen receptor β selective agonist in ameliorating portal hypertension in rats with CCl4-induced liver cirrhosis.

PubMed

Zhang, Cheng-Gang; Zhang, Bin; Deng, Wen-Sheng; Duan, Ming; Chen, Wei; Wu, Zhi-Yong

2016-05-14

To investigate the role of diarylpropionitrile (DPN), a selective agonist of estrogen receptor β (ERβ), in liver cirrhosis with portal hypertension (PHT) and isolated hepatic stellate cells (HSCs). Female Sprague-Dawley rats were ovariectomized (OVX), and liver cirrhosis with PHT was induced by CCl4 injection. DPN and PHTPP, the selective ERβ agonist and antagonist, were used as drug interventions. Liver fibrosis was assessed by hematoxylin and eosin (HE) and Masson's trichrome staining and by analyzing smooth muscle actin expression. Hemodynamic parameters were determined in vivo using colored microspheres technique. Protein expression and phosphorylation were determined by immunohistochemical staining and Western blot analysis. Messenger RNA levels were analyzed by quantitative real-time polymerase chain reaction (qRT-PCR). Collagen gel contraction assay was performed using gel lattices containing HSCs treated with DPN, PHTPP, or Y-27632 prior to ET-1 addition. Treatment with DPN in vivo greatly lowered portal pressure and improved hemodynamic parameters without affecting mean arterial pressure, which was associated with the attenuation of liver fibrosis and intrahepatic vascular resistance (IHVR). In CCl4-treated rat livers, DPN significantly decreased the expression of RhoA and ROCK II, and even suppressed ROCK II activity. Moreover, DPN remarkedly increased the levels of endothelial nitric oxide synthase (eNOS) and phosphorylated eNOS, and promoted the activities of protein kinase G (PKG), which is an NO effector in the liver. Furthermore, DPN reduced the contractility of activated HSCs in the 3-dimensional stress-relaxed collagen lattices, and decreased the ROCK II activity in activated HSCs. Finally, in vivo/in vitro experiments demonstrated that MLC activity was inhibited by DPN. For OVX rats with liver cirrhosis, DPN suppressed liver RhoA/ROCK signal, facilitated NO/PKG pathways, and decreased IHVR, giving rise to reduced portal pressure. Therefore, DPN represents a relevant treatment choice against PHT in cirrhotic patients, especially postmenopausal women.

21 CFR 522.2615 - Tripelennamine.

Code of Federal Regulations, 2014 CFR

2014-04-01

... alleviation of some signs of disease. (iii) Limitations. Do not use in horses intended for human consumption... Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS... per pound of body weight by intramuscular injection. (ii) Indications for use. For use in treating...

21 CFR 870.4340 - Cardiopulmonary bypass level sensing monitor and/or control.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Cardiopulmonary bypass level sensing monitor and/or control. 870.4340 Section 870.4340 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF... value. (b) Classification. Class II (performance standards). ...

21 CFR 870.4340 - Cardiopulmonary bypass level sensing monitor and/or control.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Cardiopulmonary bypass level sensing monitor and/or control. 870.4340 Section 870.4340 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF... value. (b) Classification. Class II (performance standards). ...

21 CFR 876.4770 - Urethrotome.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Urethrotome. 876.4770 Section 876.4770 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES.... Some urethrotomes incorporate an optical channel for visual control. (b) Classification. Class II...

21 CFR 886.4440 - AC-powered magnet.

Code of Federal Regulations, 2014 CFR

2014-04-01

... metallic foreign bodies from eye tissue. (b) Classification. Class II. ... 21 Food and Drugs 8 2014-04-01 2014-04-01 false AC-powered magnet. 886.4440 Section 886.4440 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL...