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Sample records for chloroquine analogues influence

  1. Structural characteristics of chloroquine-bridged ferrocenophane analogues of ferroquine may obviate malaria drug-resistance mechanisms.

    PubMed

    Salas, Paloma F; Herrmann, Christoph; Cawthray, Jacqueline F; Nimphius, Corinna; Kenkel, Alexander; Chen, Jessie; de Kock, Carmen; Smith, Peter J; Patrick, Brian O; Adam, Michael J; Orvig, Chris

    2013-02-28

    Five compounds displaying an unprecedented binding mode of chloroquine to ferrocene through the bridging of the cyclopentadienyl rings were studied alongside their monosubstituted ferrocene analogues and organic fragments. The antiplasmodial activity was evaluated against strains of the malaria parasite (Plasmodium falciparum). While the chloroquine-bridged ferrocenyl derivatives were less active than their five monosubstituted ferrocenyl analogues, they retained activity in the drug-resistant strains. The biological and physical properties were correlated to antiplasmodial activity. Intramolecular hydrogen bonding was associated with increased antiplasmodial action, but it is not the determining factor. Instead, balance between lipophilicity and hydrophilicity had a greater influence. It was found that calculated partition coefficient (log P) values of 4.5-5.0 and topological polar surfaces area (tPSA) values of ∼26.0 Å(2) give the best balance. The particular conformation, compact size, and lipophilicity/hydrophilicity balance observed in the bridged compounds provide them with the structural characteristics needed to escape the mechanisms responsible for resistance.

  2. Introducing New Antimalarial Analogues of Chloroquine and Amodiaquine: A Narrative Review

    PubMed Central

    Parhizgar, Arezoo Rafiee; Tahghighi, Azar

    2017-01-01

    Antimalarial drugs with the 4-aminoquinoline scaffold such as the important drugs, chloroquine (CQ) and amodiaquine (AQ), have been used to prevent and treat malaria for many years. The importance of these drugs is related to their simple usage, high efficacy, affordability, and cost-effectiveness of their synthesis. In recent years, with the spread of parasite resistance to CQ and cross-resistance to its other analogues have decreased their consumption in many geographical areas. On the other hand, AQ is an effective antimalarial drug which its usage has been restricted due to hepatic and hematological toxicities. The significance of the quinoline ring at quinoline-based antimalarial drugs has prompted research centers and pharmaceutical companies to focus on the design and synthesis of new analogues of these drugs, especially CQ and AQ analogues. Accordingly, various derivatives have been synthesized and evaluated in vitro and in vivo against the resistant strains of the malaria parasite to solve the problem of drug resistance. Also, the pharmacokinetic properties of these compounds have been evaluated to augment their efficacy and diminish their toxicity. Some of these analogues are currently in clinical and preclinical development. Consequently, the recent researches showed yet 4-aminoquinoline scaffold is active moiety in new compounds with antiplasmodial activity. Hence, the aim of this review article is to introduce of the novel synthetic analogues of CQ and AQ, which may constitute the next generation of antimalarial drugs with the 4-aminoquinoline scaffold. PMID:28360437

  3. Pentamethylcyclopentadienyl-rhodium and iridium complexes containing (N^N and N^O) bound chloroquine analogue ligands: synthesis, characterization and antimalarial properties.

    PubMed

    Ekengard, Erik; Kumar, Kamlesh; Fogeron, Thibault; de Kock, Carmen; Smith, Peter J; Haukka, Matti; Monari, Magda; Nordlander, Ebbe

    2016-03-07

    The synthesis and characterization of twenty new pentamethylcyclopentadienyl-rhodium and iridium complexes containing N^N and N^O-chelating chloroquine analogue ligands are described. The in vitro antimalarial activity of the new ligands as well as the complexes was evaluated against the chloroquine sensitive (CQS) NF54 and the chloroquine resistant (CQR) Dd2 strains of Plasmodium falciparum. The antimalarial activity was found to be good to moderate; although all complexes are less active than artesunate, some of the ligands and complexes showed better activity than chloroquine (CQ). In particular, rhodium complexes were found to be considerably more active than iridium complexes against the CQS NF54 strain. Salicylaldimine Schiff base ligands having electron-withdrawing groups (F, Cl, Br, I and NO2) in para position of the salicyl moiety and their rhodium complexes showed good antiplasmodial activity against both the CQS-NF54 and the CQR-Dd2 strains. The crystal structures of (η(5)-pentamethylcyclopentadienyl){N(1)-(7-chloroquinolin-4-yl)-N(2)-(pyridin-2-ylmethyl)ethane-1,2-diamine)} chlororhodium(III) chloride and (η(5)-pentamethylcyclopentadienyl){(4-chloro-2-(((2-((7-chloroquinolin-4-yl)amino)ethyl)imino)methyl)phenolate)}chlororhodium(III) chloride are reported. The crystallization of the amino-pyridyl complex (η(5)-pentamethylcyclopentadienyl){(N(1)-(7-chloroquinolin-4-yl)-N(2)-(pyridin-2-ylmethyl)ethane-1,2-diamine)}chloroiridium(III) chloride in acetone resulted in the formation of the imino-pyridyl derivative (η(5)-pentamethylcyclopentadienyl){(N1-(7-chloroquinolin-4-yl)-N2-(pyridin-2-ylmethylene)ethane-1,2-diamine)}chloroiridium(III) chloride, the crystal structure of which is also reported.

  4. Physical factors affecting chloroquine binding to melanin.

    PubMed

    Schroeder, R L; Pendleton, P; Gerber, J P

    2015-10-01

    Chloroquine is an antimalarial drug but is also prescribed for conditions such as rheumatoid arthritis. Long-term users risk toxic side effects, including retinopathy, thought to be caused by chloroquine accumulation on ocular melanin. Although the binding potential of chloroquine to melanin has been investigated previously, our study is the first to demonstrate clear links between chloroquine adsorption by melanin and system factors including temperature, pH, melanin type, and particle size. In the current work, two Sepia melanins were compared with bovine eye as a representative mammalian melanin. Increasing the surface anionic character due to a pH change from 4.7 to 7.4 increased each melanin's affinity for chloroquine. Although the chloroquine isotherms exhibited an apparently strong interaction with each melanin, isosteric heat analysis indicated a competitive interaction. Buffer solution cations competed effectively at low surface coverage; chloroquine adsorption occurs via buffer cation displacement and is promoted by temperature-influenced secondary structure swelling.

  5. Chloroquine Phosphate Oral

    MedlinePlus

    Chloroquine phosphate is in a class of drugs called antimalarials and amebicides. It is used to prevent and treat ... Chloroquine phosphate comes as a tablet to take by mouth. For prevention of malaria in adults, one dose is ...

  6. Do film soundtracks contain nonlinear analogues to influence emotion?

    PubMed Central

    Blumstein, Daniel T.; Davitian, Richard; Kaye, Peter D.

    2010-01-01

    A variety of vertebrates produce nonlinear vocalizations when they are under duress. By their very nature, vocalizations containing nonlinearities may sound harsh and are somewhat unpredictable; observations that are consistent with them being particularly evocative to those hearing them. We tested the hypothesis that humans capitalize on this seemingly widespread vertebrate response by creating nonlinear analogues in film soundtracks to evoke particular emotions. We used lists of highly regarded films to generate a set of highly ranked action/adventure, dramatic, horror and war films. We then scored the presence of a variety of nonlinear analogues in these film soundtracks. Dramatic films suppressed noise of all types, contained more abrupt frequency transitions and musical sidebands, and fewer noisy screams than expected. Horror films suppressed abrupt frequency transitions and musical sidebands, but had more non-musical sidebands, and noisy screams than expected. Adventure films had more male screams than expected. Together, our results suggest that film-makers manipulate sounds to create nonlinear analogues in order to manipulate our emotional responses. PMID:20504815

  7. Do film soundtracks contain nonlinear analogues to influence emotion?

    PubMed

    Blumstein, Daniel T; Davitian, Richard; Kaye, Peter D

    2010-12-23

    A variety of vertebrates produce nonlinear vocalizations when they are under duress. By their very nature, vocalizations containing nonlinearities may sound harsh and are somewhat unpredictable; observations that are consistent with them being particularly evocative to those hearing them. We tested the hypothesis that humans capitalize on this seemingly widespread vertebrate response by creating nonlinear analogues in film soundtracks to evoke particular emotions. We used lists of highly regarded films to generate a set of highly ranked action/adventure, dramatic, horror and war films. We then scored the presence of a variety of nonlinear analogues in these film soundtracks. Dramatic films suppressed noise of all types, contained more abrupt frequency transitions and musical sidebands, and fewer noisy screams than expected. Horror films suppressed abrupt frequency transitions and musical sidebands, but had more non-musical sidebands, and noisy screams than expected. Adventure films had more male screams than expected. Together, our results suggest that film-makers manipulate sounds to create nonlinear analogues in order to manipulate our emotional responses.

  8. Fetal bovine serum influences the stability and bioactivity of resveratrol analogues: A polyphenol-protein interaction approach.

    PubMed

    Tang, Fen; Xie, Yixi; Cao, Hui; Yang, Hua; Chen, Xiaoqing; Xiao, Jianbo

    2017-03-15

    Fetal bovine serum (FBS) is a universal growth supplement of cell and tissue culture media. Herein, the influences of FBS on the stability and antioxidant activity of 21 resveratrol analogues were investigated using a polyphenol-protein interaction approach. The structure-stability relationships of resveratrol analogues in FBS showed a clear decrease in the stability of hydroxylated resveratrol analogues in the order: resorcinol-type>pyrogallol-type>catechol-type. The glycosylation and methoxylation of resveratrol analogues enhanced their stability. A linear relationship between the stability of resveratrol analogues in FBS and the affinity of resveratrol analogues-FBS interaction was found. The oxidation process is not the only factor governing the stability of resveratrol analogues in FBS. These results facilitated the insightful investigation of the role of polyphenol-protein interactions in serum, thereby providing some fundamental clues for future clinical research and pharmacological studies on natural small molecules.

  9. Extrapyramidal syndrome following chloroquine therapy.

    PubMed

    Singhi, S; Singhi, P; Singh, M

    1979-02-01

    Chloroquine is considered essentially nontoxic when used for the chemosuppression of malaria, but gastrointestinal upsets, headache, blurring of vision, pruritus, and uritcaria may occur during chloroquine therapy. Recently, Bhargava et al. and Eronini and Eronini have reported the extrapyramidal syndrome (EPS) following chloroquine therapy in adults. The clinical manifestations included upward rolling of the eyeballs, retraction of neck and back, trismus with marked difficulty in speech, and coarse tremors. Observations of 4 instances of EPS in children following chloroquine therapy for malaria are reported. A 2-1/2 year old girl was admitted to the All India Institute of Medical Sciences Hospital with a 4 day history of intermittent high grade pyrexia with chills and rigors. Following treatment with oral chloroquine in the recommended therapeutic dosage, the fever responded, but the child became drowsy and developed paroxysms of involuntary movements of the tongue, torticollis, torsion dystonia of the limbs, and parosysms of tonic muscular spasms. She completely recovered spontaneously within 48 hours. The 2nd case was that of a 12-year old female brought to the hospital with a 15-day history of intermittent high grade fever with chills and rigors. The patient was started on chloroquine sulfate in the recommended therapeutic dose. After an interval of 4 days she developed coarse tremors of the hands, upward rolling of the eyeballs, episodic deviation of the angle of the mouth towards the left, and trismus. These symptoms disappeared spontaneously within 8 hours. A 6-year old girl, the 3rd case, developed episodes of opisthotonous, upward rolling of the eyeballs, protrusions of the tongue, intermittent writhing movements of the upper limbs, and drowsiness following the ingestion of 6 tablets of chloroquine sulfate for suspected diagnosis of malaria. She spontaneously recovered from EPS over a period of about 48 hours. The 4th case, a 7-year old boy, gave a history

  10. Plasmodium vivax trophozoites insensitive to chloroquine

    PubMed Central

    Sharrock, Wesley W; Suwanarusk, Rossarin; Lek-Uthai, Usa; Edstein, Michael D; Kosaisavee, Varakorn; Travers, Thomas; Jaidee, Anchalee; Sriprawat, Kanlaya; Price, Ric N; Nosten, François; Russell, Bruce

    2008-01-01

    Background Plasmodium vivax is a major cause of malaria and is still primarily treated with chloroquine. Chloroquine inhibits the polymerization of haem to inert haemozoin. Free haem monomers are thought to catalyze oxidative damage to the Plasmodium spp. trophozoite, the stage when haemoglobin catabolism is maximal. However preliminary in vitro observations on P. vivax clinical isolates suggest that only ring stages (early trophozoites) are sensitive to chloroquine. In this study, the stage specific action of chloroquine was investigated in synchronous cryopreserved isolates of P. vivax. Methods The in vitro chloroquine sensitivity of paired ring and trophozoite stages from 11 cryopreserved P. vivax clinical isolates from Thailand and two Plasmodium falciparum clones (chloroquine resistant K1 and chloroquine sensitive FC27) was measured using a modified WHO microtest method and fluorometric SYBR Green I Assay. The time each stage was exposed to chloroquine treatment was controlled by washing the chloroquine off at 20 hours after the beginning of treatment. Results Plasmodium vivax isolates added to the assay at ring stage had significantly lower median IC50s to chloroquine than the same isolates added at trophozoite stage (median IC50 12 nM vs 415 nM p < 0.01). Although only 36% (4/11) of the SYBR Green I assays for P. vivax were successful, both microscopy and SYBR Green I assays indicated that only P. vivax trophozoites were able to develop to schizonts at chloroquine concentrations above 100 nM. Conclusion Data from this study confirms the diminished sensitivity of P. vivax trophozoites to chloroquine, the stage thought to be the target of this drug. These results raise important questions about the pharmacodynamic action of chloroquine, and highlight a fundamental difference in the activity of chloroquine between P. vivax and P. falciparum. PMID:18505560

  11. Dihydroethanoanthracene Derivatives as In Vitro Malarial Chloroquine Resistance Reversal Agents

    PubMed Central

    Millet, Julie; Torrentino-Madamet, Marylin; Alibert, Sandrine; Rogier, Christophe; Santelli-Rouvier, Christiane; Mosnier, Joel; Baret, Eric; Barbe, Jacques; Parzy, Daniel; Pradines, Bruno

    2004-01-01

    The ability of four 9,10-dihydroethanoanthracene derivatives (BG920, BG932, BG958, and BG996), as well as verapamil and promethazine, to reverse chloroquine resistance was assessed against 24 chloroquine-resistant and 10 chloroquine-susceptible strains of Plasmodium falciparum from different countries. The 9,10-dihydroethanoanthracene derivatives clearly increase chloroquine susceptibility only in chloroquine-resistant isolates. PMID:15215144

  12. Chloroquine improves survival and hematopoietic recovery following lethal low dose- rate radiation

    PubMed Central

    Lim, Yiting; Hedayati, Mohammad; Merchant, Akil A.; Zhang, Yonggang; Yu, Hsiang-Hsuan M; Kastan, Michael B.; Matsui, William; DeWeese, Theodore L.

    2012-01-01

    Purpose We have previously shown that the anti-malarial agent chloroquine can abrogate the lethal cellular effects of low dose-rate (LDR) radiation in vitro, most likely by activating the ataxia-telangiectasia mutated (ATM) protein. Here, we demonstrate that chloroquine treatment also protects against lethal doses of LDR radiation in vivo. Methods and Materials C57BL/6 mice were irradiated with total of 12.8 Gy delivered at 9.4 cGy/hr. ATM null mice from the same background were used to determine the influence of ATM. Chloroquine was administered by two intraperitoneal injections of 59.4 μg per 17 g of body weight, 24 hrs and 4 hrs before irradiation. Bone marrow cells isolated from tibia, fibula and vertebral bones were transplanted into lethally irradiated CD45 congenic recipient mice by retro orbital injection. Chimerism was assessed by flow cytometry. In vitro methyl cellulose colony forming assay of whole bone marrow cells as well as FACS analysis of lineage depleted cells was used to assess the effect of chloroquine on progenitor cells. Results Mice pretreated with chloroquine prior to radiation exhibited a significantly higher survival rate compared to mice treated with radiation alone (80 vs.31 percent, p=0.0026). Chloroquine administration prior to radiation did not impact the survival of ATM null mice (p=0.86). Chloroquine also had a significant effect on the early engraftment of bone marrow cells from the irradiated donor mice 6 weeks after the transplantation (4.2 percent vs. 0.4 percent, p=0.015). Conclusion Chloroquine administration prior to radiation had a significant effect on the survival of normal but not ATM null mice strongly suggesting that the in vivo effect like the in vitro effect is also ATM dependent. Chloroquine improved the early engraftment of bone marrow cells from LDR irradiated mice, presumably by protecting the progenitor cells from radiation injury. Chloroquine thus could serve as a very useful drug for protection against the

  13. Chloroquine Improves Survival and Hematopoietic Recovery After Lethal Low-Dose-Rate Radiation

    SciTech Connect

    Lim Yiting; Hedayati, Mohammad; Merchant, Akil A.; Zhang Yonggang; Yu, Hsiang-Hsuan M.; Kastan, Michael B.; Matsui, William; DeWeese, Theodore L.

    2012-11-01

    Purpose: We have previously shown that the antimalarial agent chloroquine can abrogate the lethal cellular effects of low-dose-rate (LDR) radiation in vitro, most likely by activating the ataxia-telangiectasia mutated (ATM) protein. Here, we demonstrate that chloroquine treatment also protects against lethal doses of LDR radiation in vivo. Methods and Materials: C57BL/6 mice were irradiated with a total of 12.8 Gy delivered at 9.4 cGy/hour. ATM null mice from the same background were used to determine the influence of ATM. Chloroquine was administered by two intraperitoneal injections of 59.4 {mu}g per 17 g of body weight, 24 hours and 4 hours before irradiation. Bone marrow cells isolated from tibia, fibula, and vertebral bones were transplanted into lethally irradiated CD45 congenic recipient mice by retroorbital injection. Chimerism was assessed by flow cytometry. In vitro methylcellulose colony-forming assay of whole bone marrow cells and fluorescence activated cell sorting analysis of lineage depleted cells were used to assess the effect of chloroquine on progenitor cells. Results: Mice pretreated with chloroquine before radiation exhibited a significantly higher survival rate than did mice treated with radiation alone (80% vs. 31%, p = 0.0026). Chloroquine administration before radiation did not affect the survival of ATM null mice (p = 0.86). Chloroquine also had a significant effect on the early engraftment of bone marrow cells from the irradiated donor mice 6 weeks after transplantation (4.2% vs. 0.4%, p = 0.015). Conclusion: Chloroquine administration before radiation had a significant effect on the survival of normal but not ATM null mice, strongly suggesting that the in vivo effect, like the in vitro effect, is also ATM dependent. Chloroquine improved the early engraftment of bone marrow cells from LDR-irradiated mice, presumably by protecting the progenitor cells from radiation injury. Chloroquine thus could serve as a very useful drug for protection

  14. Theoretical study on the influence of different para-substituents on 13C NMR of the single carbonyl curcumin analogues

    NASA Astrophysics Data System (ADS)

    Jia, Fei-yun; Ran, Ming; Zhang, Bo

    2015-12-01

    The structure of eight kinds of different para-substituents curcumin analogues has been optimized at the level of B3LYP/6-31G( d, p), under which the stability has been verified by means of vibration analysis. Moreover, NMR spectra of curcumin analogues compounds have been studied at the level of B3LYP/6-311G( d, p) by GIAO method. The results show that the structure of eight compounds, a larger conjugated system, has good planarity. The effect of ortho-substituents on bond lengths and bond angles is greater than para and meta. Different substituents and different positions of substituents all have different influence on NMR of the single carbonyl curcumin analogues. In general, after the hydrogen atom on the benzene ring is substituted by other groups, the δ value of α-C changes significantly, the δ value of ortho-carbon atom may also have great change, but the δ value change of meta-carbon atoms is not too obvious. The effect of substituent electronegativity on α-C atoms presents obvious regularity, while the influence of conjugate effect on carbon atoms of benzene ring is more complex. Finally, the bigger substituted alkyl is, the more the δ value of α-C increases.

  15. Soluble Synthetic Analogs of Malaria Pigment: Structure of Mesohematin Anhydride [FeIII(MP-IX)]2 and Solution Interaction with Chloroquine

    SciTech Connect

    D Bohle; E Dodd; A Kosar; L Sharma; P Stephens; L Suarez; D Tazoo

    2011-12-31

    Changing the vinyl groups of hematin anhydride to either ethyl or hydrogen groups results in increased solubility (Por=porphyrin). Determination of the weak binding constants of the antimalarial drug chloroquine to dimers of these hematin anhydride analogues suggests that solution-phase heme/drug interactions alone are unlikely to be the origin of the action of the drug.

  16. Chloroquine-resistant isoforms of the Plasmodium falciparum chloroquine resistance transporter acidify lysosomal pH in HEK293 cells more than chloroquine-sensitive isoforms.

    PubMed

    Reeves, David C; Liebelt, David A; Lakshmanan, Viswanathan; Roepe, Paul D; Fidock, David A; Akabas, Myles H

    2006-12-01

    The emergence of chloroquine-resistant Plasmodium falciparum malaria imperils the lives of millions of people in Africa, Southeast Asia and South America. Chloroquine resistance is associated with mutations in the P. falciparum chloroquine resistance transporter (PfCRT). We expressed chloroquine-sensitive (HB3) and resistant (Dd2) pfcrt alleles in HEK293 human embryonic kidney cells. PfCRT localized to the lysosomal limiting membrane and was not detected in the plasma membrane. We observed significant acidification of lysosomes containing PfCRT HB3 and Dd2, with Dd2 acidifying significantly more than HB3. A mutant HB3 allele expressing the K76T mutation (earlier found to be key for chloroquine resistance) acidified to the same extent as Dd2, whereas the acidification by a Dd2 allele expressing the T76K "back mutation" was significantly less than Dd2. Thus, the amino acid at position 76 is both an important determinant of chloroquine resistance in parasites and of lysosomal acidification following heterologous expression. PfCRT may be capable of modulating the pH of the parasite digestive vacuole, and thus chloroquine availability. Chloroquine accumulation and glycyl-phenylalanine-2-naphthylamide-induced release of lysosomal Ca(2+) stores were unaffected by PfCRT expression. Cytoplasmic domain mutations did not alter PfCRT sorting to the lysosomal membrane. This heterologous expression system will be useful to characterize PfCRT protein structure and function, and elucidate its molecular role in chloroquine resistance.

  17. Analogue modelling of the influence of ice shelf collapse on the flow of ice sheets grounded below sea-level

    NASA Astrophysics Data System (ADS)

    Corti, Giacomo; Zeoli, Antonio

    2016-04-01

    The sudden breakup of ice shelves is expected to result in significant acceleration of inland glaciers, a process related to the removal of the buttressing effect exerted by the ice shelf on the tributary glaciers. This effect has been tested in previous analogue models, which however applied to ice sheets grounded above sea level (e.g., East Antarctic Ice Sheet; Antarctic Peninsula and the Larsen Ice Shelf). In this work we expand these previous results by performing small-scale laboratory models that analyse the influence of ice shelf collapse on the flow of ice streams draining an ice sheet grounded below sea level (e.g., the West Antarctic Ice Sheet). The analogue models, with dimensions (width, length, thickness) of 120x70x1.5cm were performed at the Tectonic Modelling Laboratory of CNR-IGG of Florence, Italy, by using Polydimethilsyloxane (PDMS) as analogue for the flowing ice. This transparent, Newtonian silicone has been shown to well approximate the rheology of natural ice. The silicone was allowed to flow into a water reservoir simulating natural conditions in which ice streams flow into the sea, terminating in extensive ice shelves which act as a buttress for their glaciers and slow their flow. The geometric scaling ratio was 10(-5), such that 1cm in the models simulated 1km in nature; velocity of PDMS (a few mm per hour) simulated natural velocities of 100-1000 m/year. Instability of glacier flow was induced by manually removing a basal silicone platform (floating on water) exerting backstresses to the flowing analogue glacier: the simple set-up adopted in the experiments isolates the effect of the removal of the buttressing effect that the floating platform exerts on the flowing glaciers, thus offering insights into the influence of this parameter on the flow perturbations resulting from a collapse event. The experimental results showed a significant increase in glacier velocity close to its outlet following ice shelf breakup, a process similar to what

  18. Biowaiver monographs for immediate release solid oral dosage forms based on biopharmaceutics classification system (BCS) literature data: chloroquine phosphate, chloroquine sulfate, and chloroquine hydrochloride.

    PubMed

    Verbeeck, R K; Junginger, H E; Midha, K K; Shah, V P; Barends, D M

    2005-07-01

    Literature data on the properties of chloroquine phosphate, chloroquine sulfate, and chloroquine hydrochloride related to the Biopharmaceutics Classification System (BCS) are reviewed. The available information indicates that these chloroquine salts can be classified as highly soluble and highly permeable, i.e., BCS class I. The qualitative composition of immediate release (IR) tablets containing these Active Pharmaceutical Ingredients (APIs) with a Marketing Authorization (MA) in Belgium (BE), Germany (DE), Finland (FI), and The Netherlands (NL) is provided. In view of these MA's and the critical therapeutic indication of chloroquine, it is assumed that the registration authorities had evidence that these formulations are bioequivalent to the innovator. It is concluded that IR tablets formulated with these excipients are candidates for a biowaiver.

  19. A Purine Analog Synergizes with Chloroquine (CQ) by Targeting Plasmodium falciparum Hsp90 (PfHsp90)

    PubMed Central

    Shahinas, Dea; Folefoc, Asongna; Taldone, Tony; Chiosis, Gabriela; Crandall, Ian; Pillai, Dylan R.

    2013-01-01

    Background Drug resistance, absence of an effective vaccine, and inadequate public health measures are major impediments to controlling Plasmodium falciparum malaria worldwide. The development of antimalarials to which resistance is less likely is paramount. To this end, we have exploited the chaperone function of P. falciparum Hsp90 (PfHsp90) that serves to facilitate the expression of resistance determinants. Methods The affinity and activity of a purine analogue Hsp90 inhibitor (PU-H71) on PfHsp90 was determined using surface plasmon resonance (SPR) studies and an ATPase activity assay, respectively. In vitro, antimalarial activity was quantified using flow cytometry. Interactors of PfHsp90 were determined by LC-MS/MS. In vivo studies were conducted using the Plasmodium berghei infection mouse model. Results PU-H71 exhibited antimalarial activity in the nanomolar range, displayed synergistic activity with chloroquine in vitro. Affinity studies reveal that the PfHsp90 interacts either directly or indirectly with the P. falciparum chloroquine resistance transporter (PfCRT) responsible for chloroquine resistance. PU-H71 synergized with chloroquine in the P.berghei mouse model of malaria to reduce parasitemia and improve survival. Conclusions We propose that the interaction of PfHsp90 with PfCRT may account for the observed antimalarial synergy and that PU-H71 is an effective adjunct for combination therapy. PMID:24098696

  20. 21 CFR 522.810 - Embutramide, chloroquine, and lidocaine solution.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 6 2012-04-01 2012-04-01 false Embutramide, chloroquine, and lidocaine solution... ANIMAL DRUGS § 522.810 Embutramide, chloroquine, and lidocaine solution. (a) Specifications. Each....; and 1.9 mg lidocaine, U.S.P. (b) Sponsor. See No. 059130 in § 510.600(c) of this chapter....

  1. 21 CFR 522.810 - Embutramide, chloroquine, and lidocaine solution.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 6 2013-04-01 2013-04-01 false Embutramide, chloroquine, and lidocaine solution... ANIMAL DRUGS § 522.810 Embutramide, chloroquine, and lidocaine solution. (a) Specifications. Each....; and 1.9 mg lidocaine, U.S.P. (b) Sponsor. See No. 000859 in § 510.600(c) of this chapter....

  2. 21 CFR 522.810 - Embutramide, chloroquine, and lidocaine solution.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 6 2014-04-01 2014-04-01 false Embutramide, chloroquine, and lidocaine solution... ANIMAL DRUGS § 522.810 Embutramide, chloroquine, and lidocaine solution. (a) Specifications. Each....; and 1.9 mg lidocaine, U.S.P. (b) Sponsor. See No. 000859 in § 510.600(c) of this chapter....

  3. 21 CFR 522.810 - Embutramide, chloroquine, and lidocaine solution.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 6 2010-04-01 2010-04-01 false Embutramide, chloroquine, and lidocaine solution... ANIMAL DRUGS § 522.810 Embutramide, chloroquine, and lidocaine solution. (a) Specifications. Each....; and 1.9 mg lidocaine, U.S.P. (b) Sponsor. See No. 059130 in § 510.600(c) of this chapter....

  4. 21 CFR 522.810 - Embutramide, chloroquine, and lidocaine solution.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 6 2011-04-01 2011-04-01 false Embutramide, chloroquine, and lidocaine solution... ANIMAL DRUGS § 522.810 Embutramide, chloroquine, and lidocaine solution. (a) Specifications. Each....; and 1.9 mg lidocaine, U.S.P. (b) Sponsor. See No. 059130 in § 510.600(c) of this chapter....

  5. Chloroquine could be used for the treatment of filoviral infections and other viral infections that emerge or emerged from viruses requiring an acidic pH for infectivity.

    PubMed

    Akpovwa, Hephzibah

    2016-06-01

    Viruses from the Filoviridae family, as many other virus families, require an acidic pH for successful infection and are therefore susceptible to the actions of 4-aminoquinolines, such as chloroquine. Although the mechanisms of action of chloroquine clearly indicate that it might inhibit filoviral infections, several clinical trials that attempted to use chloroquine in the treatment of other acute viral infections - including dengue and influenza A and B - caused by low pH-dependent viruses, have reported that chloroquine had no clinical efficacy, and these results demoted chloroquine from the potential treatments for other virus families requiring low pH for infectivity. The present review is aimed at investigating whether chloroquine could combat the present Ebola virus epidemic, and also at exploring the main reasons for the reported lack of efficacy. Literature was sourced from PubMed, Scopus, Google Scholar, reference list of articles and textbooks - Fields Virology (Volumes 1and 2), the cytokine handbook, Pharmacology in Medicine: Principles and Practice, and hydroxychloroquine and chloroquine retinopathy. The present analysis concludes that (1) chloroquine might find a place in the treatment of Ebola, either as a monotherapy or in combination therapies; (2) the ineffectiveness of chloroquine, or its analogue, hydroxychloroquine, at treating infections from low pH-dependent viruses is a result of the failure to attain and sustain a steady state concentration sufficient to increase and keep the pH of the acidic organelles to approximately neutral levels; (3) to successfully treat filoviral infections - or other viral infections that emerge or emerged from low pH-dependent viruses - a steady state chloroquine plasma concentration of at least 1 µg/mL(~3.125 μM/L) or a whole blood concentration of 16 μM/L must be achieved and be sustained until the patients' viraemia becomes undetectable. These concentrations, however, do not rule out the efficacy of

  6. Excretion of chloroquine and desethylchloroquine in human milk.

    PubMed Central

    Ogunbona, F A; Onyeji, C O; Bolaji, O O; Torimiro, S E

    1987-01-01

    The excretion of chloroquine and the major metabolite, desethylchloroquine, in breast milk was investigated in eleven lactating mothers following a single oral dose of chloroquine (600 mg base). The average milk to plasma concentration ratio at the 24th hour was 6.6 +/- 2.4 for chloroquine and 1.5 +/- 0.6 for desethylchloroquine in five of the volunteers. In five other volunteers the elimination half-life of chloroquine in milk was 8.8 +/- 4.7 days which was longer than that in saliva (3.9 +/- 1.0 days) from the same volunteers. The maximum daily dose of the drug that the infant can receive from breastfeeding was about 0.7% of the maternal start dose of the drug in malaria chemotherapy. It is, therefore, suggested that it is safe for mothers to breastfeed their infants when undergoing treatment for malaria with chloroquine. PMID:3580253

  7. Excretion of chloroquine and desethylchloroquine in human milk.

    PubMed

    Ogunbona, F A; Onyeji, C O; Bolaji, O O; Torimiro, S E

    1987-04-01

    The excretion of chloroquine and the major metabolite, desethylchloroquine, in breast milk was investigated in eleven lactating mothers following a single oral dose of chloroquine (600 mg base). The average milk to plasma concentration ratio at the 24th hour was 6.6 +/- 2.4 for chloroquine and 1.5 +/- 0.6 for desethylchloroquine in five of the volunteers. In five other volunteers the elimination half-life of chloroquine in milk was 8.8 +/- 4.7 days which was longer than that in saliva (3.9 +/- 1.0 days) from the same volunteers. The maximum daily dose of the drug that the infant can receive from breastfeeding was about 0.7% of the maternal start dose of the drug in malaria chemotherapy. It is, therefore, suggested that it is safe for mothers to breastfeed their infants when undergoing treatment for malaria with chloroquine.

  8. [Duodenal ulcers caused by chloroquine-proguanil association].

    PubMed

    Roux, X; Imbert, P; Rivière, F; Méchaï, F; Rapp, C

    2010-12-01

    Chloroquine-proguanil association is recommended for prophylaxis against falciparum malaria in countries with a low prevalence of chloroquine resistance. It is usually well tolerated with mild side effects consisting mainly of transient digestive discomfort and buccal manifestations (mouth sores or ulcers). The purpose of this report is to describe a case of duodenal ulcers presenting as epigastric pain with 10-kg weight-loss in a 32-year-old man taking chloroquine-proguanil for malaria prophylaxis during a stay in Haiti. No other causes of duodenal ulcers or weight-loss were found. Chloroquine-proguanil prophylaxis was discontinued and replaced by omeprazole for four weeks. Symptoms improved quickly and full recovery was observed within one month. To our knowledge, the occurrence of duodenal ulcers under chloroquine-proguanil association is quite rare, but possibly severe. Upper digestive endoscopy should be performed if a patient under chloroquine-proguanil develops abdominal pain especially in association with weight-loss. If endoscopy reveals duodenal ulcers, chloroquine-proguanil should be discontinued and replaced by another prophylactic regimen.

  9. In vitro antimalarial activity of a new organometallic analog, ferrocene-chloroquine.

    PubMed

    Domarle, O; Blampain, G; Agnaniet, H; Nzadiyabi, T; Lebibi, J; Brocard, J; Maciejewski, L; Biot, C; Georges, A J; Millet, P

    1998-03-01

    The in vitro activities of new organometallic chloroquine analogs, based on 4-amino-quinoleine compounds bound to a molecule of ferrocene, were evaluated against chloroquine-susceptible, chloroquine-intermediate, and chloroquine-resistant, culture-adapted Plasmodium falciparum lineages by a proliferation test. One of the ferrocene analogs totally restored the activity of chloroquine against chloroquine-resistant parasites. This compound, associated with tartaric acid for better solubility, was highly effective. The role of the ferrocene in reversing chloroquine resistance is discussed, as is its potential use for human therapy.

  10. In Vitro Antimalarial Activity of a New Organometallic Analog, Ferrocene-Chloroquine

    PubMed Central

    Domarle, O.; Blampain, G.; Agnaniet, H.; Nzadiyabi, T.; Lebibi, J.; Brocard, J.; Maciejewski, L.; Biot, C.; Georges, A. J.; Millet, P.

    1998-01-01

    The in vitro activities of new organometallic chloroquine analogs, based on 4-amino-quinoleine compounds bound to a molecule of ferrocene, were evaluated against chloroquine-susceptible, chloroquine-intermediate, and chloroquine-resistant, culture-adapted Plasmodium falciparum lineages by a proliferation test. One of the ferrocene analogs totally restored the activity of chloroquine against chloroquine-resistant parasites. This compound, associated with tartaric acid for better solubility, was highly effective. The role of the ferrocene in reversing chloroquine resistance is discussed, as is its potential use for human therapy. PMID:9517929

  11. [Chloroquine resistance and malaria control in Ivory Coast].

    PubMed

    Henry, M C; Koné, M; Guillet, P; Mouchet, J

    1998-01-01

    We present here data from the Ivory Coast on the susceptibility of Plasmodium falciparum to chloroquine, obtained since the first chloroquine-resistant strains were discovered in 1987. Susceptibility was assessed using the WHO 7-day field test. Almost all the tests were carried out in the capital, Adidjan, and in the southern forest zone. The frequency of chloroquine resistance was below 30% in most cases, the actual frequency differing between regions. The frequency of R3 chloroquine-resistant P. falciparum was very low. Such resistant parasites were found only on an oil-palm plantation and in the south west of the country, probably due to the free medical care available at both locations. In general, access to health care is limited. Fevers attributed to malaria are generally treated at home using plants or incomplete courses of chloroquine. Our data suggest that R3 chloroquine-resistant P. falciparum strains are selected by repeated high doses of chloroquine, rather than by low doses. Thus, symptomatic treatment of uncomplicated malaria and treatment at home with the "correct" medication may be more effective than systematic medication, for limiting the level of chloroquine resistance in the parasite. Pyrethroid-resistant Anopheles gambiae s.l. is present in West Africa and this may reduce the short-term effectiveness of impregnated mosquito nets. In the absence of R3 chloroquine-resistant P. falciparum, self-medication at home may be a practical and realistic way to treat malaria. However, more knowledge about the effectiveness of anti-malaria drugs, their use in various social, cultural and economic environments and the geographical distribution of insecticide-resistant vectors is required before effective strategies can be designed. However, it would certainly be of value to consistently check the quality of anti-malaria drugs and to try to improve the effectiveness of self-medication at home.

  12. Analogue Gravity.

    PubMed

    Barceló, Carlos; Liberati, Stefano; Visser, Matt

    2011-01-01

    Analogue gravity is a research programme which investigates analogues of general relativistic gravitational fields within other physical systems, typically but not exclusively condensed matter systems, with the aim of gaining new insights into their corresponding problems. Analogue models of (and for) gravity have a long and distinguished history dating back to the earliest years of general relativity. In this review article we will discuss the history, aims, results, and future prospects for the various analogue models. We start the discussion by presenting a particularly simple example of an analogue model, before exploring the rich history and complex tapestry of models discussed in the literature. The last decade in particular has seen a remarkable and sustained development of analogue gravity ideas, leading to some hundreds of published articles, a workshop, two books, and this review article. Future prospects for the analogue gravity programme also look promising, both on the experimental front (where technology is rapidly advancing) and on the theoretical front (where variants of analogue models can be used as a springboard for radical attacks on the problem of quantum gravity).

  13. Chloroquine accumulation by purified plasma membranes from Plasmodium falciparum.

    PubMed

    Elandaloussi, Laurence M; Smith, Peter J

    2006-01-01

    Resistance of Plasmodium falciparum to chloroquine (CQ) has been associated with a decrease in CQ accumulation by parasitized erythrocytes. This study aimed at investigating the role of parasite plasma membranes (PPM) in the mechanism of CQ accumulation. CQ accumulation capabilities of membranes were determined using tritiated CQ. PPM isolated from chloroquine-sensitive parasites were found to accumulate less CQ than those isolated from chloroquine-resistant parasites. However, CQ accumulation was found to be ATP-independent suggesting that this accumulation results from binding rather than transport.

  14. Chloroquine-induced hyperpigmentation of the hard palate.

    PubMed

    Brasil, Catarina da Mota Vasconcelos; Ribeiro, Camila Maria Beder; Fonseca, Deborah Daniella Diniz; Gueiros, Luiz Alcino Monteiro; Leao, Jair Carneiro

    2012-01-01

    This article reports a rare case of extensive palatal pigmentation secondary to long-term chloroquine treatment. Chloroquine was originally used as an antimalarial agent, but it is now widely used as an adjunct in the treatment of autoimmune diseases. Adverse effects of chloroquine usually include skin changes such as bullous pemphigoid, exacerbation of psoriasis, and pigmentation of the skin and mucous membranes as well as retinopathy, gastrointestinal alterations, and neuromuscular disorders. Extensive oral pigmentation is an uncommon feature of an adverse drug effect, and diagnosis should be based on clinicopathological findings.

  15. The influence of slope morphology on gullies: Terrestrial gullies in Lake George as analogues for Mars

    NASA Astrophysics Data System (ADS)

    Hobbs, S. W.; Paull, D. J.; Clarke, J. D. A.

    2013-06-01

    Terrestrial gullies provide a useful benchmark to compare martian gully forms against. We compare pole and equator facing gullies in an unnamed crater located in the martian southern mid-latitudes with gullies located on the Lake George escarpment south of Gearys Gap, New South Wales, Australia. Our investigations showed gully morphology at both sites is greatly influenced by thickness of readily erodable regolith, local slope and the presence or absence of bedrock exposures in the gullies. We found that the martian pole-facing gullies are the most similar to those of Lake George and both systems are therefore likely to have been eroded by liquid water. Although the martian gullies possessed much greater volumes of eroded sediment, they had not eroded to underlying bedrock. This contrasts with the smaller Lake George gully channels where numerous bedrock exposures, observed during our survey, affected their slope and overall morphology. Similarly, although dominated by dry processes, multiple bedrock exposures are present within the equator facing martian gullies affecting their cross sectional area and hence sediment transport. The studied sites all showed significant influence from initial slope angles, indicating that interpretation of gully forms such as slopes below the angle of repose, curved profiles and sinuosity must be placed in context of local environments. This analysis can be applied to other regions of Mars and Earth and provide a greater understanding of how geomorphologic processes operate on both worlds.

  16. Influence of long-term treatment with tuftsin analogue TP-7 on the anxiety-phobic states and body weight.

    PubMed

    Czabak-Garbacz, Róza; Cygan, Beata; Wolański, Lukasz; Kozlovsky, Igor

    2006-01-01

    TP-7 is a synthetic analogue of tuftsin. It has a structure of tuftsin, to which three natural L-amino-acids Pro-Gly-Pro are attached. This heptapeptide improves learning and memorization and causes antidepressant and anxiolytic effect. It is possible to use TP-7 in the future to optimize cognitive functions and as a potential new anxioselective, fast-acting and easy-dosed drug. Therefore, it was purposeful to study such properties of the heptapeptide as its influence on anxiety-fear and body weight under a long-term treatment regimen. The experiment was performed on 24 preselected Wistar rats with the use of Rodina's method. There were three experimental groups of animals with high initial emotional reactivity: passive control group (P), active control group (A, receiving distilled water) and group treated with TP-7 at the dose of 0.3 mg/kg (T). The rats of A and T groups received intraperitoneal injections every day. The experiments were conducted 15 min after the administration of the drug, one and two days after initial testing day, then 1, 2, 3 and 4 weeks after that. The heptapeptide reduced the anxiety-phobic states significantly starting from the second day of drug application. The observed effects persisted throughout four weeks of the experiment, which confirmed effective long-term anxiolytic properties of the heptapeptide. TP-7 did not cause any changes in the body mass by itself.

  17. Combination cyclosporine and (hydroxy)chloroquine in rheumatoid arthritis.

    PubMed

    Dijkmans, B A; Landewé, R B; van den Borne, B E; Breedveld, F C

    1999-01-01

    Antimalarials are attractive candidates for combination therapy. In vitro experiments have revealed a synergistic mode of action of cyclosporine and chloroquine which could not, however, be confirmed in a clinical trial.

  18. Chloroquine sensitizes biofilms of Candida albicans to antifungal azoles.

    PubMed

    Shinde, Ravikumar Bapurao; Raut, Jayant Shankar; Chauhan, Nitin Mahendra; Karuppayil, Sankunny Mohan

    2013-01-01

    Biofilms formed by Candida albicans, a human pathogen, are known to be resistant to different antifungal agents. Novel strategies to combat the biofilm associated Candida infections like multiple drug therapy are being explored. In this study, potential of chloroquine to be a partner drug in combination with four antifungal agents, namely fluconazole, voriconazole, amphotericin B, and caspofungin, was explored against biofilms of C. albicans. Activity of various concentrations of chloroquine in combination with a particular antifungal drug was analyzed in a checkerboard format. Growth of biofilm in presence of drugs was analyzed by XTT-assay, in terms of relative metabolic activity compared to that of drug free control. Results obtained by XTT-metabolic assay were confirmed by scanning electron microscopy. The interactions between chloroquine and four antifungal drugs were determined by calculating fractional inhibitory concentration indices. Azole resistance in biofilms was reverted significantly (p<0.05) in presence of 250μg/mL of chloroquine, which resulted in inhibition of biofilms at very low concentrations of antifungal drugs. No significant alteration in the sensitivity of biofilms to caspofungin and amphotericin B was evident in combination with chloroquine. This study for the first time indicates that chloroquine potentiates anti-biofilm activity of fluconazole and voriconazole.

  19. Hair analysis of an unusual case of Chloroquine intoxication.

    PubMed

    Imran, Muhammad; Ashiq, Muhammad Zar; Shafi, Humera; Usman, Hafiz Faisal; Wattoo, Sardar Ali; Sarwar, Muhammad; Tahir, Muhammad Ashraf

    2016-03-01

    A dead body of middle aged man was exhumed from 6.5 month earth-grave. Autopsy findings were non-specific as the body was completely putrefied. Deceased's scalp hair and kidney was sent for toxicological analysis. Hair sample (50mg) was incubated with 1M NaOH (2 ml). Chloroquine was detected in hair and kidney during basic drug screen performed on GC/MS. For confirmation and quantitation, chloroquine was extracted using Hypersep verify CX SPE cartridges while mass detector was operated in SIM mode using the ions of m/z 245.0, 290.1, 319.0 for chloroquine while ions of m/z 260 and 455 were monitored for nalorphine (internal standard). Chloroquine was present in high concentration in hair (211 ng/mg) as well as in kidney (37.3mg/kg). Moreover, chloroquine was not detected in the wash solvents, suggesting ingestion of the drug rather than an external contamination of hair. These findings strongly suggested the acute exposure of higher doses of chloroquine to the deceased before death.

  20. Chloroquine and Hydroxychloroquine Increase Retinal Pigment Epithelial Layer Permeability.

    PubMed

    Korthagen, Nicoline M; Bastiaans, Jeroen; van Meurs, Jan C; van Bilsen, Kiki; van Hagen, P Martin; Dik, Willem A

    2015-07-01

    Antimalarials chloroquine (CQ) and hydroxychloroquine (HCQ) are widely used as antiinflammatory drugs, but side effects include retinopathy and vision loss. The objective of this study was to examine the effect of CQ and HCQ on the barrier integrity of retinal pigment epithelial (RPE) cell monolayers in vitro. Permeability of ARPE-19 cell monolayers was determined using Fluorescein isothiocyanate (FITC)-labeled dextran. The influence of CQ and HCQ on cell death and the expression tight junction molecules was examined. CQ and HCQ significantly increased ARPE-19 monolayer permeability after 3 and 18 h, respectively, and enhanced mRNA levels for claudin-1 and occludin. Cytotoxicity was only observed after 18 h exposure. Thus, CQ and HCQ rapidly enhance RPE barrier permeability in vitro, independent of cytotoxicity or loss of zonula occludens-1, claudin-1, and occludin expression. Our findings suggest that CQ/HCQ-induced permeability of the RPE layer may contribute to blood-retinal barrier breakdown in case of CQ/HCQ-induced retinopathy.

  1. Effect of chloroquine on the urinary excretion of ciprofloxacin.

    PubMed

    Ilo, Cajetan E; Ezejiofor, Ndidi A; Agbakoba, Nneka; Brown, Sinye A; Maduagwuna, Chinonye A; Agbasi, Patrick U; Orisakwe, Orish E; Orisakweph, Orish E

    2008-01-01

    Ciprofloxacin is an inexpensive antibacterial, whereas chloroquine is an inexpensive antimalarial. The coadministration of chloroquine and ciprofloxacin is easily encountered because both drugs are commonly prescribed to patients in the tropics. Five healthy male volunteers aged 19 to 31 years who were not taking any of the prescribed medications and who had no sensitivity to either ciprofloxacin or chloroquine each received 500 mg ciprofloxacin orally with 250 mL of water, and after a 2-week washout period, 500 mg ciprofloxacin plus 600 mg chloroquine was administered orally with 250 mL of water after providing informed consent. A urine sample (7 mL) was collected just before taking the drug at 8:00 AM representing 0 hour and continued afterward at 1, 2, 4, 8, 12, and 24 hours the next day. The samples were stored at -20 degrees C until analyzed. The minimum inhibitory concentrations by diffusion through agar technique were used for the assay of urine ciprofloxacin. The rate of ciprofloxacin excretion and cumulative urine ciprofloxacin were significantly increased. The coadministration of chloroquine increased the cumulative urinary concentration and excretion rate of ciprofloxacin.

  2. Characterization of the Chloroquine Resistance Transporter Homologue in Toxoplasma gondii

    PubMed Central

    Warring, Sally D.; Dou, Zhicheng; Carruthers, Vern B.; McFadden, Geoffrey I.

    2014-01-01

    Mutations in the Plasmodium falciparum chloroquine resistance transporter (PfCRT) protein confer resistance to the antimalarial drug chloroquine. PfCRT localizes to the parasite digestive vacuole, the site of chloroquine action, where it mediates resistance by transporting chloroquine out of the digestive vacuole. PfCRT belongs to a family of transporter proteins called the chloroquine resistance transporter family. CRT family proteins are found throughout the Apicomplexa, in some protists, and in plants. Despite the importance of PfCRT in drug resistance, little is known about the evolution or native function of CRT proteins. The apicomplexan parasite Toxoplasma gondii contains one CRT family protein. We demonstrate that T. gondii CRT (TgCRT) colocalizes with markers for the vacuolar (VAC) compartment in these parasites. The TgCRT-containing VAC is a highly dynamic organelle, changing its morphology and protein composition between intracellular and extracellular forms of the parasite. Regulated knockdown of TgCRT expression resulted in modest reduction in parasite fitness and swelling of the VAC, indicating that TgCRT contributes to parasite growth and VAC physiology. Together, our findings provide new information on the role of CRT family proteins in apicomplexan parasites. PMID:24859994

  3. In Vivo Confocal Microscopy in Chloroquine-Induced Keratopathy

    PubMed Central

    Paladini, Iacopo; Menchini, Ugo; Mencucci, Rita

    2013-01-01

    In vivo confocal microscopy is becoming a mandatory examination to study corneal abnormalities such as drug deposits in systemic disease. A female diagnosed with fibromyalgia on systemic chloroquine for 9 months presented for an ophthalmic examination. Confocal microscopy was performed using the Confoscan 4 (Nidek Co. Ltd., Gamagori, Japan) and multiple highly reflective deposits in the epithelial basal cells were found, that were consistent with choloquine. Deposits were also present in the wing cell layer. In the anterior stroma these deposits were rare. Atypically shaped and branched nerves were also present in the anterior stroma. Corneal deposits of chloroquine can be evaluated by confocal microscopy. Confocal microscopy provides information on corneal metabolism and physiology. Chloroquine keratopathy can affect the anterior stroma in addition to the epithelium. PMID:23580857

  4. Electro-Oculograms in the Early Diagnosis of Chloroquine Retinopathy

    PubMed Central

    Weinreb, Marvin S.

    1967-01-01

    Funduscopy, electro-oculography and electroretinography are all valuable in early detection of chloroquine retinopathy, which is reversible if detected early. Simplified instrumentation for electro-oculography was utilized in testing 12 normal controls, one patient with diabetic retinopathy and 15 patients with potential or actual cases of chloroquine retinopathy. Normal controls, and all but one of the patients without clinical evidence of retinopathy, had electro-oculographic ratios above 180. All patients having evidence of retinopathy had ratios below 180. ImagesFigure 1.Figure 2. PMID:6039185

  5. The Synergistic Effect of Everolimus and Chloroquine on Endothelial Cell Number Reduction Is Paralleled by Increased Apoptosis and Reduced Autophagy Occurrence

    PubMed Central

    Grimaldi, Anna; Balestrieri, Maria Luisa; D'Onofrio, Nunzia; Di Domenico, Gilda; Nocera, Cosimo; Lamberti, Monica; Tonini, Giuseppe; Zoccoli, Alice; Santini, Daniele; Caraglia, Michele; Pantano, Francesco

    2013-01-01

    Endothelial Progenitor Cells (EPCs), a minor subpopulation of the mononuclear cell fraction in peripheral blood, play a critical role in cancer development as they contribute to angiogenesis-mediated pathological neovascularization. In response to tumor cytokines, including VEGF, EPCs mobilize from the bone marrow into the peripheral circulation and move to the tumor bed where they incorporate into sprouting neovessels. In the present study, we evaluated the effects of everolimus (Afinitor, Novartis), a rapamycin analogue, alone or in combination with chloroquine, a 4-alkylamino substituted quinoline family member, one of the autophagy inhibitors, on EPCs biological functions. We found that either everolimus or chloroquine induce growth inhibition on EPCs in a dose-dependent manner after 72 h from the beginning of incubation. The combined administration of the two drugs to EPC was synergistic in inducing growth inhibition; in details, the maximal pharmacological synergism between everolimus and chloroquine in inducing growth inhibition on EPCs cells was recorded when chloroquine was administered 24 h before everolimus. Moreover, we have studied the mechanisms of cell death induced by the two agents alone or in combination on EPCs and we have found that the synergistic effect of combination on EPC growth inhibition was paralleled by increased apoptosis induction and reduced autophagy. These effects occurred together with biochemical features that are typical of reduced autophagic death such as increased co-immunoprecipitation between Beclin 1 and Bcl-2. Chloroquine antagonized the inhibition of the activity of Akt→4EBP1 axis mediated by everolimus and at the same time it blocked the feed-back activation of Erk-1/2 induced by RAD in EPCs. These data suggest a new strategy in order to block angiogenesis in tumours in which this process plays a key role in both the sustainment and spreading of cancer cells. PMID:24244540

  6. Effective treatment with a tetrandrine/chloroquine combination for chloroquine-resistant falciparum malaria in Aotus monkeys

    PubMed Central

    2013-01-01

    Background In vitro evidence indicates that tetrandrine (TT) can potentiate the action of chloroquine 40-fold against choloquine-resistant Plasmodium falciparum. The key question emanating from that study is “would tetrandine and chloroquine be highly effective in a live Aotus monkey model with chloroquine-resistant parasites”. This study was designed to closely mimic the pharmacological/anti-malarial activity in man. Methods The Vietnam Smith/RE strain of P. falciparum, which is chloroquine-resistant was used in this study. Previous experimental procedures were followed. Panamanian owl monkeys (Aotus) were inoculated with 5×106 erythrocytes parasitized with the CQ-resistant strain of P. falciparum. Oral drug treatment was with CQ (20 mg/kg) and/or tetrandrine at 15 mg/Kg, 30 mg/Kg or 60 mg/Kg or 25 mg/Kg depending on experimental conditions. Results and Discussion Parasitaemia was cleared rapidly with CQ and TT while CQ treatment alone was ineffective. Recrudescence of malaria occurred after seven days post-infection. However, four animals were treated orally with TT and CQ parasites were cleared. It is likely that monkeys were cured via a combination of both drug and host immune responses. A single Aotus monkey infected with P. falciparum and untreated with drugs, died. No side effects were observed with these drug treatments. Conclusions This combination of chloroquine and tetrandrine forms the basis of a new attack on chloroquine-resistant malaria - one based upon inhibition of the basis of chloroquine resistance, the multiple drug resistance pump. Previous studies demonstrated that the parasite MDR pump was found on parasite membranes using 3H azidopine photoaffinity labelling. Since MDR-based choloroquine resistance is induced by chloroquine, the basis of the action of tetrandrine is the following: 1) tetrandrine inhibits the MDR pump by stimulating MDR ATPase which limits the energy of the pump by depletion of parasite ATP, 2) tetrandrine blocks the

  7. Impact of Chloroquine on Viral Load in Breast Milk

    PubMed Central

    Semrau, Katherine; Kuhn, Louise; Kasonde, Prisca; Sinkala, Moses; Kankasa, Chipepo; Shutes, Erin; Vwalika, Cheswa; Ghosh, Mrinal; Aldrovandi, Grace; Thea, Donald M.

    2006-01-01

    Summary The anti-malarial agent chloroquine has activity against HIV. We compared the effect of chloroquine (n = 18) to an anti-malarial agent without known anti-HIV-activity, sulfadoxine-pyrimethamine (n = 12), on breast milk HIV RNA levels among HIV-infected breastfeeding women in Zambia. After adjusting for CD4 count and plasma viral load, chloroquine was associated with a trend towards lower levels of HIV RNA in breast milk compared with sulfadoxine-pyrimethamine (P 0.05). Higher breastmilk viral load was also observed among women receiving presumptive treatment = for symptomatic malaria compared with asymptomatic controls and among controls reporting fever in the prior week. Further research is needed to determine the potential role of chloroquine in prevention of HIV transmission through breastfeeding. Impacte de la chloroquine sur la charge virale dans le lait maternelle La chloroquine, agent antimalarique, a une activité contre le VIH. Nous avons comparé l’effet de la chloroquine à celui d’un autre agent antimalarique, la sulfadoxine-pyrimethamine, dont l’activité sur le VIH n’est pas connue, en mesurant les taux d’ARN de VIH dans le lait maternel de femmes allaitantes infectées par le VIH en Zambie. Après ajustement pour les taux de CD4 et la charge virale dans le plasma, la chloroquine comparée à la sulfadoxine pyrimethamine était associée à une tendance vers des teneurs plus bas en ARN de VIH dans le lait maternel (P = 0,05). Des charges virales plus élevées dans le lait maternel étaient aussi observées chez des femmes recevant un traitement présomptif pour des symptômes de malaria par rapport aux contrôles asymptomatiques et par rapport à des contrôles rapportant de la fièvre durant la première semaine. Des études supplémentaires sont nécessaires pour déterminer le rôle potentiel de la chloroquine dans la prévention de la transmission du VIH par l’allaitement maternel. mots clésVIH, malaria, allaitement maternel

  8. Effect of chloroquine on feline infectious peritonitis virus infection in vitro and in vivo.

    PubMed

    Takano, Tomomi; Katoh, Yasuichiroh; Doki, Tomoyoshi; Hohdatsu, Tsutomu

    2013-08-01

    Feline infectious peritonitis (FIP) is a feline coronavirus-induced fatal disease in domestic and wild cats. Several studies have investigated potential treatments for FIP. However, there have been no reports on agents that have exhibited a therapeutic effect. Recently, chloroquine has been reported to antiviral effect. We investigated whether chloroquine can be used to treat FIP in vitro and in vivo. It was demonstrated that chloroquine has inhibitory effect against the replication of FIPV and anti-inflammatory effect in vitro. In vivo study using cats with experimentally induced FIP, the clinical score of chloroquine-treatment groups were better than in chloroquine-untreated group. However, alanine aminotransferase levels increased in the chloroquine-treated groups. It will be necessary to further investigate the possibility of FIP treatment with a combination of chloroquine and other agents.

  9. Differential Stimulation of the Na+/H+ Exchanger Determines Chloroquine Uptake in Plasmodium falciparum

    PubMed Central

    Wünsch, Stefan; Sanchez, Cecilia P.; Gekle, Michael; Große-Wortmann, Lars; Wiesner, Jochen; Lanzer, Michael

    1998-01-01

    Here we describe the identification and characterization of a physiological marker that is associated with the chloroquine-resistant (CQR) phenotype in the human malarial parasite Plasmodium falciparum. Single cell in vivo pH measurements revealed that CQR parasites consistently have an elevated cytoplasmic pH compared to that of chloroquine-sensitive (CQS) parasites because of a constitutively activated Na+/H+ exchanger (NHE). Together, biochemical and physiological data suggest that chloroquine activates the plasmodial NHE of CQS parasites, resulting in a transitory phase of rapid sodium/hydrogen ion exchange during which chloroquine is taken up by this protein. The constitutively stimulated NHE of CQR parasites are capable of little or no further activation by chloroquine. We propose that the inability of chloroquine to stimulate its own uptake through the constitutively activated NHE of resistant parasites constitutes a minimal and necessary event in the generation of the chloroquine-resistant phenotype. PMID:9442109

  10. Testing the influence of vertical, pre-existing joints on normal faulting using analogue and 3D discrete element models (DEM)

    NASA Astrophysics Data System (ADS)

    Kettermann, Michael; von Hagke, Christoph; Virgo, Simon; Urai, Janos L.

    2015-04-01

    Brittle rocks are often affected by different generations of fractures that influence each other. We study pre-existing vertical joints followed by a faulting event. Understanding the effect of these interactions on fracture/fault geometries as well as the development of dilatancy and the formation of cavities as potential fluid pathways is crucial for reservoir quality prediction and production. Our approach combines scaled analogue and numerical modeling. Using cohesive hemihydrate powder allows us to create open fractures prior to faulting. The physical models are reproduced using the ESyS-Particle discrete element Modeling Software (DEM), and different parameters are investigated. Analogue models were carried out in a manually driven deformation box (30x28x20 cm) with a 60° dipping pre-defined basement fault and 4.5 cm of displacement. To produce open joints prior to faulting, sheets of paper were mounted in the box to a depth of 5 cm at a spacing of 2.5 cm. Powder was then sieved into the box, embedding the paper almost entirely (column height of 19 cm), and the paper was removed. We tested the influence of different angles between the strike of the basement fault and the joint set (0°, 4°, 8°, 12°, 16°, 20°, and 25°). During deformation we captured structural information by time-lapse photography that allows particle imaging velocimetry analyses (PIV) to detect localized deformation at every increment of displacement. Post-mortem photogrammetry preserves the final 3-dimensional structure of the fault zone. We observe that no faults or fractures occur parallel to basement-fault strike. Secondary fractures are mostly oriented normal to primary joints. At the final stage of the experiments we analyzed semi-quantitatively the number of connected joints, number of secondary fractures, degree of segmentation (i.e. number of joints accommodating strain), damage zone width, and the map-view area fraction of open gaps. Whereas the area fraction does not change

  11. The pharmacokinetics of three multiple dose regimens of chloroquine: implications for malaria chemoprophylaxis.

    PubMed Central

    Wetsteyn, J C; De Vries, P J; Oosterhuis, B; Van Boxtel, C J

    1995-01-01

    The pharmacokinetics of chloroquine were studied in healthy volunteers who received one of three different multiple-dose regimens for 3 weeks: once weekly 300 mg, twice weekly 200 mg and once daily 50 mg chloroquine. Plasma concentrations of chloroquine and metabolites were determined by h.p.l.c. with fluorescence detection. The concentration-time course was fitted to a multiple-dose pharmacokinetic model. Volume of distribution, elimination half-life and clearance were not different for the three regimens, ranging from 250-302 l kg-1, 374-479 h and 0.44-0.58 l h-1 kg-1 respectively. After the first week of all dosage regimens, peak and trough concentrations of chloroquine were above 16 micrograms l-1, sufficiently suppressive for chloroquine-sensitive P. falciparum strains. These data suggest that once daily chloroquine could be combined with proguanil in a single tablet and should improve compliance when given for malaria chemoprophylaxis. PMID:7654492

  12. Antimalarial Activity and Mechanisms of Action of Two Novel 4-Aminoquinolines against Chloroquine-Resistant Parasites

    PubMed Central

    Aguiar, Anna Caroline Campos; Santos, Raquel de Meneses; Figueiredo, Flávio Júnior Barbosa; Cortopassi, Wilian Augusto; Pimentel, André Silva; França, Tanos Celmar Costa; Meneghetti, Mario Roberto; Krettli, Antoniana Ursine

    2012-01-01

    Chloroquine (CQ) is a cost effective antimalarial drug with a relatively good safety profile (or therapeutic index). However, CQ is no longer used alone to treat patients with Plasmodium falciparum due to the emergence and spread of CQ-resistant strains, also reported for P. vivax. Despite CQ resistance, novel drug candidates based on the structure of CQ continue to be considered, as in the present work. One CQ analog was synthesized as monoquinoline (MAQ) and compared with a previously synthesized bisquinoline (BAQ), both tested against P. falciparum in vitro and against P. berghei in mice, then evaluated in vitro for their cytotoxicity and ability to inhibit hemozoin formation. Their interactions with residues present in the NADH binding site of P falciparum lactate dehydrogenase were evaluated using docking analysis software. Both compounds were active in the nanomolar range evaluated through the HRPII and hypoxanthine tests. MAQ and BAQ derivatives were not toxic, and both compounds significantly inhibited hemozoin formation, in a dose-dependent manner. MAQ had a higher selectivity index than BAQ and both compounds were weak PfLDH inhibitors, a result previously reported also for CQ. Taken together, the two CQ analogues represent promising molecules which seem to act in a crucial point for the parasite, inhibiting hemozoin formation. PMID:22649514

  13. Inhibitory properties of nerve-specific human glutamate dehydrogenase isozyme by chloroquine.

    PubMed

    Choi, Myung-Min; Kim, Eun-A; Choi, Soo Young; Kim, Tae Ue; Cho, Sung-Woo; Yang, Seung-Ju

    2007-11-30

    Human glutamate dehydrogenase exists in hGDH1 (housekeeping isozyme) and in hGDH2 (nerve-specific isozyme), which differ markedly in their allosteric regulation. In the nervous system, GDH is enriched in astrocytes and is important for recycling glutamate, a major excitatory neurotransmitter during neurotransmission. Chloroquine has been known to be a potent inhibitor of house-keeping GDH1 in permeabilized liver and kidney-cortex of rabbit. However, the effects of chloroquine on nerve-specific GDH2 have not been reported yet. In the present study, we have investigated the effects of chloroquine on hGDH2 at various conditions and showed that chloroquine could inhibit the activity of hGDH2 at dose-dependent manner. Studies of the chloroquine inhibition on enzyme activity revealed that hGDH2 was relatively less sensitive to chloroquine inhibition than house-keeping hGDH1. Incubation of hGDH2 was uncompetitive with respect of NADH and non-competitive with respect of 2-oxoglutarate. The inhibitory effect of chloroquine on hGDH2 was abolished, although in part, by the presence of ADP and L-leucine, whereas GTP did not change the sensitivity to chloroquine inhibition. Our results show a possibility that chloroquine may be used in regulating GDH activity and subsequently glutamate concentration in the central nervous system.

  14. Chloroquine-resistant Plasmodium vivax malaria in Debre Zeit, Ethiopia

    PubMed Central

    Teka, Hiwot; Petros, Beyene; Yamuah, Lawrence; Tesfaye, Gezahegn; Elhassan, Ibrahim; Muchohi, Simon; Kokwaro, Gilbert; Aseffa, Abraham; Engers, Howard

    2008-01-01

    Background Plasmodium vivax accounts for about 40% of all malaria infection in Ethiopia. Chloroquine (CQ) is the first line treatment for confirmed P. vivax malaria in the country. The first report of CQ treatment failure in P. vivax was from Debre Zeit, which suggested the presence of chloroquine resistance. Methods An in vivo drug efficacy study was conducted in Debre Zeit from June to August 2006. Eighty-seven patients with microscopically confirmed P. vivax malaria, aged between 8 months and 52 years, were recruited and treated under supervision with CQ (25 mg/kg over three days). Clinical and parasitological parameters were assessed during the 28 day follow-up period. CQ and desethylchloroquine (DCQ) blood and serum concentrations were determined with high performance liquid chromatography (HPLC) in patients who showed recurrent parasitaemia. Results Of the 87 patients recruited in the study, one was lost to follow-up and three were excluded due to P. falciparum infection during follow-up. A total of 83 (95%) of the study participants completed the follow-up. On enrolment, 39.8% had documented fever and 60.2% had a history of fever. The geometric mean parasite density of the patients was 7045 parasites/μl. Among these, four patients had recurrent parasitaemia on Day 28. The blood CQ plus DCQ concentrations of these four patients were all above the minimal effective concentration (> 100 ng/ml). Conclusion Chloroquine-resistant P. vivax parasites are emerging in Debre Zeit, Ethiopia. A multi-centre national survey is needed to better understand the extent of P. vivax resistance to CQ in Ethiopia. PMID:18959774

  15. Confirmed Plasmodium vivax Resistance to Chloroquine in Central Vietnam.

    PubMed

    Thanh, Pham Vinh; Hong, Nguyen Van; Van, Nguyen Van; Louisa, Melva; Baird, Kevin; Xa, Nguyen Xuan; Peeters Grietens, Koen; Hung, Le Xuan; Duong, Tran Thanh; Rosanas-Urgell, Anna; Speybroeck, Niko; D'Alessandro, Umberto; Erhart, Annette

    2015-12-01

    Plasmodium vivax resistance to chloroquine (CQ) is currently reported in almost all countries where P. vivax is endemic. In Vietnam, despite a first report on P. vivax resistance to chloroquine published in the early 2000s, P. vivax was still considered sensitive to CQ. Between May 2009 and December 2011, a 2-year cohort study was conducted in central Vietnam to assess the recommended radical cure regimen based on a 10-day course of primaquine (0.5 mg/kg/day) together with 3 days of CQ (25 mg/kg). Here we report the results of the first 28-day follow-up estimating the cumulative risk of P. vivax recurrences together with the corresponding CQ blood concentrations, among other endpoints. Out of 260 recruited P. vivax patients, 240 completed treatment and were followed up to day 28 according to the WHO guidelines. Eight patients (3.45%) had a recurrent P. vivax infection, at day 14 (n = 2), day 21 (n = 1), and day 28 (n = 5). Chloroquine blood concentrations, available for 3/8 recurrent infections (days 14, 21, and 28), were above the MIC (>100 ng/ml whole blood) in all of these cases. Fever and parasitemia (both sexual and asexual stages) were cleared by day 3. Anemia was common at day 0 (35.8%), especially in children under 10 years (50%), and hemoglobin (Hb) recovery at day 28 was substantial among anemic patients (median change from day 0 to 28, +1.7 g/dl; interquartile range [IQR], +0.7 to +3.2). This report, based on CQ blood levels measured at the time of recurrences, confirms for the first time P. vivax CQ resistance in central Vietnam and calls for further studies using standardized protocols for accurately monitoring the extent and evolution of P. vivax resistance to chloroquine in Vietnam. These results, together with the mounting evidence of artemisinin resistance in central Vietnam, further highlight the increasing threat of antimalarial drug resistance to malaria elimination in Vietnam.

  16. Chloroquine-resistant malaria in travelers returning from Haiti after 2010 earthquake.

    PubMed

    Gharbi, Myriam; Pillai, Dylan R; Lau, Rachel; Hubert, Véronique; Khairnar, Krishna; Existe, Alexandre; Kendjo, Eric; Dahlström, Sabina; Guérin, Philippe J; Le Bras, Jacques

    2012-08-01

    We investigated chloroquine sensitivity to Plasmodium falciparum in travelers returning to France and Canada from Haiti during a 23-year period. Two of 19 isolates obtained after the 2010 earthquake showed mixed pfcrt 76K+T genotype and high 50% inhibitory concentration. Physicians treating malaria acquired in Haiti should be aware of possible chloroquine resistance.

  17. A STUDY OF THE PHARMACOLOGY AND TOXICOLOGY OF VISION IN THE SOLDIER. 1. CHLOROQUINE AND HYDROXYCHLOROQUINE.

    DTIC Science & Technology

    A critical evaluation of reports on the toxic effects of chloroquine and hydroxychloroquine on vision has revealed a relationship between the dosage...revealed a possible explanation of the retinal toxicity of chloroquine and hydroxychloroquine . This phenomenon merits future study because reactions of

  18. Reversal of Plasmodium Falsiparum Resistance to Chloroquine in Panamanian Aotus Monkeys

    DTIC Science & Technology

    1993-01-01

    chlorpromazine, proch- lorperazine, cyproheptadine , ketotifen, a tiapamil analog (Ro 11-2933), and a chlorprom- azine analog (SKF 2133-A). Combinations of...prochlorperazine ;: desipramine >> Ro 11-2933 (tiapamil analog) > ketotifen. Cyproheptadine and verapamil were not effective in reversing chloroquine resistance...chloroquine laria models, verapamil, cyproheptadine , keto- was used. This strain, designated Vietnam Smitlh/ tifen, and amlodipine have been shown to

  19. The Effect of Chloroquine on Immune Activation and Interferon Signatures Associated with HIV-1.

    PubMed

    Jacobson, Jeffrey M; Bosinger, Steven E; Kang, Minhee; Belaunzaran-Zamudio, Pablo; Matining, Roy M; Wilson, Cara C; Flexner, Charles; Clagett, Brian; Plants, Jill; Read, Sarah; Purdue, Lynette; Myers, Laurie; Boone, Linda; Tebas, Pablo; Kumar, Princy; Clifford, David; Douek, Daniel; Silvestri, Guido; Landay, Alan L; Lederman, Michael M

    2016-07-01

    Immune activation associated with HIV-1 infection contributes to morbidity and mortality. We studied whether chloroquine, through Toll-like receptor (TLR) antagonist properties, could reduce immune activation thought to be driven by TLR ligands, such as gut-derived bacterial elements and HIV-1 RNAs. AIDS Clinical Trials Group A5258 was a randomized, double-blind, placebo-controlled study in 33 HIV-1-infected participants off antiretroviral therapy (ART) and 37 participants on ART. Study participants in each cohort were randomized 1:1 to receive chloroquine 250 mg orally for the first 12 weeks then cross over to placebo for 12 weeks or placebo first and then chloroquine. Combining the periods of chloroquine use in both arms of the on-ART cohort yielded a modest reduction in the proportions of CD8 T cells co-expressing CD38 and DR (median decrease = 3.0%, p = .003). The effect on immune activation in the off-ART cohort was likely confounded by increased plasma HIV-1 RNA during chloroquine administration (median 0.29 log10 increase, p < .001). Transcriptional analyses in the off-ART cohort showed decreased expression of interferon-stimulated genes in 5 of 10 chloroquine-treated participants and modest decreases in CD38 and CCR5 RNAs in all chloroquine-treated participants. Chloroquine modestly reduced immune activation in ART-treated HIV-infected participants. Clinical Trials Registry Number: NCT00819390.

  20. Chloroquine Inhibits HMGB1 Inflammatory Signaling and Protects Mice from Lethal Sepsis

    PubMed Central

    Yang, Minghua; Cao, Lizhi; Xie, Min; Yu, Yan; Kang, Rui; Yang, Liangchun; Zhao, Mingyi; Tang, Daolin

    2013-01-01

    Sepsis is caused by an overwhelming immune response to bacterial infection. The discovery of high mobility group box 1 (HMGB1) as a late mediator of lethal sepsis has prompted investigation into the development of new therapeutics which specifically target this protein. Here, we show that chloroquine, an anti-malarial drug, prevents lethality in mice with established endotoxemia or sepsis. This effect is still observed even if administration of chloroquine is delayed. The protective effects of chloroquine were mediated through inhibition of HMGB1 release in macrophages, monocytes, and endothelial cells, thereby preventing its cytokine-like activities. As an inhibitor of autophagy, chloroquine specifically inhibited HMGB1-induced Iκ-B degradation and NF-κB activation. These findings define a novel mechanism for the anti-inflammatory effects of chloroquine and also suggest a new potential clinical use for this drug in the setting of sepsis. PMID:23707973

  1. Plasmodium falciparum mdr1 mutations and in vivo chloroquine resistance in Indonesia.

    PubMed

    Gómez-Saladín, E; Fryauff, D J; Taylor, W R; Laksana, B S; Susanti, A I; Purnomo; Subianto, B; Richie, T L

    1999-08-01

    Mutations in the Pfmdr1 gene are reported to be associated with chloroquine resistance in some Plasmodium falciparum isolates. A polymerase chain reaction/restriction fragment length polymorphism method was used for the detection of Pfmdr1 mutations in chloroquine-resistant field isolates of P. falciparum collected in Irian Jaya. The frequency of Pfmdr1 mutations was significantly higher in chloroquine-resistant P. falciparum parasites than background frequencies observed in the same location. The 7G8 mutation was identified in some parasites although always in a mixed genotype status. Chloroquine-resistant P. falciparum specimens were characterized using the World Health Organization 28-day criteria, supplemented by demonstrating adequate chloroquine absorption and genetic analysis.

  2. Molecular epidemiology of malaria in Cameroon. XIV. Plasmodium falciparum chloroquine resistance transporter (PFCRT) gene sequences of isolates before and after chloroquine treatment.

    PubMed

    Basco, Leonardo K; Ndounga, Mathieu; Ngane, Vincent Foumane; Soula, Georges

    2002-10-01

    Laboratory studies have strongly suggested that the gene coding for Plasmodium falciparum chloroquine resistance transporter (PFCRT) may play a determinant role in chloroquine resistance. A clinical study in Mali also found evidence for selection of the key PFCRT amino acid substitution, Lys76Thr, in patients who fail to respond to chloroquine treatment. To test the hypothesis that in vivo selection of mutant PFCRT alleles occurs after chloroquine treatment, PFCRT and merozoite surface antigen 2 (msa-2) polymorphisms were compared between 61 pretreatment and posttreatment paired samples from children with either clinical or parasitologic failure. There were six wild-type PFCRT alleles, 44 mutant alleles, and 11 mixed alleles among pretreatment isolates. All posttreatment parasites had mutant PFCRT alleles. Recrudescence accounted for 42 of 61 posttreatment infections, while 19 posttreatment infections were due to new infection (including all isolates with Lys-76 before treatment and Thr-76 after treatment). Seven pretreatment isolates with mixed PFCRT alleles had only Thr-76 on recrudescence, providing a direct evidence for in vivo selection for mutant PFCRT. Although the presence of mutant PFCRT alleles in pretreatment isolates is not predictive of chloroquine treatment failure, our data support the hypothesis that in vivo selection for recrudescent parasites carrying mutant PFCRT alleles occurs. These results may have important implications for the future surveillance of chloroquine resistance by the use of molecular markers.

  3. Use of pre-packaged chloroquine for the home management of presumed malaria in Malagasy children

    PubMed Central

    Ratsimbasoa, Arsène; Randrianarivelojosia, Milijaona; Millet, Pascal; Soarès, Jean Louis; Rabarijaona, Leon; Rakotoson, Benjamin; Malvy, Denis; Ménard, Didier

    2006-01-01

    Objective The main objective of this study was to assess the quality of home malaria management with pre-packaged chloroquine in two areas in the Moramanga district of Madagascar. The knowledge, attitude and practices of care providers in terms of home treatment options were evaluated and compared. The availability of treatment options by studying retailers and community-based service providers was also investigated. Methods A cross-sectional investigation in two communities, in the hamlets and villages located close to carers, retailers, community-based service providers and primary health centres was carried out. Results Carers in the two districts were equally well aware of the use of pre-packaged chloroquine. Their first response to the onset of fever was to treat children with this antimalarial drug at home. The dose administered and treatment compliance were entirely satisfactory (100%) with pre-packaged chloroquine and rarely satisfactory (1.6% to 4.5%) with non pre-packaged chloroquine. In cases of treatment failure, the carers took patients to health centres. Chloroquine was supplied principally by private pharmacies and travelling salesmen selling unpackaged chloroquine tablets. Non pre-packaged chloroquine was the most common drug used at health centres. The frequency of positive rapid malaria tests (P = 0.01) was significantly higher in children treated with non pre-packaged chloroquine (38%) than in children treated with pre-packaged chloroquine (1.3%). Conclusion Home malaria management should be improved in Madagascar. Efforts should focus on communication, the training of community-based service providers, access to pre-packaged drugs and the gradual withdrawal of pre-packaged chloroquine and its replacement by pre-packaged artemisinin-based combination therapies. PMID:16972985

  4. [Occurrence of chloroquine-induced myopathy after low-dose treatment of rheumatoid arthritis for seven years].

    PubMed

    Haberl, A; Fischer, P; Pongratz, D; Sieb, J P

    2005-05-01

    The myotoxicity of chloroquine and hydroxychloroquine has been known for decades. Limb-girdle weakness due to a vacuolar myopathy may occur occasionally in a dose-dependent manner during the first 24 months on chloroquine. However, we report on a case in which muscular weakness developed after a daily intake of 250 chloroquine phosphate (= 155 mg chloroquine base) for a period of 7 years. Even after long-term and apparently well-tolerated chloroquine treatment, the occurrence of severe side-effects is possible.

  5. Chloroquine Has a Cytotoxic Effect on Acanthamoeba Encystation through Modulation of Autophagy

    PubMed Central

    Jha, Bijay Kumar; Jung, Hui-Jung; Seo, Incheol; Kim, Hyun Ah; Suh, Seong-Il; Suh, Min-Ho

    2014-01-01

    Encystation of Acanthamoeba castellanii is associated with resistance to chemotherapeutic agents. Blocking the encystation process could potentiate the efficacy of chemotherapeutic agents and biocides. During encystation, autophagy is highly stimulated and required for proper encystation of Acanthamoeba. In this study, the cytotoxic effect of chloroquine, a well-known autophagy-inhibitory drug, was tested in A. castellanii. Chloroquine was able to selectively reduce cell survival during the encystation of A. castellanii. However, A. castellanii trophozoites and mature cysts were resistant to chloroquine. Chloroquine treatment led to an increase in the number and size of lysosomes in encysting cells. Moreover, chloroquine inhibited the degradation of long-lived proteins in the encysting cells. Decreased autophagic flux, indicated by an increased number of lysosomes and decreased degradation of long-lived proteins, may be the mechanism by which cell death is induced by chloroquine in encysting Acanthamoeba. These results suggest a potential novel therapeutic application of chloroquine as an anti-Acanthamoeba drug. Our findings also suggest that targeting autophagy could be a therapeutic strategy against Acanthamoeba infection. PMID:25114131

  6. Chloroquine has a cytotoxic effect on Acanthamoeba encystation through modulation of autophagy.

    PubMed

    Jha, Bijay Kumar; Jung, Hui-Jung; Seo, Incheol; Kim, Hyun Ah; Suh, Seong-Il; Suh, Min-Ho; Baek, Won-Ki

    2014-10-01

    Encystation of Acanthamoeba castellanii is associated with resistance to chemotherapeutic agents. Blocking the encystation process could potentiate the efficacy of chemotherapeutic agents and biocides. During encystation, autophagy is highly stimulated and required for proper encystation of Acanthamoeba. In this study, the cytotoxic effect of chloroquine, a well-known autophagy-inhibitory drug, was tested in A. castellanii. Chloroquine was able to selectively reduce cell survival during the encystation of A. castellanii. However, A. castellanii trophozoites and mature cysts were resistant to chloroquine. Chloroquine treatment led to an increase in the number and size of lysosomes in encysting cells. Moreover, chloroquine inhibited the degradation of long-lived proteins in the encysting cells. Decreased autophagic flux, indicated by an increased number of lysosomes and decreased degradation of long-lived proteins, may be the mechanism by which cell death is induced by chloroquine in encysting Acanthamoeba. These results suggest a potential novel therapeutic application of chloroquine as an anti-Acanthamoeba drug. Our findings also suggest that targeting autophagy could be a therapeutic strategy against Acanthamoeba infection.

  7. Influence of using a blend of rennet casein and whey protein concentrate as protein source on the quality of Mozzarella cheese analogue.

    PubMed

    Dhanraj, Padhiyar; Jana, Atanu; Modha, Hiral; Aparnathi, K D

    2017-03-01

    The effect of incorporating whey protein concentrate (WPC) on the quality characteristics of Mozzarella cheese analogue (MCA) based on rennet casein (RC) was studied. The proportion of RC:WPC tried out were 95:5, 90:10, and 85:15 w/w. The formulation of MCA comprised of 23.5% of blend of RC and WPC, 15% specialty vegetable fat, 2.75% trisodium citrate + disodium hydrogen orthophosphate (2.5:1, w/w), 0.07% calcium chloride, 0.6% citric acid, 1.1% NaCl, 1.5% cheese bud flavoring, and rest water. Varying the proportion of RC and WPC had a significant influence on the composition, textural properties, baking qualities and sensory quality of MCA judged as a topping on pizza pie. MCA made using protein blends (RC:WPC-90:10 or 85:15) behaved satisfactorily during pizza baking trials. However, looking at the superiority of MCA made using RC:WPC (90:10) with regard to shred quality and marginal superiority in terms of the total sensory score of cheese, judged as pizza topping, the former blend (i.e. RC:WPC, 90:10) was selected. The MCA obtained employing such protein blend had composition similar to that of Pizza cheese prepared from cheese milk and had requisite baking characteristics needed as a pizza topping. It is recommended to use a blend of RC and WPC (90:10) as the protein source in the formulation of MCA to obtain nutritionally superior cheese product having desired functional properties for its end use in baking applications.

  8. Chloroquine: An Old Drug with New Perspective Against Giardiasis.

    PubMed

    Escobedo, Angel A; Almirall, Pedro; Cimerman, Sérgio; Lalle, Marco; Pacheco, Frank; Acanda, Carlos Z; Sánchez, Niurka

    2015-01-01

    The occurrence of treatment failures to first-line treatment for giardiasis, one of the most widespread although neglected parasitic disease, has long been recognised. Nowadays, it starts to represent a great challenge to clinicians, especially in endemic countries. This requires the introduction of new drug interventions, but the development of novel drugs is a time and money consuming effort with most of the compounds never reaching the market. Consequently, alternative strategies are needed, especially for the treatment of giardiasis. Chloroquine (CQ), a synthetic drug developed as antimalarial agent, has been shown to also exert antigiardial activity. Here, we present a mini-research summarizing results on the treatment of human clinical cases with CQ, going through in vitro research, case report, and case series to human clinical trials, highlighting the benefits and mentioning possible adverse effects.

  9. Synthesis, structure-activity relationship, and mode-of-action studies of antimalarial reversed chloroquine compounds.

    PubMed

    Burgess, Steven J; Kelly, Jane X; Shomloo, Shawheen; Wittlin, Sergio; Brun, Reto; Liebmann, Katherine; Peyton, David H

    2010-09-09

    We have previously shown that a "reversed chloroquine (RCQ)" molecule, composed of a chloroquine-like moiety and a resistance reversal-like moiety, can overcome chloroquine resistance in P. falciparum ( Burgess , S. J. ; Selzer , A. ; Kelly , J. X. ; Smilkstein , M. J. ; Riscoe , M. K. ; Peyton , D. H. J. Med. Chem. 2006 , 49 , 5623 . Andrews , S. ; Burgess , S. J. ; Skaalrud , D. ; Kelly , J. X. ; Peyton , D. H. J. Med. Chem. 2010 , 53 , 916 ). Here, we present an investigation into the structure-activity relationship of the RCQ structures, resulting in an orally active molecule with good in vitro and in vivo antimalarial activity. We also present evidence of the mode of action, indicating that the RCQ molecules inhibit hemozoin formation in the parasite's digestive vacuole in a manner similar to that of chloroquine.

  10. Chloroquine, an Endocytosis Blocking Agent, Inhibits Zika Virus Infection in Different Cell Models

    PubMed Central

    Delvecchio, Rodrigo; Higa, Luiza M.; Pezzuto, Paula; Valadão, Ana Luiza; Garcez, Patrícia P.; Monteiro, Fábio L.; Loiola, Erick C.; Dias, André A.; Silva, Fábio J. M.; Aliota, Matthew T.; Caine, Elizabeth A.; Osorio, Jorge E.; Bellio, Maria; O’Connor, David H.; Rehen, Stevens; de Aguiar, Renato Santana; Savarino, Andrea; Campanati, Loraine; Tanuri, Amilcar

    2016-01-01

    Zika virus (ZIKV) infection in utero might lead to microcephaly and other congenital defects. Since no specific therapy is available thus far, there is an urgent need for the discovery of agents capable of inhibiting its viral replication and deleterious effects. Chloroquine is widely used as an antimalarial drug, anti-inflammatory agent, and it also shows antiviral activity against several viruses. Here we show that chloroquine exhibits antiviral activity against ZIKV in Vero cells, human brain microvascular endothelial cells, human neural stem cells, and mouse neurospheres. We demonstrate that chloroquine reduces the number of ZIKV-infected cells in vitro, and inhibits virus production and cell death promoted by ZIKV infection without cytotoxic effects. In addition, chloroquine treatment partially reveres morphological changes induced by ZIKV infection in mouse neurospheres. PMID:27916837

  11. Differences in trans-stimulated chloroquine efflux kinetics are linked to PfCRT in Plasmodium falciparum

    PubMed Central

    Sanchez, Cecilia P.; Rohrbach, Petra; McLean, Jeremy E.; Fidock, David A.; Stein, Wilfred D.; Lanzer, Michael

    2010-01-01

    Summary The mechanism underpinning chloroquine drug resistance in the human malarial parasite Plasmodium falciparum has remained controversial. Currently discussed models include a carrier or a channel for chloroquine, the former actively expelling the drug, the latter facilitating its passive diffusion, out of the parasite’s food vacuole, where chloroquine accumulates and inhibits haem detoxification. Here we have challenged both models using an established trans-stimulation efflux protocol. While carriers may demonstrate trans-stimulation, channels do not. Our data reveal that extracellular chloroquine stimulates chloroquine efflux in the presence and absence of metabolic energy in both chloroquine-sensitive and -resistant parasites, resulting in a hyperbolic increase in the apparent initial efflux rates as the concentration of external chloroquine increases. In the absence of metabolic energy, the apparent initial efflux rates were comparable in both parasites. Significant differences were only observed in the presence of metabolic energy, where consistently higher apparent initial efflux rates were found in chloroquine-resistant parasites. As trans-stimulation is characteristic of a carrier, and not a channel, we interpret our data in favour of a carrier for chloroquine being present in both chloroquine-sensitive and -resistant parasites, however, with different transport modalities. PMID:17493125

  12. Basis of antimalarial action: non-weak base effects of chloroquine on acid vesicle pH

    SciTech Connect

    Krogstad, D.J.; Schlesinger, P.H.

    1987-03-01

    Biologically active concentrations of chloroquine increase the pH of the parasite's acid vesicles within 3-5 min. This increase in pH results from two mechanisms, one of which is markedly reduced in chloroquine-resistant parasites. Because chloroquine is a weak base, it increases vesicle pH by that mechanism in chloroquine-susceptible and resistant parasites and mammalian cells (based on its two pKs and on the delta pH between the acid vesicle and the extracellular environment). In chloroquine-susceptible parasites, but not resistant parasites or mammalian cells, chloroquine increases the pH of acid vesicles 700- to 800-fold more than can be accounted for by its properties as a weak base. The increase in acid vesicle pH caused by these non-weak base effects of nanomolar chloroquine in susceptible parasites suggests that chloroquine acts by interfering with acid vesicle functions in the parasite such as the endocytosis and proteolysis of hemoglobin, and the intracellular targeting of lysosomal enzymes. The non-weak base effects of nanomolar chloroquine on parasite vesicle pH are also responsible for its safety because these chloroquine concentrations do not affect mammalian cells.

  13. Chloroquine inhibits human CD4+ T-cell activation by AP-1 signaling modulation

    PubMed Central

    Schmidt, Ralf L. J.; Jutz, Sabrina; Goldhahn, Katrin; Witzeneder, Nadine; Gerner, Marlene C.; Trapin, Doris; Greiner, Georg; Hoermann, Gregor; Steiner, Guenter; Pickl, Winfried F.; Burgmann, Heinz; Steinberger, Peter; Ratzinger, Franz; Schmetterer, Klaus G.

    2017-01-01

    Chloroquine (CQ) is widely used as an anti-inflammatory therapeutic for rheumatic diseases. Although its modes of action on the innate immune system are well described, there is still insufficient knowledge about its direct effects on the adaptive immune system. Thus, we evaluated the influence of CQ on activation parameters of human CD4+ T-cells. CQ directly suppressed proliferation, metabolic activity and cytokine secretion of T-cells following anti-CD3/anti-CD28 activation. In contrast, CQ showed no effect on up-regulation of T-cell activation markers. CQ inhibited activation of all T helper cell subsets, although IL-4 and IL-13 secretion by Th2 cells were less influenced compared to other Th-specific cytokines. Up to 10 μM, CQ did not reduce cell viability, suggesting specific suppressive effects on T-cells. These properties of CQ were fully reversible in re-stimulation experiments. Analyses of intracellular signaling showed that CQ specifically inhibited autophagic flux and additionally activation of AP-1 by reducing phosphorylation of c-JUN. This effect was mediated by inhibition of JNK catalytic activity. In summary, we characterized selective and reversible immunomodulatory effects of CQ on human CD4+ T-cells. These findings provide new insights into the biological actions of JNK/AP-1 signaling in T-cells and may help to expand the therapeutic spectrum of CQ. PMID:28169350

  14. Effect of chloroquine on biosynthesis, processing and secretion of proteins from PC12 cells

    SciTech Connect

    Sarmalkar, M.; Kuhn, L.J.; Sabban, E.L.

    1986-05-01

    Chloroquine is a lysomotropic agent that can raise intraorganelle pH, and has been proposed to divert secretion from a regulated to a constitutive pathway. The authors examined the effect of chloroquine on biosynthesis of dopamine ..beta..-hydroxylase (DBH) in PC12 pheochromocytoma cells. DBH is normally present as a 77,000-Mr and a 73,000-Mr subunit form in near equal amounts. The 77K membrane-bound form is a precursor of the 73K soluble form, which can be secreted with norepinephrine. Pretreatment for 1 hr with 50 ..mu..M -1 mM chloroquine and labelling in its presence for 4 hrs inhibited protein synthesis by approx. 50% with 200 ..mu..M and approx. 90% with 1 mM chloroquine. The overall profile of proteins synthesized was unaltered. However, in the presence of 200 ..mu..M chloroquine, the 73K form of DBH predominated. Thus, chloroquine enhanced the post-translational processing of the 77K to the 73K form. Endoglycosidase H digestion of the 73K form from chloroquine-treated or untreated cells yielded a 67.3 K product. Treatment with 200 ..mu..M and 1 mM chloroquine essentially prevented the release of (/sup 35/S)Met-labeled proteins which normally accompany the release of norepinephrine, and allowed the stimulated release of a new set of proteins (<68,000 daltons). The results are very similar to those obtained with monensin. Thus, elevation in intraorganelle pH appears to enhance processing of DBH and impede the secretory process.

  15. Chloroquine synergizes sunitinib cytotoxicity via modulating autophagic, apoptotic and angiogenic machineries.

    PubMed

    Abdel-Aziz, Amal Kamal; Shouman, Samia; El-Demerdash, Ebtehal; Elgendy, Mohamed; Abdel-Naim, Ashraf B

    2014-06-25

    Tyrosine kinases play a pivotal role in oncogenesis. Although tyrosine kinase inhibitors as sunitinib malate are used in cancer therapy, emerging studies report compromised cytotoxicity when used as monotherapy and thus combinations with other anti-cancer agents is recommended. Chloroquine is a clinically available anti-malarial agent which has been shown to exhibit anti-cancer activity. In the current study, we questioned whether chloroquine can modulate sunitinib cytotoxicity. We found that chloroquine synergistically augmented sunitinib cytotoxicity on human breast (MCF-7 and T-47D), cervical (Hela), colorectal (Caco-2 and HCT116), hepatocellular (HepG2), laryngeal (HEp-2) and prostate (PC3) cancer cell lines as indicated by combination and concentration reduction indices. These results were also consistent with that of Ehrlich ascites carcinoma (EAC) Swiss albino mice models as confirmed by tumor volume, weight, histopathological examination and PCNA expression. Sunitinib induced autophagy via upregulating beclin-1 expression which was blocked by chloroquine as evidenced by accumulated SQTSM1/p62 level. Furthermore, chloroquine augmented sunitinib-induced apoptosis by decreasing survivin level and increasing caspase 3 activity. Chloroquine also enhanced the antiangiogenic capacity of sunitinib as indicated by decreased CD34 expression and peritoneal/skin angiogenesis. Sunitinib when combined with chloroquine also increased reactive nitrogen species production via increasing inducible nitric oxide synthase expression and nitric oxide level whilst reduced reactive oxygen species production by increasing GSH level, activities of glutathione peroxidase and catalase and reducing lipid peroxides compared to sunitinib-only treated group. Taken together, these findings suggest that chloroquine enhanced sunitinib cytotoxicity in a synergistic manner via inducing apoptosis while switching off autophagic and angiogenic machineries. Nevertheless, further studies are

  16. Fractions of an antimalarial neem-leaf extract have activities superior to chloroquine, and are gametocytocidal.

    PubMed

    Udeinya, I J; Brown, N; Shu, E N; Udeinya, F I; Quakeyie, I

    2006-01-01

    The antimalarial activities of two fractions (IRDN-A and IRDN-B) of an extract from the leaves of the neem tree (Azadirachta indica) were compared with those of chloroquine, in in-vitro assays against Plasmodium falciparum. The asexual stages of a chloroquine-sensitive clone (ITG2F6) and a chloroquine-resistant isolate (W2) and the gametocytes of the NF 54 (BD-7) isolate of P. falciparum were used as the drug targets. Activity against the asexual stages was generally evaluated as the concentrations inhibiting the parasitaemias recorded in the control cultures, after an incubation of 48-72 h, by 50% (IC50) or 100% (IC100). For the ITG2F6 strain, the IC50 and IC100 (in microg/ml) were, respectively, 10(-5) and 10(-4) for IRDN-A, 10(-3) and 10(-2) for IRDN-B, and 10(-2) and 1.0 for chloroquine. The corresponding values for the W2 strain were 10(-5) and 1.0 for IRDN-A, and 10.0 and >100 for chloroquine (even at 100 microg/ml, chloroquine only inhibited the parasitaemia by 85%). Each of the two neem-leaf fractions lysed 50% and 100% of developing gametocytes, at 10(-3) and 1.0 microg/ml, respectively; and 50% and 100% of mature gametocytes at 10(-3) and 10(2) microg/ml, respectively. If they are found safe and effective in vivo, the neem-leaf fractions may form the basis of new antimalarial drugs that not only cure chloroquine-sensitive and chloroquine-resistant malaria but also markedly reduce transmission.

  17. Spectral-Domain Optical Coherence Tomography of Preclinical Chloroquine Maculopathy in Egyptian Rheumatoid Arthritis Patients

    PubMed Central

    Allam, Riham S. H. M.; Abd-Elmohsen, Mai N.; Khafagy, Mohamed M.; Raafat, Karim A.; Sheta, Sherif M.

    2015-01-01

    Purpose. To evaluate the role of spectral-domain optical coherence tomography (SD-OCT) in early detection of Chloroquine maculopathy in rheumatoid arthritis (RA) patients. Methods. 40 left eyes of 40 female rheumatoid arthritis patients who received treatment chloroquine for more than one year were recruited in the study. All patients had no symptoms or signs of Chloroquine retinopathy. They were evaluated using SD-OCT, where the Central Foveal Thickness (CFT), parafoveal thickness and perifoveal thickness, average Retinal Nerve Fiber Layer (RNFL) thickness, and Ganglion Cell Complex (GCC) measurements were measured and compared to 40 left eyes of 40 normal females. Results. The mean CFT was found to be thinner in the Chloroquine group (238.15 µm ± 22.49) than the normal controls (248.2 µm ± 19.04), which was statistically significant (p value = 0.034). The mean parafoveal thickness was lesser in the Chloroquine group than the control group in all quadrants (p value <0.05). The perifoveal thickness in both groups showed no statistically significant difference (p value >0.05) in all quadrants. No significant difference was detected between the two groups regarding RNFL, GCC, or IS/OS junction. Conclusions. Preclinical Chloroquine toxicity can lead to early thinning in the central fovea as well as the parafoveal regions that is detected by SD-OCT. PMID:26301102

  18. Molecular epidemiology of malaria in Cameroon. XIII. Analysis of pfcrt mutations and in vitro chloroquine resistance.

    PubMed

    Basco, Leonardo K

    2002-10-01

    The key Lys76Thr amino-acid substitution in Plasmodium falciparum chloroquine-resistance transporter (PfCRT) has been shown to be a reliable marker associated with chloroquine-resistant phenotype in reference clones, but few discordant results have been observed in field isolates. To further examine the relationship between in vitro chloroquine response and pfcrt alleles, the entire exon 2 of the pfcrt gene of 157 Cameroonian isolates was sequenced. All isolates were characterized as having either Cys-72, Met-74, Asn-75, and Lys-76 (wild-type alleles), Cys-72, Ile-74, Glu-75, and Thr-76 (mutant alleles), or mixed alleles. The hypothetical threshold 50% inhibitory concentration (IC50) set at 100 nM distinguished between isolates carrying the wild-type alleles and those with mutant alleles in a large majority of cases (135 of 139 isolates with unmixed pfcrt alleles). Isolates presenting discordant results generally had IC50s within an intermediate range. In vitro chloroquine response of isolates with mixed pfcrt alleles was highly variable. Although discordant results between chloroquine-resistant phenotype and pfcrt alleles were not explained by the immediate adjacent codons, the key Lys76Thr codon may prove to be a highly reliable genetic marker for the epidemiologic monitoring of chloroquine resistance by means of molecular techniques.

  19. Fold-and-thrust belt evolution influenced by along and across strike thickness variations: new insights from brittle-ductile centrifuge analogue models

    NASA Astrophysics Data System (ADS)

    Santolaria Otin, Pablo; Harris, Lyal; Casas, Antonio; Soto, Ruth

    2014-05-01

    Using a new centrifuge analogue modelling approach, 38 models were performed to study the influence of along and across strike thickness variations of a ductile-brittle layered sequence on the kinematics and deformation style of fold-and-thrust belts. Four different series, changing the brittle-ductile thickness ratio in models with i) constant thickness, ii) across strike varying thickness, iii) along strike varying thickness and iv) along and across-strike varying thickness, were performed. The brittle sedimentary cover was simulated by "Moon Sand™", regular fine-grained quartz sand coated by polymer and synthetic rubber binders, allowing layers to be placed vertically in the centrifuge (impossible with normal sand). The ductile décollement (evaporites) was simulated by silicone putty (Crazy Aaron Enterprise's Thinking Putty™). Models were run step by step in a high-acceleration centrifuge attaining 900 g, what allows to drastically reduce the experimental time. In addition to surface observation and serial cross-sections at the end of the models, CT scans portray the progressive 3- and 4-dimensional evolution of several models. With constant thickness, the increase of the brittle-ductile ratio results in the decrease of the number of structures where shortening is accommodated and the development of structures does not follow a linear sequence. Across-strike thickness variations trigger the location of deformation towards the wedge front, precluding the emplacement of structures in the hinterland. Along-strike thickness changes result in the lateral variation of the number of structure and a differential displacement of the deformation front. The occurrence of oblique structures is enhanced in wedges with across and along strike thickness variations where, in addition, rotational domains are observed. Comparison with the South Pyrenean Central Unit, in the Southern Pyrenees, characterized by a west- and southward thinning of the pretectonic Mesozoic series

  20. Survey of Analogue Spacetimes

    NASA Astrophysics Data System (ADS)

    Visser, Matt

    Analogue spacetimes (and more boldly, analogue models both of and for gravity), have attracted significant and increasing attention over the last decade and a half. Perhaps the most straightforward physical example, which serves as a template for most of the others, is Bill Unruh's model for a dumb hole,(mute black hole, acoustic black hole), wherein sound is dragged along by a moving fluid—and can even be trapped behind an acoustic horizon. This and related analogue models for curved spacetimes are useful in many ways: analogue spacetimes provide general relativists with extremely concrete physical models to help focus their thinking, and conversely the techniques of curved spacetime can sometimes help improve our understanding of condensed matter and/or optical systems by providing an unexpected and countervailing viewpoint. In this chapter, I shall provide a few simple examples of analogue spacetimes as general background for the rest of the contributions.

  1. Chitosan/Sterculia striata polysaccharides nanocomplex as a potential chloroquine drug release device.

    PubMed

    Magalhães, Guilherme A; Moura Neto, Erico; Sombra, Venícios G; Richter, Ana R; Abreu, Clara M W S; Feitosa, Judith P A; Paula, Haroldo C B; Goycoolea, Francisco M; de Paula, Regina C M

    2016-07-01

    Nanoparticles are produced by means of polyelectrolyte complexation (PEC) of oppositely charged polycationic chitosan (CH) with polyanionic polysaccharide extracted from Sterculia striata exudates (rhamnogalacturonoglycan (RG)-type polysaccharide). The nanoparticles formed with low-molar-mass CH are larger than those formed with high-molar-mass CH. This behavior is in contrast with that previously observed for other systems and may be attributed to different mechanisms related to the association of CH with RG of higher persistence length chain than that of CH. Nanoparticles harnessed with a charge ratio (n(+)/n(-)) of <1 are smaller than particles with an excess of polycations. Particles with hydrodynamic sizes smaller than 100nm are achieved using a polyelectrolyte concentration of 10(-4)gmL(-1) and charge ratio (n(+)/n(-)) of <1. The CH/RG nanoparticles are associated with chloroquine (CQ) with an efficiency of 28% and release it for up to ∼60% within ∼10h, whereas in the latter, only ∼40% of the CQ was released after 24h. The main factor that influenced drug release rate is the nanoparticle charge ratio.

  2. Genetics of chloroquine-resistant malaria: a haplotypic view

    PubMed Central

    Awasthi, Gauri; Das, Aparup

    2013-01-01

    The development and rapid spread of chloroquine resistance (CQR) in Plasmodium falciparum have triggered the identification of several genetic target(s) in the P. falciparum genome. In particular, mutations in the Pfcrt gene, specifically, K76T and mutations in three other amino acids in the region adjoining K76 (residues 72, 74, 75 and 76), are considered to be highly related to CQR. These various mutations form several different haplotypes and Pfcrt gene polymorphisms and the global distribution of the different CQR- Pfcrt haplotypes in endemic and non-endemic regions of P. falciparum malaria have been the subject of extensive study. Despite the fact that the Pfcrt gene is considered to be the primary CQR gene in P. falciparum , several studies have suggested that this may not be the case. Furthermore, there is a poor correlation between the evolutionary implications of the Pfcrt haplotypes and the inferred migration of CQR P. falciparum based on CQR epidemiological surveillance data. The present paper aims to clarify the existing knowledge on the genetic basis of the different CQR- Pfcrt haplotypes that are prevalent in worldwide populations based on the published literature and to analyse the data to generate hypotheses on the genetics and evolution of CQR malaria. PMID:24402147

  3. Polycyclic amines as chloroquine resistance modulating agents in Plasmodium falciparum.

    PubMed

    Joubert, Jacques; Kapp, Erika; Taylor, Dale; Smith, Peter J; Malan, Sarel F

    2016-02-15

    Pentacycloundecylamines (PCUs) and adamantane amines, such as NGP1-01 (1) and amantadine, have shown significant channel blocking activities. They are postulated to act as chemosensitizers and circumvent the resistance of the plasmodia parasite against chloroquine (CQ) by inhibiting the p-glycoprotein efflux pump and enabling the accumulation of CQ inside the parasite digestive vacuole. Twelve polycyclic amines containing either a PCU or adamantane amine moiety conjugated to different aromatic functionalities through various tethered linkers were selected based on their channel blocking abilities and evaluated as potential chemosensitizers. Compounds 2, 4, 5 and 10 showed significant voltage-gated calcium channel (VGCC) blocking ability (IC50=0.27-35 μM) and were able to alter the CQ IC50 in differing degrees (45-81%) in the multidrug resistant Plasmodium falciparum Dd2 isolate. Among them, the PCU-dansyl amine compound (4) displayed the best potential to act as a chemosensitizer against the Dd2 strain at a 1 μM concentration (RMI=0.19) while displaying moderate antiplasmodial activity (Dd2 IC50=6.25 μM) and low in vitro cytotoxicity against a mammalian cell line (CHO, IC50=119 μM). Compounds 2 and 10 also showed some promising chemosensitizing abilities (RMI=0.36 and 0.35 respectively). A direct correlation was found between the VGCC blocking ability of these polycyclic amines and their capacity to act as CQ resistance modulating agents.

  4. Chloroquine-resistant Plasmodium vivax in transmigration settlements of West Kalimantan, Indonesia.

    PubMed

    Fryauff, D J; Tuti, S; Mardi, A; Masbar, S; Patipelohi, R; Leksana, B; Kain, K C; Bangs, M J; Richie, T L; Baird, J K

    1998-10-01

    Malariometric surveys were conducted during July 1996 in native Dayak villages and predominantly Javanese transmigration settlements in Ketapang district of West Kalimantan, Indonesia. Malaria prevalence ranged from 0.9% to 2.7% in Dayak villages and from 1% to 20% in the transmigration settlements. Plasmodium falciparum accounted for 67% of the cases among Dayaks but P. vivax was dominant among transmigrants, accounting for more than 72% of the infections. Chloroquine sensitivity/resistance was assessed by 28-day in vivo testing of uncomplicated malaria infections and measurement of chloroquine blood levels in cases where parasitemias reappeared within the 28-day test period. Resistance was based on the appearance of asexual parasites against chloroquine plus desethylchloroquine levels exceeding the minimally effective whole blood concentrations proposed for sensitive parasite strains (P. vivax, 100 ng/ml; P. falciparum, 200 ng/ml). All parasitemias cleared initially within four days of beginning supervised chloroquine therapy (25 mg base/kg over a 48-hr period), but asexual parasites reappeared within 28 days in 27 of 52 P. vivax and three of 12 P. falciparum cases. Chloroquine blood levels at the time of recurrent parasitemias revealed resistance in 12 of the 27 P. vivax cases and in one of the three P. falciparum cases. Genotypes of nine of the 12 recurrent P. vivax isolates matched with their primary isolates and ruled out reinfection. These findings establish the presence of chloroquine-resistant P. vivax on the island of Borneo. The pattern of malaria and the high frequency of chloroquine resistance by P. vivax at the West Kalimantan location may relate to demographic, ecologic, agricultural, and socioeconomic changes associated with transmigration.

  5. Fluorescent properties of DNA base analogue tC upon incorporation into DNA — negligible influence of neighbouring bases on fluorescence quantum yield

    PubMed Central

    Sandin, Peter; Wilhelmsson, L. Marcus; Lincoln, Per; Powers, Vicki E. C.; Brown, Tom; Albinsson, Bo

    2005-01-01

    The quantum yield of the fluorescent tricyclic cytosine analogue, 1,3-diaza-2-oxophenothiazine, tC, is high and virtually unaffected by incorporation into both single- and double-stranded DNA irrespective of neighbouring bases (0.17–0.24 and 0.16–0.21, respectively) and the corresponding fluorescence decay curves are all mono-exponential, properties that are unmatched by any base analogue so far. The fluorescence lifetimes increase when going from tC free in solution (3.2 ns) to single- and double-stranded DNA (on average 5.7 and 6.3 ns, respectively). The mono-exponential decays further support previous NMR results where it was found that tC has a well-defined position and geometry within the DNA helix. Furthermore, we find that the oxidation potential of tC is 0.4 V lower than for deoxyguanosine, the natural base with the lowest oxidation potential. This suggests that tC may be of interest in charge transfer studies in DNA as an electron hole acceptor. We also present a novel synthetic route to the phosphoramidite form of tC. The results presented here together with previous work show that tC is a very good C-analogue that induces minimal perturbation to the native structure of DNA. This makes tC unique as a fluorescent base analogue and is thus highly interesting in a range of applications for studying e.g. structure, dynamics and kinetics in nucleic acid systems. PMID:16147985

  6. Influence of the degree of unsaturation of the acyl side chain upon the interaction of analogues of 1-arachidonoylglycerol with monoacylglycerol lipase and fatty acid amide hydrolase.

    PubMed

    Vandevoorde, Séverine; Saha, Bijali; Mahadevan, Anu; Razdan, Raj K; Pertwee, Roger G; Martin, Billy R; Fowler, Christopher J

    2005-11-11

    Little is known as to the structural requirements of the acyl side chain for interaction of acylglycerols with monoacylglycerol lipase (MAGL), the enzyme chiefly responsible for the metabolism of the endocannabinoid 2-arachidonoylglycerol (2-AG) in the brain. In the present study, a series of twelve analogues of 1-AG (the more stable regioisomer of 2-AG) were investigated with respect to their ability to inhibit the metabolism of 2-oleoylglycerol by cytosolic and membrane-bound MAGL. In addition, the ability of the compounds to inhibit the hydrolysis of anandamide by fatty acid amide hydrolase (FAAH) was investigated. For cytosolic MAGL, compounds with 20 carbon atoms in the acyl chain and 2-5 unsaturated bonds inhibited the hydrolysis of 2-oleoylglycerol with similar potencies (IC50 values in the range 5.1-8.2 microM), whereas the two compounds with a single unsaturated bond were less potent (IC50 values 19 and 21 microM). The fully saturated analogue 1-monoarachidin did not inhibit the enzyme, whereas the lower side chain analogues 1-monopalmitin and 1-monomyristin inhibited the enzyme with IC50 values of 12 and 32 microM, respectively. The 22-carbon chain analogue of 1-AG was also potent (IC50 value 4.5 microM). Introduction of an alpha-methyl group for the C20:4, C20:3, and C22:4 compounds did not affect potency in a consistent manner. For the FAAH and the membrane-bound MAGL, there was no obvious relationship between the degree of unsaturation of the acyl side chain and the ability to inhibit the enzymes. It is concluded that increasing the number of unsaturated bonds on the acyl side chain of 1-AG from 1 to 5 has little effect on the affinity of acylglycerols for cytosolic MAGL.

  7. ABT-737, a Bcl-2 Selective Inhibitor, and Chloroquine Synergistically Kill Renal Cancer Cells.

    PubMed

    Yin, Pei; Jia, Jinpeng; Li, Jijun; Song, Yan; Zhang, Yiyan; Chen, Fengkun

    2016-01-01

    Renal cell carcinoma (RCC) is the most common malignancy in the kidney in the world, and the 5-year overall survival for patients remains poor due to the lack of effective treatment strategies. Although ABT-737, as a Bcl-2/Bcl-xL inhibitor, has recently emerged as a novel cancer therapeutic reagent, apoptosis induced by ABT-737 is often blocked in several types of cancer cells. This study investigated whether the combination of the small-molecule BH3 mimetic ABT-737 and the lysosome inhibitor chloroquine was an effective strategy for treating renal cancer cells. We found that the combination of ABT-737 and chloroquine synergistically decreased cell viability when compared to treatment with either single reagent. Cell apoptosis induced by a combined treatment was markedly inhibited by the caspase inhibitors z-DEVD-FMK and z-VAD-FMK. It was also inhibited by cathepsin inhibitor E-64 and CTSI (cathepsin inhibitor), which suggested that apoptosis was dependent on the cascade of caspase activation and cathepsins released from lysosomes. Furthermore, we found that ABT-737 could increase the cell level of ROS, which triggers cathepsin-mediated cell death and augments the role of chloroquine in cell death. So the combination of ABT-737 and chloroquine was an effective strategy for the treatment of renal cancer cells, and this combined strategy may widen the therapeutic window of ABT-737 and chloroquine as well as enhance the clinical efficacy of synergistic drug combinations.

  8. Therapeutic efficacy of chloroquine and sulfadoxine/pyrimethamine against Plasmodium falciparum infection in Somalia.

    PubMed Central

    Warsame, M.; Abdillahi, A.; Duale, O. Nur; Ismail, A. Nur; Hassan, A. M.; Mohamed, A.; Warsame, A.

    2002-01-01

    OBJECTIVE: To assess the efficacy of chloroquine and sulfadoxine/pyrimethamine in the treatment of uncomplicated Plasmodium falciparum infections in Somalia. METHODS: Patients with clinical malaria in Merca, an area of high transmission of the disease, were treated with the standard regimens of chloroquine (25 mg/kg) or sulfadoxine/pyrimethamine (25 mg sulfadoxine and 1.25 mg pyrimethamine per kg). Similar patients in Gabiley, an area of low transmission, received the standard regimen of chloroquine. The clinical and parasitological responses were monitored for 14 days. FINDINGS: Chloroquine treatment resulted in clinical failure in 33% (n = 60) and 51% (n = 49) of the patients in Merca and Gabiley respectively. There were corresponding parasitological failures of 77% RII/RIII and 35% RII/RIII. Patients who experienced clinical failure had significantly higher initial parasitaemia than those in whom there was an adequate clinical response, both in Merca (t = 2.2; P t = 2.8; P n = 50) of the patients achieved an adequate clinical response despite a parasitological failure rate of 76% RII/RIII. CONCLUSION: Chloroquine should no longer be considered adequate for treating clinical falciparum malaria in vulnerable groups in the areas studied. Doubts about the therapeutic life of sulfadoxine/pyrimethamine in relation to malaria are raised by the high levels of resistance in the Merca area and underline the need to identify suitable alternatives. PMID:12378287

  9. Chloroquine in cancer therapy: a double-edged sword of autophagy.

    PubMed

    Kimura, Tomonori; Takabatake, Yoshitsugu; Takahashi, Atsushi; Isaka, Yoshitaka

    2013-01-01

    Autophagy is a homeostatic cellular recycling system that is responsible for degrading damaged or unnecessary cellular organelles and proteins. Cancer cells are thought to use autophagy as a source of energy in the unfavorable metastatic environment, and a number of clinical trials are now revealing the promising role of chloroquine, an autophagy inhibitor, as a novel antitumor drug. On the other hand, however, the kidneys are highly vulnerable to chemotherapeutic agents. Recent studies have shown that autophagy plays a protective role against acute kidney injury, including cisplatin-induced kidney injury, and thus, we suspect that the use of chloroquine in combination with anticancer drugs may exacerbate kidney damage. Moreover, organs in which autophagy also plays a homeostatic role, such as the neurons, liver, hematopoietic stem cells, and heart, may be sensitive to the combined use of chloroquine and anticancer drugs. Here, we summarize the functions of autophagy in cancer and kidney injury, especially focusing on the use of chloroquine to treat cancer, and address the possible side effects in the combined use of chloroquine and anticancer drugs.

  10. Whole blood chloroquine concentrations with Plasmodium vivax infection in Irian Jaya, Indonesia.

    PubMed

    Baird, J K; Leksana, B; Masbar, S; Suradi; Sutanihardja, M A; Fryauff, D J; Subianto, B

    1997-06-01

    Whole blood concentrations of self-administered chloroquine (CQ) and its metabolite desethylchloroquine (DCQ) were measured in 168 patients with microscopically confirmed infection by Plasmodium vivax in northeastern Irian Jaya, Indonesia. The study consisted of both survey and passive case detection in four separate villages between 1992 and 1994. The subjects were Javanese people 4-51 years old who had lived in the Arso region for up to two years. The sum of CQ and DCQ ranged from 0 to 8,342 ng/ml of whole blood, and 122 subjects (73%) had > or = 100 ng/ml of CQ plus DCQ, the estimated minimally effective concentration (MEC) in whole blood against chloroquine-sensitive P. vivax. Among 56 subjects reporting to a clinic with symptoms of malaria, 53 (95%) had ordinarily effective levels of chloroquine in blood. Among 109 largely asymptomatic malaria patients found by survey case detection, 69 (63%) had chloroquine blood levels greater than the MEC. Virtually all clinical and most subclinical vivax malaria in this region occurs despite ordinarily effective levels of chloroquine in blood.

  11. Chloroquine Engages the Immune System to Eradicate Irradiated Breast Tumors in Mice

    SciTech Connect

    Ratikan, Josephine Anna; Sayre, James William

    2013-11-15

    Purpose: This study used chloroquine to direct radiation-induced tumor cell death pathways to harness the antitumor activity of the immune system. Methods and Materials: Chloroquine given immediately after tumor irradiation increased the cure rate of MCaK breast cancer in C3H mice. Chloroquine blocked radiation-induced autophagy and drove MCaK cells into a more rapid apoptotic and more immunogenic form of cell death. Results: Chloroquine treatment made irradiated tumor vaccines superior at inducing strong interferon gamma-associated immune responses in vivo and protecting mice from further tumor challenge. In vitro, chloroquine slowed antigen uptake and degradation by dendritic cells, although T-cell stimulation was unaffected. Conclusions: This study illustrates a novel approach to improve the efficacy of breast cancer radiation therapy by blocking endosomal pathways, which enhances radiation-induced cell death within the field and drives antitumor immunity to assist therapeutic cure. The study illuminates and merges seemingly disparate concepts regarding the importance of autophagy in cancer therapy.

  12. Evaluation of influence of Ap4A analogues on Fhit-positive HEK293T cells; cytotoxicity and ability to induce apoptosis.

    PubMed

    Krakowiak, Agnieszka; Pęcherzewska, Róża; Kaczmarek, Renata; Tomaszewska, Agnieszka; Nawrot, Barbara; Stec, Wojciech J

    2011-08-15

    Fragile histidine triad (Fhit) protein encoded by tumour suppressor FHIT gene is a proapoptotic protein with diadenosine polyphosphate (Ap(n)A, n=2-6) hydrolase activity. It has been hypothesised that formation of Fhit-substrate complex results in an apoptosis initiation signal while subsequent hydrolysis of Ap(n)A terminates this action. A series of Ap(n)A analogues have been identified in vitro as strong Fhit ligands [Varnum, J. M.; Baraniak, J.; Kaczmarek, R.; Stec, W. J.; Brenner, C. BMC Chem. Biol.2001, 1, 3]. We assumed that in Fhit-positive cells these compounds might preferentially bind to Fhit and inhibit its hydrolytic activity what would prolong the lifetime of apoptosis initiation signalling complex. Therefore, several Fhit inhibitors were tested for their cytotoxicity and ability to induce apoptosis in Fhit-positive HEK293T cells. These experiments have shown that Ap(4)A analogue, containing a glycerol residue instead of the central pyrophosphate and two terminal phosphorothioates [A(PS)-CH(2)CH(OH)CH(2)-(PS)A (1)], is the most cytotoxic among test compounds (IC(50)=17.5±4.2 μM) and triggers caspase-dependent cell apoptosis. The Fhit-negative HEK293T cells (in which Fhit was silenced by RNAi) were not sensitive to compound 1. These results indicate that the Ap(4)A analogue 1 induces Fhit-dependent apoptosis and therefore, it can be considered as a drug candidate for anticancer therapy in Fhit-positive cancer cells and in Fhit-negative cancer cells, in which re-expression of Fhit was accomplished by gene therapy.

  13. Overcoming Chloroquine Resistance in Malaria: Design, Synthesis, and Structure-Activity Relationships of Novel Hybrid Compounds

    PubMed Central

    Boudhar, Aicha; Ng, Xiao Wei; Loh, Chiew Yee; Chia, Wan Ni; Tan, Zhi Ming; Nosten, Francois

    2016-01-01

    Resistance to antimalarial therapies, including artemisinin, has emerged as a significant challenge. Reversal of acquired resistance can be achieved using agents that resensitize resistant parasites to a previously efficacious therapy. Building on our initial work describing novel chemoreversal agents (CRAs) that resensitize resistant parasites to chloroquine (CQ), we herein report new hybrid single agents as an innovative strategy in the battle against resistant malaria. Synthetically linking a CRA scaffold to chloroquine produces hybrid compounds with restored potency toward a range of resistant malaria parasites. A preferred compound, compound 35, showed broad activity and good potency against seven strains resistant to chloroquine and artemisinin. Assessment of aqueous solubility, membrane permeability, and in vitro toxicity in a hepatocyte line and a cardiomyocyte line indicates that compound 35 has a good therapeutic window and favorable drug-like properties. This study provides initial support for CQ-CRA hybrid compounds as a potential treatment for resistant malaria. PMID:26953199

  14. Short report: polymorphisms in the chloroquine resistance transporter gene in Plasmodium falciparum isolates from Lombok, Indonesia.

    PubMed

    Huaman, Maria Cecilia; Yoshinaga, Kazumi; Suryanatha, Aan; Suarsana, Nyoman; Kanbara, Hiroji

    2004-07-01

    The polymorphisms in the Plasmodium falciparum multidrug resistance 1 (pfmdr1) and P. falciparum chloroquine resistance transporter (pfcrt) genes, which are associated with chloroquine resistance, were examined in 48 P. falciparum isolates from uncomplicated malaria patients from the West Lombok District in Indonesia. The point mutation N86Y in pfmdr1 was present in 35.4% of the isolates and mutation K76T in pfcrt was found in all but one of the samples studied. Identified pfcrt haplotypes were mainly identical to the Papua New Guinea type S(agt)VMNT (42 of 48, 87.5%), and a few isolates had the Southeast Asia type CVIET (5 of 48, 10.4%). Moreover, one P. falciparum isolate harbored the K76N mutation, giving rise to the haplotype CVMNN, which was not previously reported in field isolates. Our findings suggest that chloroquine resistance in this area might have the same origin as in Papua New Guinea.

  15. Metabolic and structural consequences of ethanol and chloroquin administration during gestation on the developing fetus

    SciTech Connect

    Sharma, A.; Rawat, A.K.

    1987-05-01

    In the present study the effects of ethanol and chloroquin administration during gestation have been investigated on the developing rat fetus. Ethanol was given in liquid Sustacal diet as 30% of calories and controls were fed isocaloric sucrose-diet. Chloroquin was given intragastrically corresponding controls received saline. Chloroquin resulted in prenatal growth retardation leading to maximum decrease of 46% in body weight of the fetus. It also resulted in 30% higher incidence of hepatomegaly; 15% higher incidence of liquification of visceral organs; 34% decrease in the ossification of sternum; 9% higher defects of cleft palate, wrist drop, clubbed foot and brain liquification compared to the corresponding controls. Ethanol resulted in pre and post-natal growth retardation, cleft palate, still births and lowered brain weights. Fetuses from the ethanol-fed group also showed inhibited protein synthesis, RNA and DNA synthesis in the brain compared to the controls.

  16. Colorimetric and thin-layer chromatographic methods for field assay of chloroquine and its metabolites in urine*

    PubMed Central

    Mount, D. L.; Patchen, L. C.; Williams, S. B.; Churchill, F. C.

    1987-01-01

    Three field-adapted methods for the quantification of the antimalarial drug chloroquine are described. Two of the methods are modifications of the Haskins test and are based on ion-pair formation between chloroquine and methyl orange in either dichloromethane or chloroform. Absorbance values measured at 420 nm with a hand-held, battery-operated filter photometer were linearly related to chloroquine concentrations in urine up to 100 μmol/l (32 μg/ml) for both methods. The contribution of the desethylchloroquine metabolite to the measured absorbance for both methods is less than that of chloroquine; the relative sensitivity for this metabolite is about 50% of that of chloroquine for both methods. The detection limit for modification I is 1 μmol/l (0.3 μg/ml), while that for modification II is 3 μmol/l (1 μg/ml). A single dose of chloroquine diphosphate (300 mg as base) administered to each of three volunteers yielded detectable levels by modification I of chloroquine in the urine for 28 days after dosing. Results for the colorimetric methods correlated well with the liquid chromatographic reference method used. The related thin-layer chromatographic method confirmed the presence of chloroquine and desethylchloroquine in the urine and permitted independent estimation of the concentration of these two compounds if desired. The two colorimetric methods may be used in remote locations where no electricity is available. PMID:3501342

  17. Chloroquine Treatment Enhances Regulatory T Cells and Reduces the Severity of Experimental Autoimmune Encephalomyelitis

    PubMed Central

    Thomé, Rodolfo; Moraes, Adriel S.; Bombeiro, André Luis; Farias, Alessandro dos Santos; Francelin, Carolina; da Costa, Thiago Alves; Di Gangi, Rosária; dos Santos, Leonilda Maria Barbosa; de Oliveira, Alexandre Leite Rodrigues; Verinaud, Liana

    2013-01-01

    Background The modulation of inflammatory processes is a necessary step, mostly orchestrated by regulatory T (Treg) cells and suppressive Dendritic Cells (DCs), to prevent the development of deleterious responses and autoimmune diseases. Therapies that focused on adoptive transfer of Treg cells or their expansion in vivo achieved great success in controlling inflammation in several experimental models. Chloroquine (CQ), an anti-malarial drug, was shown to reduce inflammation, although the mechanisms are still obscure. In this context, we aimed to access whether chloroquine treatment alters the frequency of Treg cells and DCs in normal mice. In addition, the effects of the prophylactic and therapeutic treatment with CQ on Experimental Autoimmune Encephalomyelitis (EAE), an experimental model for human Multiple Sclerosis, was investigated as well. Methodology/Principal Findings EAE was induced in C57BL/6 mice by immunization with myelin oligodendrocyte glycoprotein (MOG35–55) peptide. C57BL/6 mice were intraperitoneally treated with chloroquine. Results show that the CQ treatment provoked an increase in Treg cells frequency as well as a decrease in DCs. We next evaluated whether prophylactic CQ administration is capable of reducing the clinical and histopathological signs of EAE. Our results demonstrated that CQ-treated mice developed mild EAE compared to controls that was associated with lower infiltration of inflammatory cells in the central nervous system CNS) and increased frequency of Treg cells. Also, proliferation of MOG35–55-reactive T cells was significantly inhibited by chloroquine treatment. Similar results were observed when chloroquine was administrated after disease onset. Conclusion We show for the first time that CQ treatment promotes the expansion of Treg cells, corroborating previous reports indicating that chloroquine has immunomodulatory properties. Our results also show that CQ treatment suppress the inflammation in the CNS of EAE

  18. Comparison of in vivo and in vitro tests of resistance in patients treated with chloroquine in Yaoundé, Cameroon.

    PubMed Central

    Ringwald, P.; Basco, L. K.

    1999-01-01

    The usefulness of an isotopic in vitro assay in the field was evaluated by comparing its results with the therapeutic response determined by the simplified WHO in vivo test in symptomatic Cameroonian patients treated with chloroquine. Of the 117 enrolled patients, 102 (87%) completed the 14-day follow-up, and 95 isolates obtained from these patients (46 children, 49 adults) yielded an interpretable in vitro test. A total of 57 of 95 patients (60%; 28 children and 29 adults) had an adequate clinical response with negative smears (n = 46) or with an asymptomatic parasitaemia (n = 11) on day 7 and/or day 14. The geometric mean 50% inhibitory concentration of the isolates obtained from these patients was 63.3 nmol/l. Late and early treatment failure was observed in 29 (30.5%) and 9 (9.5%) patients, respectively. The geometric mean 50% inhibitory concentrations of the corresponding isolates were 173 nmol/l and 302 nmol/l. Among the patients responding with late and early treatment failure, five isolates and one isolate, respectively, yielded a discordant result (in vivo resistance and in vitro sensitivity). The sensitivity, specificity, and predictive value of the in vitro test to detect chloroquine-sensitive cases was 67%, 84% and 86%, respectively. There was moderate concordance between the in vitro and in vivo tests (kappa value = 0.48). The in vitro assay agrees relatively well with the therapeutic response and excludes several host factors that influence the results of the in vivo test. However, in view of some discordant results, the in vitro test cannot substitute for in vivo data on therapeutic efficacy. The only reliable definition of "resistance" in malaria parasites is based on clinical and parasitological response in symptomatic patients, and the in vivo test provides the standard method to determine drug sensitivity or resistance as well as to guide national drug policies. PMID:10063659

  19. Significant reduction in chloroquine bioavailability following coadministration with the Sudanese beverages Aradaib, Karkadi and Lemon.

    PubMed

    Mahmoud, B M; Ali, H M; Homeida, M M; Bennett, J L

    1994-05-01

    Chloroquine bioavailability in healthy males was examined following oral coadministration of 600 mg with three common Sudanese beverages, Aradaib (Tamarindus indica), Karkadi (Hibiscus sabdarifa) and Lemon (Citrus limetta) and drinking water. The tablets and beverages were taken on an empty stomach after an overnight fast. The plasma chloroquine concentrations were measured by HPLC. The extent and rate of chloroquine bioavailability were described by the area under the plasma concentrations versus time curve (AUC), the peak plasma concentration (Cmax) and with the time to reach Cmax (Tmax), respectively. The mean (+/- S.E.) AUC values after administration with water (control) and Aradaib, Karkadi and Lemon, respectively, were 7.52 +/- 0.87, 2.60 +/- 0.24, 2.16 +/- 0.30 and 2.41 +/- 0.29 mg.h/L. The corresponding mean Cmax values were 553 +/- 17.8, 184 +/- 21.3, 148 +/- 14.1 and 210 +/- 17.4 mg/L and the corresponding Tmax values were 3.0 +/- 1.0, 3.2 +/- 1.2, 2.6 +/- 0.8 and 2.5 +/- 1.0 h. The results indicate a statistically significant reduction in the AUC and Cmax of chloroquine as a result of a coadministration with each of the three beverages. A parallel reduction in the drugs antimalarial efficacy might be expected.

  20. In vivo resistance to chloroquine by Plasmodium vivax and Plasmodium falciparum at Nabire, Irian Jaya, Indonesia.

    PubMed

    Baird, J K; Wiady, I; Fryauff, D J; Sutanihardja, M A; Leksana, B; Widjaya, H; Kysdarmanto; Subianto, B

    1997-06-01

    A survey of resistance to chloroquine by Plasmodium vivax and P. falciparum was conducted during May 1995 at three mesoendemic villages 30 km southeast of Nabire, near the central northern coast of Irian Jaya, Indonesia. The prevalence of malaria at Urusumu (n = 157), Margajaya (n = 573), and Topo (n = 199) was 18%. 9%, and 9%, respectively, with spleen rates among children of 79%, 10%, and 27%. Infected patients among those screened formed a study population of 64 subjects eligible for a 28-day in vivo test of resistance to chloroquine. Sixty-three patients successfully completed the test; 45 males and 18 females 1-60 years of age, of whom 29 were Javanese transmigrants of five years residence in Irian Jaya and 34 were native to Irian Jaya. The seven-day day cumulative incidence of therapeutic failure for P. vivax and P. falciparum was 15% (n = 34) and 30% (n = 37). The 14- and 28-day estimates of cumulative incidence were 45% and 64% for P. vivax and 58% and 89% for P. falciparum. Almost all recurrences appeared in the face of ordinarily effective levels of chloroquine and its major metabolite, desethylchloroquine, in whole blood (> or = 100 ng/ml). Four infections by P. malariae in subjects enrolled in this study cleared by day 2 and none reappeared within 28 days. Chloroquine no longer provides effective therapy for falciparum or vivax malaria along the northern coast of Irian Jaya, Indonesia.

  1. Fluoxetine Hydrochloride Enhances In Vitro Susceptibility to Chloroquine in Resistant Plasmodium falciparum

    DTIC Science & Technology

    1992-12-01

    chloroquine- (12), ketotifen (1), tetrandrine (20, 21), and cyproheptadine susceptible clone D6 (50% inhibitory concentration [IC 5o], (16). !s3 ng/ml). IC... CYPROHEPTADINE KETOTIFEN N OCN3 HICO N ’IN ~~OCH3 NN H 0 OCH.3 TETRANDRINE FIG. 1. Structures of fluoxetine and other drugs that have been reported to

  2. Chloroquine alleviates etoposide-induced centrosome amplification by inhibiting CDK2 in adrenocortical tumor cells

    PubMed Central

    Chen, T-Y; Syu, J-S; Lin, T-C; Cheng, H-l; Lu, F-l; Wang, C-Y

    2015-01-01

    The antitumor drug etoposide (ETO) is widely used in treating several cancers, including adrenocortical tumor (ACT). However, when used at sublethal doses, tumor cells still survive and are more susceptible to the recurring tumor due to centrosome amplification. Here, we checked the effect of sublethal dose of ETO in ACT cells. Sublethal dose of ETO treatment did not induce cell death but arrested the ACT cells in G2/M phase. This resulted in centrosome amplification and aberrant mitotic spindle formation leading to genomic instability and cellular senescence. Under such conditions, Chk2, cyclin A/CDK2 and ERK1/2 were aberrantly activated. Pharmacological inactivation of Chk2, CDK2 or ERK1/2 or depletion of CDK2 or Chk2 inhibited the centrosome amplification in ETO-treated ACT cells. In addition, autophagy was activated by ETO and was required for ACT cell survival. Chloroquine, the autophagy inhibitor, reduced ACT cell growth and inhibited ETO-induced centrosome amplification. Chloroquine alleviated CDK2 and ERK, but not Chk2, activation and thus inhibited centrosome amplification in either ETO- or hydroxyurea-treated ACT cells. In addition, chloroquine also inhibited centrosome amplification in osteosarcoma U2OS cell lines when treated with ETO or hydroxyurea. In summary, we have demonstrated that chloroquine inhibited ACT cell growth and alleviated DNA damage-induced centrosome amplification by inhibiting CDK2 and ERK activity, thus preventing genomic instability and recurrence of ACT. PMID:26690546

  3. Non-Selective Cation Channels Mediate Chloroquine-Induced Relaxation in Precontracted Mouse Airway Smooth Muscle

    PubMed Central

    Li, Wen-Er; Ma, Yun-Fei; Chen, Weiwei; Zhai, Kui; Qin, Gangjian; Guo, Donglin; Zheng, Yun-Min; Wang, Yong-Xiao; Shen, Jin-Hua; Ji, Guangju; Liu, Qing-Hua

    2014-01-01

    Bitter tastants can induce relaxation in precontracted airway smooth muscle by activating big-conductance potassium channels (BKs) or by inactivating voltage-dependent L-type Ca2+ channels (VDLCCs). In this study, a new pathway for bitter tastant-induced relaxation was defined and investigated. We found nifedipine-insensitive and bitter tastant chloroquine-sensitive relaxation in epithelium-denuded mouse tracheal rings (TRs) precontracted with acetylcholine (ACH). In the presence of nifedipine (10 µM), ACH induced cytosolic Ca2+ elevation and cell shortening in single airway smooth muscle cells (ASMCs), and these changes were inhibited by chloroquine. In TRs, ACH triggered a transient contraction under Ca2+-free conditions, and, following a restoration of Ca2+, a strong contraction occurred, which was inhibited by chloroquine. Moreover, the ACH-activated whole-cell and single channel currents of non-selective cation channels (NSCCs) were blocked by chloroquine. Pyrazole 3 (Pyr3), an inhibitor of transient receptor potential C3 (TRPC3) channels, partially inhibited ACH-induced contraction, intracellular Ca2+ elevation, and NSCC currents. These results demonstrate that NSCCs play a role in bitter tastant-induced relaxation in precontracted airway smooth muscle. PMID:24992312

  4. Balancing drug resistance and growth rates via compensatory mutations in the Plasmodium falciparum chloroquine resistance transporter.

    PubMed

    Petersen, Ines; Gabryszewski, Stanislaw J; Johnston, Geoffrey L; Dhingra, Satish K; Ecker, Andrea; Lewis, Rebecca E; de Almeida, Mariana Justino; Straimer, Judith; Henrich, Philipp P; Palatulan, Eugene; Johnson, David J; Coburn-Flynn, Olivia; Sanchez, Cecilia; Lehane, Adele M; Lanzer, Michael; Fidock, David A

    2015-07-01

    The widespread use of chloroquine to treat Plasmodium falciparum infections has resulted in the selection and dissemination of variant haplotypes of the primary resistance determinant PfCRT. These haplotypes have encountered drug pressure and within-host competition with wild-type drug-sensitive parasites. To examine these selective forces in vitro, we genetically engineered P. falciparum to express geographically diverse PfCRT haplotypes. Variant alleles from the Philippines (PH1 and PH2, which differ solely by the C72S mutation) both conferred a moderate gain of chloroquine resistance and a reduction in growth rates in vitro. Of the two, PH2 showed higher IC50 values, contrasting with reduced growth. Furthermore, a highly mutated pfcrt allele from Cambodia (Cam734) conferred moderate chloroquine resistance and enhanced growth rates, when tested against wild-type pfcrt in co-culture competition assays. These three alleles mediated cross-resistance to amodiaquine, an antimalarial drug widely used in Africa. Each allele, along with the globally prevalent Dd2 and 7G8 alleles, rendered parasites more susceptible to lumefantrine, the partner drug used in the leading first-line artemisinin-based combination therapy. These data reveal ongoing region-specific evolution of PfCRT that impacts drug susceptibility and relative fitness in settings of mixed infections, and raise important considerations about optimal agents to treat chloroquine-resistant malaria.

  5. Prolonged neuropsychiatric effects following management of chloroquine intoxication with psychotropic polypharmacy

    PubMed Central

    Maxwell, Nicole M; Nevin, Remington L; Stahl, Stephen; Block, Jerald; Shugarts, Sarah; Wu, Alan H B; Dominy, Stephen; Solano-Blanco, Miguel Alonso; Kappelman-Culver, Sharon; Lee-Messer, Christopher; Maldonado, Jose; Maxwell, Andrew J

    2015-01-01

    Key Clinical Message Susceptibility to quinoline antimalarial intoxication may reflect individual genetic and drug-induced variation in neuropharmacokinetics. In this report, we describe a case of chloroquine intoxication that appeared to be prolonged by subsequent use of multiple psychotropic medications. This case highlights important new considerations for the management of quinoline antimalarial intoxication. PMID:26185633

  6. Efficacy of chloroquine in the treatment of uncomplicated Plasmodium falciparum infection in East Timor, 2000.

    PubMed

    Ezard, Nadine; Burns, Matthew; Lynch, Caroline; Cheng, Qin; Edstein, Michael D

    2003-09-01

    Access to an efficacious antimalarial drug is one of the cornerstones of the Roll Back Malaria initiative to decrease malaria morbidity and mortality. This is particularly important in emergency and post-emergency settings where access to treatment in the event of therapeutic failure may be restricted. In the aftermath of violence securing the independence of East Timor (1999), chloroquine continued to be used as first line therapy for the treatment of malaria. However, reliable data on the efficacy of chloroquine was not available. This paper represents the first attempt to document treatment failure with chloroquine in East Timor. The study was conducted using modified WHO guidelines in a rural hospital outpatient department in an area where there is seasonal transmission of both Plasmodium vivax and Plasmodium falciparum. 48 subjects presenting with fever and microscopically confirmed P. falciparum monoinfection were given supervised oral treatment with quality controlled chloroquine (25 mg/kg over 3 days) and followed clinically and parasitologically for 28 days. 32 of the 48 subjects had recurrent parasitaemia, and PCR confirmed that 28 of these were likely to be due to recrudescent parasites. The corrected treatment failure was, therefore, 58.3% (28/48), with all but one (2.1%) defined as late treatment failures (7-28 days after treatment). Further research into appropriate chemotherapy, including sulphadoxine-pyrimethamine and combination therapy for example with artemesinin or its derivatives, should be undertaken to select the most appropriate first line therapy for the management of uncomplicated malaria in East Timor.

  7. Chloroquine Sensitizes Nasopharyngeal Carcinoma Cells but Not Nasoepithelial Cells to Irradiation by Blocking Autophagy

    PubMed Central

    Makowska, Anna; Eble, Michael; Prescher, Kirsten; Hoß, Mareike; Kontny, Udo

    2016-01-01

    Background Treatment of nasopharyngeal carcinoma requires the application of high dosages of radiation, leading to severe long-term complications in the majority of patients. Sensitizing tumor cells to radiation could be a means to increase the therapeutic window of radiation. Nasopharyngeal carcinoma cells display alterations in autophagy and blockade of autophagy has been shown to sensitize them against chemotherapy. Methods We investigated the effect of chloroquine, a known inhibitor of autophagy, on sensitization against radiation-induced apoptosis in a panel of five nasopharyngeal carcinoma cell lines and a SV40-transformed nasoepithelial cell line. Autophagy was measured by immunoblot of autophagy-related proteins, immunofluorescence of autophagosomic microvesicles and electron microscopy. Autophagy was blocked by siRNA against autophagy-related proteins 3, 5, 6 and 7 (ATG3, ATG5, ATG6 and ATG7). Results Chloroquine sensitized four out of five nasopharyngeal cancer cell lines towards radiation-induced apoptosis. The sensitizing effect was based on the blockade of autophagy as inhibition of ATG3, ATG5, ATG6 and ATG7 by specific siRNA could substitute for the effect of chloroquine. No sensitization was seen in nasoepithelial cells. Conclusion Chloroquine sensitizes nasopharyngeal carcinoma cells but not nasoepithelial cells towards radiation-induced apoptosis by blocking autophagy. Further studies in a mouse-xenograft model are warranted to substantiate this effect in vivo. PMID:27902742

  8. Imported chloroquine-resistant Plasmodium vivax in Singapore: case report and literature review.

    PubMed

    Lim, Poh Lian; Mok, Ying Juan; Lye, David C; Leo, Yee Sin

    2010-01-01

    Chloroquine-resistant Plasmodium vivax (CRPV) infection is emerging as a clinically significant problem. Detailed travel history is crucial to the management of imported malarial cases. We report a 58-year-old business traveler who returned from Indonesia and experienced relapse due to CRPV. The epidemiology and diagnostic challenges of CRPV for travel medicine clinicians are reviewed.

  9. Prevalence of the K76T mutation in the pfcrt gene of Plasmodium falciparum among chloroquine responders in India.

    PubMed

    Vinayak, Sumiti; Biswas, Sukla; Dev, Vas; Kumar, Ashwani; Ansari, M A; Sharma, Y D

    2003-07-01

    Chloroquine-resistant Plasmodium falciparum needs to be monitored in the field for effective malaria control strategies. A point mutation K76T in the P. falciparum chloroquine resistance transporter (Pfcrt) protein has recently been proposed as a molecular marker for the faster detection of chloroquine-resistant falciparum malaria in field. We describe here the evaluation of this marker in Indian P. falciparum isolates. A total of 274 Indian P. falciparum isolates were analyzed for the K76T mutation. This mutation was detected in all the clinical isolates obtained from the in vivo chloroquine non-responders. But majority of the clinical isolates from chloroquine responders (71 of 74 patients, i.e. 96%) also harbored this mutation. The K76T mutation was indeed highly prevalent (91%) among 213 clinical isolates. There was a significant association between K76T mutation and the in vitro chloroquine response (P<0.05) but six isolates showed discordant results. In conclusion, the K76T mutation fails to differentiate majority of the chloroquine responders from that of the non-responders and thus will be of limited use in the field in India.

  10. Synergistic killing effect of chloroquine and androgen deprivation in LNCaP cells

    SciTech Connect

    Kaini, Ramesh R.; Hu, Chien-An A.

    2012-08-24

    Highlights: Black-Right-Pointing-Pointer Chloroquine synergistically killed LNCaP cells during androgen deprivation treatment. Black-Right-Pointing-Pointer Chloroquine inhibited the function of autolysosomes and decreases the cytosolic ATP. Black-Right-Pointing-Pointer Chloroquine induced nuclear and DNA fragmentation in androgen deprived LNCaP. Black-Right-Pointing-Pointer Chloroquine may be an useful adjuvant in hormone ablation therapy in PCa patients. -- Abstract: Modulation of autophagy is a new paradigm in cancer therapeutics. Recently a novel function of chloroquine (CLQ) in inhibiting degradation of autophagic vesicles has been revealed, which raises the question whether CLQ can be used as an adjuvant in targeting autophagic pro-survival mechanism in prostate cancer (PCa). We previously showed that autophagy played a protective role during hormone ablation therapy, in part, by consuming lipid droplets in PCa cells. In addition, blocking autophagy by genetic and pharmacological means in the presence of androgen deprivation caused cell death in PCa cells. To further investigate the importance of autophagy in PCa survival and dissect the role of CLQ in PCa death, we treated hormone responsive LNCaP cells with CLQ in combination with androgen deprivation. We observed that CLQ synergistically killed LNCaP cells during androgen deprivation in a dose- and time-dependent manner. We further confirmed that CLQ inhibited the maturation of autophagic vesicles and decreased the cytosolic ATP. Moreover, CLQ induced nuclear condensation and DNA fragmentation, a hallmark of apoptosis, in androgen deprived LNCaP cells. Taken together, our finding suggests that CLQ may be an useful adjuvant in hormone ablation therapy to improve the therapeutic efficacy.

  11. Mechanism of inhibition of adenovirus DNA replication by the acyclic nucleoside triphosphate analogue (S)-HPMPApp: influence of the adenovirus DNA binding protein.

    PubMed Central

    Mul, Y M; van Miltenburg, R T; De Clercq, E; van der Vliet, P C

    1989-01-01

    The acyclic adenosine analogue (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine [S]-HPMPA) is a potent and selective inhibitor of adenovirus (Ad) replication in cell culture. We studied the mechanism of inhibition using a reconstituted in vitro DNA replication system. The diphosphoryl derivative (S)-HPMPApp, but not (S)-HPMPA, inhibited the DNA replication of origin containing fragments strongly. The inhibitory effect was exerted at the level of elongation, while initiation was resistant to the drug. Remarkably, the elongation of short strands was only slightly impaired, while inhibition was maximal upon synthesis of long DNA fragments. (S)-HPMPApp appeared to be competitive with dATP, suggesting that the Ad DNA polymerase is the prime target for the drug. We purified the Ad DNA polymerase in complex to the precursor terminal protein to homogeneity from cells infected with overproducing recombinant vaccinia viruses. Employing gapped DNA or poly(dT).oligo(dA) templates, only a weak inhibition was observed. However, inhibition was strongly enhanced in the presence of the adenovirus DNA binding protein (DBP). We interpret this to mean that the increased processivity of the polymerization reaction in the presence of DBP leads to increased drug sensitivity. Images PMID:2587248

  12. Influence of the Charge State on the Structures and Interactions of Vancomycin Antibiotics with Cell-Wall Analogue Peptides: Experimental and Theoretical Studies

    SciTech Connect

    Yang, Zhibo; Vorpagel, Erich R.; Laskin, Julia

    2009-02-16

    In this study we examined the effect of the charge state on the energetics and dynamics of dissociation of the non-covalent complex between the vancomycin and the cell wall peptide analogue Nα,Nε-diacetyl-L-Lys-D-Ala-D-Ala (V-Ac2KDADA). The binding energies between the vancomycin and the peptide were obtained from the RRKM modeling of the time- and energy resolved surface-induced dissociation (SID) experiments. Our results demonstrate that the stability of the complex toward fragmentation increases in the order: [V+Ac2KDADA+H]+2 < [V+Ac2KDADA+H]+ < [V+Ac2KDADA-H]-. Dissociation of the singly protonated and singly deprotonated complex is characterized by very large entropy effects indicating substantial increase in the conformational flexibility of the resulting products. The experimental threshold energies of 1.75 eV and 1.34 eV obtained for the [V+Ac2KDADA-H]- and [V+Ac2KDADA+H]+ , respectively, are in excellent agreement with the results of density functional theory (DFT) calculations. The increased stability of the deprotonated complex observed experimentally is attributed to the presence of three charged sites in the deprotonated complex as compared to only one charged site in the singly protonated complex. The low binding energy of 0.93 eV obtained for the doubly protonated complex suggests that this ion is destabilized by Coulomb repulsion between the singly protonated vancomycin and the singly protonated peptide comprising the complex.

  13. In vitro chloroquine susceptibility and PCR analysis of pfcrt and pfmdr1 polymorphisms in Plasmodium falciparum isolates from Senegal.

    PubMed

    Thomas, Susan M; Ndir, Omar; Dieng, Therese; Mboup, Souleymane; Wypij, David; Maguire, James H; Wirth, Dyann F

    2002-05-01

    Chloroquine resistance has been linked to mutations in the pfcrt and pfmdr1 genes of Plasmodium falciparum. To estimate the prevalence of the pfcrt K76T, pfmdr1 N86Y, and pfmdr1 D1246Y polymorphisms, isolates of P. falciparum from Senegal, West Africa, were analyzed, and the results were compared to in vitro chloroquine susceptibility. By the in vitro DELI test, 31% of these samples were resistant to chloroquine. Polymerase chain reaction-based assays and confirmatory sequencing demonstrated the pfcrt T76, pfmdr1 Y86, and pfmdr1 Y1246 alleles in 79%, 31%, and 2% of the isolates, respectively. All three mutant alleles were present in both in vitro susceptible and resistant isolates. On the basis of these findings, it appears that these molecular markers are not consistently predictive of in vitro chloroquine resistance in Senegal.

  14. Aspartame and Its Analogues

    NASA Astrophysics Data System (ADS)

    Pavlova, L. A.; Komarova, T. V.; Davidovich, Yurii A.; Rogozhin, S. V.

    1981-04-01

    The results of studies on the biochemistry of the sweet taste are briefly reviewed. The methods of synthesis of "aspartame" — a sweet dipeptide — are considered, its structural analogues are described, and quantitative estimates are made of the degree of sweetness relative to sucrose. Attention is concentrated mainly on problems of the relation between the structure of the substance and its taste in the series of aspartyl derivatives. The bibliography includes 118 references.

  15. Quantum analogue computing.

    PubMed

    Kendon, Vivien M; Nemoto, Kae; Munro, William J

    2010-08-13

    We briefly review what a quantum computer is, what it promises to do for us and why it is so hard to build one. Among the first applications anticipated to bear fruit is the quantum simulation of quantum systems. While most quantum computation is an extension of classical digital computation, quantum simulation differs fundamentally in how the data are encoded in the quantum computer. To perform a quantum simulation, the Hilbert space of the system to be simulated is mapped directly onto the Hilbert space of the (logical) qubits in the quantum computer. This type of direct correspondence is how data are encoded in a classical analogue computer. There is no binary encoding, and increasing precision becomes exponentially costly: an extra bit of precision doubles the size of the computer. This has important consequences for both the precision and error-correction requirements of quantum simulation, and significant open questions remain about its practicality. It also means that the quantum version of analogue computers, continuous-variable quantum computers, becomes an equally efficient architecture for quantum simulation. Lessons from past use of classical analogue computers can help us to build better quantum simulators in future.

  16. The influence of cooling on the advance of lava flows: insights from analogue experiments on the feedbacks between flow dynamics and thermal structure

    NASA Astrophysics Data System (ADS)

    Garel, F.; Kaminski, E.; Tait, S.; Limare, A.

    2012-12-01

    During an effusive volcanic eruption, the crisis management is mainly based on the prediction of lava flows advance and its velocity. The spreading of a lava flow, seen as a gravity current, depends on its "effective rheology" and the eruptive mass flux. These two parameters are not known a priori during an eruption and a key question is how to evaluate them in near real-time (rather than afterwards.) There is no generic macroscopic model for the rheology of an advancing lava flow, and analogue modelling is a precious tool to empirically estimate the rheology of a complex flow. We investigate through laboratory experiments the simultaneous spreading and cooling of horizontal currents fed at constant rate from a point source. The materials used are silicone oil (isoviscous), and poly-ethylene glycol (PEG) wax injected in liquid state and solidiying during its advance. In the isoviscous case, the temperature field is a passive tracer of the flow dynamics, whereas in the PEG experiments there is a feedback between the cooling of the flow and its effective rheology. We focus on the evolution of the current area and of the surface thermal structure, imaged with an infrared camera, to assess how the thermal structure can be related to the flow rate. The flow advance is continuous in the viscous case, and follows the predictions of Huppert (1982); in that case the surface temperature become steady after a transient time and the radiated heat flux is shown to be proportional to the input rate. For the PEG experiments, the spreading occurs through an alternation of stagnation and overflow phases, with a mean spreading rate decreasing as the experiment goes on. As in the case of lava flows, these experiments can exhibit a compound flow field, solid levees, thermal erosion, liquid overflows and channelization. A key observation is that the effective rheology of the solifying PEG material depends on the input flow rate, with high input rates yielding a rheology closer to the

  17. A Translational Approach to Validate in Vivo Anti-tumor Effects of Chloroquine on Breast Cancer Risk

    DTIC Science & Technology

    2013-05-01

    control number. PLEASE DO NOT RETURN YOUR FORM TO THE ABOVE ADDRESS. 1. REPORT DATE May 2013 2. REPORT TYPE Annual 3. DATES COVERED 1 May 2012...breast cancer in genetically programmed rats by 37%. METHODS & SCOPE: About 65% of Peace Corps volunteers received chloroquine prophylactically between...chloroquine, an off-patent anti-malarial drug with a 60-year history of use by millions, reduces the incidence of breast cancer in genetically programmed

  18. Antagonistic effects of chloroquine on autophagy occurrence potentiate the anticancer effects of everolimus on renal cancer cells.

    PubMed

    Grimaldi, A; Santini, D; Zappavigna, S; Lombardi, A; Misso, G; Boccellino, M; Desiderio, V; Vitiello, P P; Di Lorenzo, G; Zoccoli, A; Pantano, F; Caraglia, M

    2015-01-01

    Renal cell carcinoma is an aggressive disease often asymptomatic and weakly chemo-radiosensitive. Currently, new biologic drugs are used among which everolimus, an mTOR inhibitor, that has been approved for second-line therapy. Since mTOR is involved in the control of autophagy, its antitumor capacity is often limited. In this view, chloroquine, a 4-alkylamino substituted quinoline family member, is an autophagy inhibitor that blocks the fusion of autophagosomes and lysosomes. In the present study, we evaluated the effects of everolimus alone or in combination with chloroquine on renal cancer cell viability and verified possible synergism. Our results demonstrate that renal cancer cells are differently sensitive to everolimus and chloroquine and the pharmacological combination everolimus/chloroquine was strongly synergistic inducing cell viability inhibition. In details, the pharmacological synergism occurs when chloroquine is administered before everolimus. In addition, we found a flow autophagic block and shift of death mechanisms to apoptosis. This event was associated with decrease of Beclin-1/Bcl(-)2 complex and parallel reduction of anti-apoptotic protein Bcl(-)2 in combined treatment. At last, we found that the enhancement of apoptosis induced by drug combination occurs through the intrinsic mitochondrial apoptotic pathway activation, while the extrinsic pathway is involved only partly following its activation by chloroquine. These results provide the basis for new therapeutic strategies for the treatment of renal cell carcinoma after appropriate clinical trial.

  19. Molecular epidemiology of malaria in Cameroon. XII. In vitro drug assays and molecular surveillance of chloroquine and proguanil resistance.

    PubMed

    Basco, Leonardo K

    2002-10-01

    Chloroquine-proguanil combination is one of the options for chemoprophylaxis. The rapid evolution of drug resistance status requires a constant upgrade of epidemiologic data. Due to various difficulties in conducting prospective clinical studies on the prophylactic efficacy of the drug combination, especially in highly chloroquine-resistant zones, in vitro drug sensitivity assays and specific molecular markers for chloroquine (Plasmodium falciparum chloroquine-resistance transporter, pfcrt) and cycloguanil (a biologically active metabolite of proguanil; dihydrofolate reductase, dhfr) resistance were evaluated as an alternative approach in this study. Of 116 isolates, 62 (53.4%) were doubly resistant in vitro to chloroquine (IC50 > or = 100 nM) and cycloguanil (IC50 > or = 15 nM). Likewise, 62 of 118 isolates (52.5%) carried both the mutant Thr-76 pfcrt allele and at least one dhfr mutant allele (1 with a single Asn-108 allele, 8 with double Arg-59 and Asn-108 mutations, and 53 with triple Ile-51, Arg-59, and Asn-108 mutations). The in vitro drug response corresponded with the presence or absence of key mutation(s) in the pfcrt and dhfr genes. These results suggest the high proportion of P. falciparum isolates in southern Cameroon that may not respond to chloroquine-proguanil combination.

  20. Chloroquine triggers Epstein-Barr virus replication through phosphorylation of KAP1/TRIM28 in Burkitt lymphoma cells

    PubMed Central

    Li, Xiaofan

    2017-01-01

    Trials to reintroduce chloroquine into regions of Africa where P. falciparum has regained susceptibility to chloroquine are underway. However, there are long-standing concerns about whether chloroquine increases lytic-replication of Epstein-Barr virus (EBV), thereby contributing to the development of endemic Burkitt lymphoma. We report that chloroquine indeed drives EBV replication by linking the DNA repair machinery to chromatin remodeling-mediated transcriptional repression. Specifically, chloroquine utilizes ataxia telangiectasia mutated (ATM) to phosphorylate the universal transcriptional corepressor Krüppel-associated Box-associated protein 1/tripartite motif-containing protein 28 (KAP1/TRIM28) at serine 824 –a mechanism that typically facilitates repair of double-strand breaks in heterochromatin, to instead activate EBV. Notably, activation of ATM occurs in the absence of detectable DNA damage. These findings i) clarify chloroquine’s effect on EBV replication, ii) should energize field investigations into the connection between chloroquine and endemic Burkitt lymphoma and iii) provide a unique context in which ATM modifies KAP1 to regulate persistence of a herpesvirus in humans. PMID:28249048

  1. Antagonistic effects of chloroquine on autophagy occurrence potentiate the anticancer effects of everolimus on renal cancer cells

    PubMed Central

    Grimaldi, A; Santini, D; Zappavigna, S; Lombardi, A; Misso, G; Boccellino, M; Desiderio, V; Vitiello, P P; Di Lorenzo, G; Zoccoli, A; Pantano, F; Caraglia, M

    2015-01-01

    Renal cell carcinoma is an aggressive disease often asymptomatic and weakly chemo-radiosensitive. Currently, new biologic drugs are used among which everolimus, an mTOR inhibitor, that has been approved for second-line therapy. Since mTOR is involved in the control of autophagy, its antitumor capacity is often limited. In this view, chloroquine, a 4-alkylamino substituted quinoline family member, is an autophagy inhibitor that blocks the fusion of autophagosomes and lysosomes. In the present study, we evaluated the effects of everolimus alone or in combination with chloroquine on renal cancer cell viability and verified possible synergism. Our results demonstrate that renal cancer cells are differently sensitive to everolimus and chloroquine and the pharmacological combination everolimus/chloroquine was strongly synergistic inducing cell viability inhibition. In details, the pharmacological synergism occurs when chloroquine is administered before everolimus. In addition, we found a flow autophagic block and shift of death mechanisms to apoptosis. This event was associated with decrease of Beclin-1/Bcl-2 complex and parallel reduction of anti-apoptotic protein Bcl-2 in combined treatment. At last, we found that the enhancement of apoptosis induced by drug combination occurs through the intrinsic mitochondrial apoptotic pathway activation, while the extrinsic pathway is involved only partly following its activation by chloroquine. These results provide the basis for new therapeutic strategies for the treatment of renal cell carcinoma after appropriate clinical trial. PMID:25866016

  2. [Emergence of chloroquine-resistant malaria in West Africa: the case of Sokode (Togo)].

    PubMed

    Gbary, A R; Guiguemdé, T R; Ouedraogo, J B

    1988-06-01

    Within the framework of its surveillance of Plasmodium falciparum chloroquine sensitivity in eight West African countries (Benin, Burkina Faso, Côte d'lvoire, Mali, Mauritany, Niger, Senegal, and Togo) the Reference Centre for Chemoresistant Malaria (CRCP) at the Organization for Coordination and Cooperation to Control Major Endemic Diseases (O.C.C.G.E.) conducted an in vivo survey in February, 1987, in Sokodé (Togo). Two groups of 67 children, aged 2 to 9, received, for the first group a single 10 mg/kg dose of chloroquine; for the second group a 3-day 25 mg/kg dose, according to the WHO methodology. Thick and thin blood smears were examined on D0, D2, D3 when necessary, D4 and D7. Within the 23 children who received the 10 mg/kg dose, seven (30.4%) presented a "resistance", of which six were early RI type and 1 was RII type. Out of 44 children who received the standard dose of 25 mg/kg, two (4.6%) were resistant (early RI type resistance). These data show for the first time the appearance of in vivo chloroquine resistance in this country, and call for a withdrawal of the 10 mg/kg dose of chloroquine in the treatment of fever attacks to the benefit of a 25 mg/kg dose. Thorough studies, using in vivo and in vitro techniques, should be undertaken as soon as possible, not only in Togo but in other West African countries too, to take the exact measure of the issue.

  3. Binding of chloroquine-conjugated gold nanoparticles with bovine serum albumin.

    PubMed

    Joshi, Prachi; Chakraborty, Soumyananda; Dey, Sucharita; Shanker, Virendra; Ansari, Z A; Singh, Surinder P; Chakrabarti, Pinak

    2011-03-15

    We have conjugated chloroquine, an anti-malarial, antiviral and anti-tumor drug, with thiol-functionalized gold nanoparticles and studied their binding interaction with bovine serum albumin (BSA) protein. Gold nanoparticles have been synthesized using sodium borohydride as reducing agent and 11-mercaptoundecanoic acid as thiol functionalizing ligand in aqueous medium. The formation of gold nanoparticles was confirmed from the characteristic surface plasmon absorption band at 522 nm and transmission electron microscopy revealed the average particle size to be ~7 nm. Chloroquine was conjugated to thiolated gold nanoparticles by using EDC/NHS chemistry and the binding was analyzed using optical density measurement and Fourier transform infrared spectroscopy. The chloroquine-conjugated gold nanoparticles (GNP-Chl) were found to interact efficiently with BSA. Thermodynamic parameters suggest that the binding is driven by both enthalpy and entropy, accompanied with only a minor alteration in protein's structure. Competitive drug binding assay revealed that the GNP-Chl bind at warfarin binding site I in subdomain IIA of BSA and was further supported by Trp212 fluorescence quenching measurements. Unraveling the nature of interactions of GNP-Chl with BSA would pave the way for the design of nanotherapeutic agents with improved functionality, enriching the field of nanomedicine.

  4. In utero exposure to chloroquine alters sexual development in the male fetal rat

    SciTech Connect

    Clewell, Rebecca A. Pluta, Linda; Thomas, Russell S.; Andersen, Melvin E.

    2009-06-15

    Chloroquine (CQ), a drug that has been used extensively for the prevention and treatment of malaria, is currently considered safe for use during pregnancy. However, CQ has been shown to disrupt steroid homeostasis in adult rats and similar compounds, such as quinacrine, inhibit steroid production in the Leydig cell in vitro. To explore the effect of in utero CQ exposure on fetal male sexual development, pregnant Sprague-Dawley rats were given a daily dose of either water or chloroquine diphosphate from GD 16-18 by oral gavage. Chloroquine was administered as 200 mg/kg CQ base on GD 16, followed by two maintenance doses of 100 mg/kg CQ base on GD 16 and 18. Three days of CQ treatment resulted in reduced maternal and fetal weight on GD 19 and increased necrosis and steatosis in the maternal liver. Fetal livers also displayed mild lipid accumulation. Maternal serum progesterone was increased after CQ administration. Fetal testes testosterone, however, was significantly decreased. Examination of the fetal testes revealed significant alterations in vascularization and seminiferous tubule development after short-term CQ treatment. Anogenital distance was not altered. Microarray and RT-PCR showed down-regulation of several genes associated with cholesterol transport and steroid synthesis in the fetal testes. This study indicates that CQ inhibits testosterone synthesis and normal testis development in the rat fetus at human relevant doses.

  5. Macroautophagy is dispensable for growth of KRAS mutant tumors and chloroquine efficacy

    PubMed Central

    Eng, Christina H.; Wang, Zuncai; Tkach, Diane; Toral-Barza, Lourdes; Ugwonali, Savuth; Liu, Shanming; Fitzgerald, Stephanie L.; George, Elizabeth; Frias, Elizabeth; Cochran, Nadire; De Jesus, Rowena; McAllister, Gregory; Hoffman, Gregory R.; Bray, Kevin; Lemon, LuAnna; Lucas, Judy; Fantin, Valeria R.; Abraham, Robert T.; Murphy, Leon O.; Nyfeler, Beat

    2016-01-01

    Macroautophagy is a key stress-response pathway that can suppress or promote tumorigenesis depending on the cellular context. Notably, Kirsten rat sarcoma (KRAS)-driven tumors have been reported to rely on macroautophagy for growth and survival, suggesting a potential therapeutic approach of using autophagy inhibitors based on genetic stratification. In this study, we evaluated whether KRAS mutation status can predict the efficacy to macroautophagy inhibition. By profiling 47 cell lines with pharmacological and genetic loss-of-function tools, we were unable to confirm that KRAS-driven tumor lines require macroautophagy for growth. Deletion of autophagy-related 7 (ATG7) by genome editing completely blocked macroautophagy in several tumor lines with oncogenic mutations in KRAS but did not inhibit cell proliferation in vitro or tumorigenesis in vivo. Furthermore, ATG7 knockout did not sensitize cells to irradiation or to several anticancer agents tested. Interestingly, ATG7-deficient and -proficient cells were equally sensitive to the antiproliferative effect of chloroquine, a lysosomotropic agent often used as a pharmacological tool to evaluate the response to macroautophagy inhibition. Moreover, both cell types manifested synergistic growth inhibition when treated with chloroquine plus the tyrosine kinase inhibitors erlotinib or sunitinib, suggesting that the antiproliferative effects of chloroquine are independent of its suppressive actions on autophagy. PMID:26677873

  6. Azithromycin-chloroquine and the intermittent preventive treatment of malaria in pregnancy

    PubMed Central

    Chico, R Matthew; Pittrof, Rudiger; Greenwood, Brian; Chandramohan, Daniel

    2008-01-01

    In the high malaria-transmission settings of sub-Saharan Africa, malaria in pregnancy is an important cause of maternal, perinatal and neonatal morbidity. Intermittent preventive treatment of malaria in pregnancy (IPTp) with sulphadoxine-pyrimethamine (SP) reduces the incidence of low birth-weight, pre-term delivery, intrauterine growth-retardation and maternal anaemia. However, the public health benefits of IPTp are declining due to SP resistance. The combination of azithromycin and chloroquine is a potential alternative to SP for IPTp. This review summarizes key in vitro and in vivo evidence of azithromycin and chloroquine activity against Plasmodium falciparum and Plasmodium vivax, as well as the anticipated secondary benefits that may result from their combined use in IPTp, including the cure and prevention of many sexually transmitted diseases. Drug costs and the necessity for external financing are discussed along with a range of issues related to drug resistance and surveillance. Several scientific and programmatic questions of interest to policymakers and programme managers are also presented that would need to be addressed before azithromycin-chloroquine could be adopted for use in IPTp. PMID:19087267

  7. Augmentation of gastric acid secretion by chloroquine and amodiaquine in the rat stomach.

    PubMed

    Ajeigbe, K O; Emikpe, B O; Olaleye, S B

    2012-06-07

    Gastrointestinal mucosal integrity has been shown to be altered by chloroquine and amodiaquine, although the exact mechanism is not clear. Since Gastric Acid Secretion (GAS) plays significant role in the etiology of ulcer, the present study was aimed at investigating the effect of chloroquine and amodiaquine on GAS, Parietal Cell Mass (PCM) and Gastric Mucous Cell Population (GMP) in rats. Male albino wistar rats were randomly assigned into three groups viz: control, chloroquine (CQ, 3 mg/kg), amodiaquine (AQ, 10 mg/kg). Basal GAS as well as secretion in response to histamine and carbachol was measured by continuous perfusion of the stomach with normal saline (1ml/minute) under urethane anaesthesia (0.6 mg/100 g). After obtaining a steady basal output response to normal saline in all animals, the antimalaria drugs were administered intramuscularly and the peak responses to each drug obtained. Further assessment of the roles of histaminergic and muscarinic receptors were done using ranitidine (H2 antagonist) and atropine (M antagonist) in the treated animals. PCM and GMP were determined in the stomach samples by histometry. The basal acid output was 0.70 ± 0.01 mmol/10 mins. Chloroquine and amodiaquine produced increase in acid output to a peak of 1.35 ±0.03 mmol/10 mins (92.9%) and 1.40 ± 0.03 mmol/10 mins (100%) respectively. Histamine and carbachol elicited 107% and 100% increase acid secretion when compared with the basal output respectively. CQ and AQ potentiated histamine-induced secretory rate which peaked at 1.60 ± 0.02 mmol/10 mins and 1.70 ± 0.03 mmol/10 mins respectively. Similarly, the carbachol-induced acid secretory response was potentiated by CQ and AQ to a peak of 1.45 ± 0.02 mmol/10 mins and 1.50 ± 0.03 mmol/10 mins. Ranitidine and atropine attenuated histamine and carbachol induced acid secretion, but did not abolish it. CQ and AQ increased significantly the parietal cell numbers in the gastric mucosa (21±0.7 and 24±0.7 versus 15.2±0

  8. Analogue-to-Digital and Digital-to-Analogue Conversion.

    ERIC Educational Resources Information Center

    Gregory, Martin

    1997-01-01

    Discusses circuits for three-bit and four-bit analogue digital converters and digital analogue converters. These circuits feature slow operating speeds that enable the circuitry to be used to demonstrate the mode of operation using oscilloscopes and signal generators. (DDR)

  9. N-cinnamoylation of antimalarial classics: quinacrine analogues with decreased toxicity and dual-stage activity.

    PubMed

    Gomes, Ana; Pérez, Bianca; Albuquerque, Inês; Machado, Marta; Prudêncio, Miguel; Nogueira, Fátima; Teixeira, Cátia; Gomes, Paula

    2014-02-01

    Plasmodium falciparum, the causative agent of the most lethal form of malaria, is becoming increasingly resistant to most available drugs. A convenient approach to combat parasite resistance is the development of analogues of classical antimalarial agents, appropriately modified in order to restore their relevance in antimalarial chemotherapy. Following this line of thought, the design, synthesis and in vitro evaluation of N-cinnamoylated quinacrine surrogates, 9-(N-cinnamoylaminobutyl)-amino-6-chloro-2-methoxyacridines, is reported. The compounds were found to be highly potent against both blood-stage P.falciparum, chloroquine-sensitive 3D7 (IC50 =17.0-39.0 nM) and chloroquine-resistant W2 and Dd2 strains (IC50 =3.2-41.2 and 27.1-131.0 nM, respectively), and liver-stage P.berghei (IC50 =1.6-4.9 μM) parasites. These findings bring new hope for the possible future "rise of a fallen angel" in antimalarial chemotherapy, with a potential resurgence of quinacrine-related compounds as dual-stage antimalarial leads.

  10. Synergism between Pfcrt and Pfmdr1 genes could account for the slow recovery of chloroquine sensitive Plasmodium falciparum strains in Ghana after chloroquine withdrawal.

    PubMed

    Asare, Kwame K; Boampong, Johnson N; Duah, Nancy O; Afoakwah, Richmond; Sehgal, Rakesh; Quashie, Neils B

    Unlike other countries, the chloroquine resistant marker Pfcrt T76 mutant has remained fairly stable in Ghana several years after official disuse of chloroquine. Certain mutations in Pfmdr1 may potentiate Pfcrt T76, offering a possible explanation for this observation. To understand the phenomenon, the co-existence of mutations in Pfmdr1 with Pfcrt T76 in Ghanaian Plasmodium falciparum isolates was studied. The reported presence of parasites with reduced sensitivity to amodiaquine and quinine in the country was also studied. Blood samples collected from confirmed malaria patients presenting at health facilities in two distinct ecological zones were analyzed. The prevalence of Pfcrt K76T and the five point mutations in Pfmdr1 were determined using nested PCR followed by RFLP analysis. The association between genes was determined by chi square analysis, and synergism between the two genes was ascertained using the Jonckheere-Terptra (J-T) test followed by Monte Carlo simulation (MCS). Nearly fifty-four percent (53.7%) of the P. falciparum isolates examined had the Pfcrt T76 gene, out of which 18.3% had both K76 and T76 alleles. Mutations at codon 86, 184, 1034, 1042 and 1246 of the Pfmdr1 gene were detected in 36.0%, 87.9%, 71.0%, 91.6% and 8.4% of the isolates, respectively. The haplotypes of Pfmdr1 present were NFCDD (43.46%), YFCDD (27.57%), NFSDD (7.48%), NYSNY (5.14%) and YFSDD (4.67%). Pfcrt T76 was significantly associated with a double mutation at codon 86 and 184 of Pfmdr1 (YF; χ(2)=18.045, p=0.006). Associations were observed between Pfcrt K76T and Pfmdr1 triple mutation at codons 86, 184 and 1034 (NFC; χ(2)=13.770, p=0.032 and YFC; χ(2)=16.489, p=0.011). The J-T test showed significant synergism between Pfcrt 76 and Pfmdr1 polymorphisms (p<0.0001), which was confirmed by MCS at 99% CI. Synergism between Pfcrt and Pfmdr1 mutant genes could account for the slow recovery of chloroquine sensitive P. falciparum in Ghana. The same phenomenon could explain

  11. Functionalized Congener Approach to Muscarinic Antagonists: Analogues of Pirenzepine

    PubMed Central

    Karton, Yishai; Bradbury, Barton J.; Baumgold, Jesse; Paek, Robert; Jacobson, Kenneth A.

    2012-01-01

    The M1-selective muscarinic receptor antagonist pirenzepine (5,11-dihydro-11-[(4-methyl-1-piperazinyl)acetyl]-6H-pyrido[2,3-b] [1,4]benzodiazepin-6-one) was derivatized to explore points of attachment of functionalized side chains for the synthesis of receptor probes and ligands for affinity chromatography. The analogues prepared were evaluated in competitive binding assays versus [3H]-N-methylscopolamine at four muscarinic receptor subtypes (m1AChR-m4AChR) in membranes from rat heart tissue and transfected A9L cells. 9-(Hydroxymethyl)pirenzepine, 8-(methylthio)pirenzepine, and a series of 8-aminosulfonyl derivatives were synthesized. Several 5-substituted analogues of pirenzepine also were prepared. An alternate series of analogues substituted on the 4-position of the piperazine ring was prepared by reaction of 4-desmethylpirenzepine with various electrophiles. An N-chloroethyl analogue of pirenzepine was shown to form a reactive aziridine species in aqueous buffer yet failed to affinity label muscarinic receptors. Within a series of aminoalkyl analogues, the affinity increased as the length of the alkyl chain increased. Shorter chain analogues were generally much less potent than pirenzepine, and longer analogues (7–10 carbons) were roughly as potent as pirenzepine at m1 receptors, but were nonselective. Depending on the methylene chain length, acylation or alkyl substitution of the terminal amine also influenced the affinity at muscarinic receptors. PMID:2066986

  12. Chloroquine Clinical Failures in P. falciparum Malaria Are Associated with Mutant Pfmdr-1, Not Pfcrt in Madagascar

    PubMed Central

    Andriantsoanirina, Valérie; Ratsimbasoa, Arsène; Bouchier, Christiane; Tichit, Magali; Jahevitra, Martial; Rabearimanana, Stéphane; Raherinjafy, Rogelin; Mercereau-Puijalon, Odile; Durand, Rémy; Ménard, Didier

    2010-01-01

    Molecular studies have demonstrated that mutations in the Plasmodium falciparum chloroquine resistance transporter gene (Pfcrt) play a major role in chloroquine resistance, while mutations in P. falciparum multidrug resistance gene (Pfmdr-1) act as modulator. In Madagascar, the high rate of chloroquine treatment failure (44%) appears disconnected from the overall level of in vitro CQ susceptibility (prevalence of CQ-resistant parasites <5%) or Pfcrt mutant isolates (<1%), strongly contrasting with sub-Saharan African countries. Previous studies showed a high frequency of Pfmdr-1 mutant parasites (>60% of isolates), but did not explore their association with P. falciparum chloroquine resistance. To document the association of Pfmdr-1 alleles with chloroquine resistance in Madagascar, 249 P. falciparum samples collected from patients enrolled in a chloroquine in vivo efficacy study were genotyped in Pfcrt/Pfmdr-1 genes as well as the estimation of the Pfmdr-1 copy number. Except 2 isolates, all samples displayed a wild-type Pfcrt allele without Pfmdr-1 amplification. Chloroquine treatment failures were significantly associated with Pfmdr-1 86Y mutant codon (OR = 4.6). The cumulative incidence of recurrence of patients carrying the Pfmdr-1 86Y mutation at day 0 (21 days) was shorter than patients carrying Pfmdr-1 86N wild type codon (28 days). In an independent set of 90 selected isolates, in vitro susceptibility to chloroquine was not associated with Pfmdr-1 polymorphisms. Analysis of two microsatellites flanking Pfmdr-1 allele showed that mutations occurred on multiple genetic backgrounds. In Madagascar, Pfmdr-1 polymorphism is associated with late chloroquine clinical failures and unrelated with in vitro susceptibility or Pfcrt genotype. These results highlight the limits of the current in vitro tests routinely used to monitor CQ drug resistance in this unique context. Gaining insight about the mechanisms that regulate polymorphism in Pfmdr1 remains important

  13. Mammary Analogue Secretory Carcinoma.

    PubMed

    Stevens, Todd M; Parekh, Vishwas

    2016-09-01

    Mammary analogue secretory carcinoma (MASC) is a recently described salivary gland tumor that shares the same histologic appearance and ETV6 gene (12p13) rearrangement as secretory carcinoma of the breast. Prior to its recognition, MASC cases were commonly labeled acinic cell carcinoma and adenocarcinoma, not otherwise specified. Despite distinctive histologic features, MASC may be difficult to distinguish from other salivary gland tumors, in particular zymogen-poor acinic cell carcinoma and low-grade salivary duct carcinoma. Although characteristic morphologic and immunohistochemical features form the basis of a diagnosis of MASC, the presence of an ETV6-NTRK3 gene fusion is confirmatory. Given its recent recognition the true prognostic import of MASC is not yet clearly defined.

  14. Sensitive radioimmunoassay and enzyme-linked immunosorbent assay for the simultaneous determination of chloroquine and its metabolites in biological fluids

    SciTech Connect

    Escande, C.; Chevalier, P.; Verdier, F.; Bourdon, R. )

    1990-01-01

    Two new methods for the simultaneous determination of chloroquine and its two main metabolites (monodesethylchloroquine and bisdesethylchloroquine) in biological samples, radioimmunoassay (RIA) and enzyme-linked immunosorbent assay (ELISA), are described. Antiserum is produced in rabbits immunized with N-(2-carboxyethyl)desethylchloroquine:protein conjugate. Besides chloroquine, this antiserum recognizes with good affinity the two main metabolites, monodesethylchloroquine and bisdesethylchloroquine (70 and 40% of crossreaction, respectively). Amodiaquine cross reacts by 4.5%; cross reactions with monodesethylamodiaquine, bisdesethylamodiaquine, and other antimalarial drugs are less than 1%. No extraction step or sample preparation is required for either system. Sensitivity limits are, respectively, 0.70 nM (3 pg of chloroquine sulfate measured in 10 microL of plasma sample) for RIA, and 10 nM (22 pg of chloroquine sulfate measured in 5 microL of plasma sample) for ELISA. The interassay coefficients of variation are, respectively, less than 10 and less than 16% for RIA and ELISA in the range 14-410 nM (6-180 ng/mL). The results of both methods are well correlated (r = 0.97) and correlate with spectrophotometry (r = 0.98) and HPLC results (r = 0.93). Because of their high sensitivity, both methods can be used in the case of chloroquine poisoning and in the control of malaria prophylaxis and treatment.

  15. A Randomized Comparison of Chloroquine versus Dihydroartemisinin–Piperaquine for the Treatment of Plasmodium vivax Infection in Vietnam

    PubMed Central

    Thuan, Phung Duc; Ca, Nguyen Thuy Nha; Van Toi, Pham; Nhien, Nguyen Thanh Thuy; Thanh, Ngo Viet; Anh, Nguyen Duc; Phu, Nguyen Hoan; Thai, Cao Quang; Hong Thai, Le; Hoa, Nhu Thi; Thanh Dong, Le; Loi, Mai Anh; Son, Do Hung; Khanh, Tran Tinh Ngoc; Dolecek, Christiane; Nhan, Ho Thi; Wolbers, Marcel; Thwaites, Guy; Farrar, Jeremy; White, Nicholas J.; Hien, Tran Tinh

    2016-01-01

    A total of 128 Vietnamese patients with symptomatic Plasmodium vivax mono-infections were enrolled in a prospective, open-label, randomized trial to receive either chloroquine or dihydroartemisinin–piperaquine (DHA-PPQ). The proportions of patients with adequate clinical and parasitological responses were 47% in the chloroquine arm (31 of 65 patients) and 66% in the DHA-PPQ arm (42 of 63 patients) in the Kaplan–Meier intention-to-treat analysis (absolute difference 19%, 95% confidence interval = 0–37%), thus establishing non-inferiority of DHA-PPQ. Fever clearance time (median 24 versus 12 hours, P = 0.02), parasite clearance time (median 36 versus 18 hours, P < 0.001), and parasite clearance half-life (mean 3.98 versus 1.80 hours, P < 0.001) were all significantly shorter in the DHA-PPQ arm. All cases of recurrent parasitemia in the chloroquine arm occurred from day 33 onward, with corresponding whole blood chloroquine concentration lower than 100 ng/mL in all patients. Chloroquine thus remains efficacious for the treatment of P. vivax malaria in southern Vietnam, but DHA-PPQ provides more rapid symptomatic and parasitological recovery. PMID:26856909

  16. Predictors of the failure of treatment with chloroquine plus chlorpheniramine, in children with acute, uncomplicated, Plasmodium falciparum malaria.

    PubMed

    Sowunmi, A; Fateye, B A; Adedeji, A A; Fehintola, F A; Gbotosho, G O; Happi, T C; Oduola, A M J

    2005-06-01

    Resistance to chloroquine in Plasmodium falciparum can be reversed, both in vitro and in vivo, by chlorpheniramine, a histamine H(1) receptor antagonist. This reversal raises the possibility of using chlorpheniramine to prolong the clinical usefulness of chloroquine in resource-poor communities. The factors that identify children at risk of treatment failure after being given chloroquine plus chlorpheniramine have now been evaluated in 281 children with uncomplicated, P. falciparum malaria. The children, who had taken part in six trials of antimalarial drugs between February 1996 and September 1999, in a hyper-endemic area of south-western Nigeria, were enrolled prospectively for the present study. Following treatment with chloroquine plus chlorpheniramine, 13 (5%) of the children failed treatment by day 7 or 14. In a multivariate analysis, an age of < or =3 years (adjusted odds ratio = 11.1; 95% confidence interval = 2.2-55.3; P = 0.003) and a parasitaemia that took >3 days to clear (adjusted odds ratio=7.9; 95% confidence interval = 1.3-49.4; P = 0.027) were found to be independent predictors of treatment failure. In addition, compared with the children who had a lower axillary temperature then, the children who had an axillary temperature of > or =38 degrees C 2 days after commencing treatment were significantly more likely to be treatment failures. In resource-poor communities using chloroquine plus chlorpheniramine, the easily identifiable predictors of treatment failure might be used to identify children requiring alternative antimalarial drugs.

  17. In silico attempt for adduct agent(s) against malaria: Combination of chloroquine with alkaloids of Adhatoda vasica.

    PubMed

    Swain, Shasank S; Sahu, Mahesh C; Padhy, Rabindra N

    2015-10-01

    With the aim of controlling drug resistant Plasmodium falciparum, a computational attempt of designing novel adduct antimalarial drugs through the molecular docking method of combining chloroquine with five alkaloids, individually is presented. These alkaloids were obtained from the medicinal plant, Adhatoda vasica. From the obtained individual docking values of important derivatives of quinine and chloroquine, as well as, individual alkaloids and adduct agents of chloroquine with Adhatoda alkaloids as ligands, it was discernible that the 'adduct agent-1 with chloroquine and adhatodine' combination had the minimum energy of interaction, as the docking score value of -11.144 kcal/mol against the target protein, triosephosphate isomerase (TIM), the key enzyme of glycolytic pathway. Drug resistance of P. falciparum is due to a mutation in the polypeptide of TIM. Moratorium of mutant TIM would disrupt the metabolism during the control of the drug resistant P. falciparum. This in silico work helped to locate the 'adduct agent-1 with chloroquine and adhatodine', which could be taken up by pharmacology for further development of this compound as a new drug against drug resistant Plasmodium.

  18. NASA/ESMD Analogue Mission Plans

    NASA Technical Reports Server (NTRS)

    Hoffman, Stephen J.

    2007-01-01

    A viewgraph presentation exploring Earth and its analogues is shown. The topics include: 1) ESMD Goals for the Use of Earth Analogues; 2) Stakeholders Summary; 3) Issues with Current Analogue Situation; 4) Current state of Analogues; 5) External Implementation Plan (Second Step); 6) Recent Progress in Utilizing Analogues; 7) Website Layout Example-Home Page; 8) Website Layout Example-Analogue Site; 9) Website Layout Example-Analogue Mission; 10) Objectives of ARDIG Analog Initiatives; 11) Future Plans; 12) Example: Cold-Trap Sample Return; 13) Example: Site Characterization Matrix; 14) Integrated Analogue Studies-Prerequisites for Human Exploration; and 15) Rating Scale Definitions.

  19. Mechanisms of hematin crystallization and inhibition by the antimalarial drug chloroquine

    PubMed Central

    Olafson, Katy N.; Ketchum, Megan A.; Rimer, Jeffrey D.; Vekilov, Peter G.

    2015-01-01

    Hematin crystallization is the primary mechanism of heme detoxification in malaria parasites and the target of the quinoline class of antimalarials. Despite numerous studies of malaria pathophysiology, fundamental questions regarding hematin growth and inhibition remain. Among them are the identity of the crystallization medium in vivo, aqueous or organic; the mechanism of crystallization, classical or nonclassical; and whether quinoline antimalarials inhibit crystallization by sequestering hematin in the solution, or by blocking surface sites crucial for growth. Here we use time-resolved in situ atomic force microscopy (AFM) and show that the lipid subphase in the parasite may be a preferred growth medium. We provide, to our knowledge, the first evidence of the molecular mechanisms of hematin crystallization and inhibition by chloroquine, a common quinoline antimalarial drug. AFM observations demonstrate that crystallization strictly follows a classical mechanism wherein new crystal layers are generated by 2D nucleation and grow by the attachment of solute molecules. We identify four classes of surface sites available for binding of potential drugs and propose respective mechanisms of drug action. Further studies reveal that chloroquine inhibits hematin crystallization by binding to molecularly flat {100} surfaces. A 2-μM concentration of chloroquine fully arrests layer generation and step advancement, which is ∼104× less than hematin’s physiological concentration. Our results suggest that adsorption at specific growth sites may be a general mode of hemozoin growth inhibition for the quinoline antimalarials. Because the atomic structures of the identified sites are known, this insight could advance the future design and/or optimization of new antimalarials. PMID:25831526

  20. New quinoline di-Mannich base compounds with greater antimalarial activity than chloroquine, amodiaquine, or pyronaridine.

    PubMed Central

    Kotecka, B M; Barlin, G B; Edstein, M D; Rieckmann, K H

    1997-01-01

    We have compared the ex vivo antimalarial activity of 12 new quinoline di-Mannich base compounds containing the 7-dichloroquinoline or 7-trifluoromethylquinoline nucleus with amodiaquine, chloroquine, and pyronaridine using the Saimiri-bioassay model. Each compound was administered orally (30 mg/kg of body weight) to three or more noninfected Saimiri sciureus monkeys, and serum samples were collected at various times after drug administration and serially diluted with drug-free (control) serum. In vitro activity against the multidrug-resistant K1 isolate of Plasmodium falciparum was determined in serum samples by measuring the maximum inhibitory dilution at which the treated monkey serum inhibited schizont maturation in vitro. Of the 12 Mannich bases tested, 8 were associated with levels of ex vivo antimalarial activity in serum greater than those of amodiaquine, chloroquine, or pyronaridine 1 to 7 days after drug administration. Further studies were carried out with four of these compounds, and the results showed that the areas under the serum drug concentration-time curves for the four compounds were between 7- and 26-fold greater than that obtained for pyronaridine. Activity against four multidrug-resistant strains of P. falciparum was also much greater in serum samples collected from monkeys after administration of these four compounds than in serum samples collected after administration of pyronaridine or chloroquine. These findings suggest that these four quinoline Mannich base compounds possess a very marked and prolonged antimalarial activity and that further studies should be performed to determine their value as antimalarial drugs. PMID:9174201

  1. Chloroquine Analog Interaction with C2- and Iota-Toxin in Vitro and in Living Cells

    PubMed Central

    Kronhardt, Angelika; Beitzinger, Christoph; Barth, Holger; Benz, Roland

    2016-01-01

    C2-toxin from Clostridium botulinum and Iota-toxin from Clostridium perfringens belong both to the binary A-B-type of toxins consisting of two separately secreted components, an enzymatic subunit A and a binding component B that facilitates the entry of the corresponding enzymatic subunit into the target cells. The enzymatic subunits are in both cases actin ADP-ribosyltransferases that modify R177 of globular actin finally leading to cell death. Following their binding to host cells’ receptors and internalization, the two binding components form heptameric channels in endosomal membranes which mediate the translocation of the enzymatic components Iota a and C2I from endosomes into the cytosol of the target cells. The binding components form ion-permeable channels in artificial and biological membranes. Chloroquine and related 4-aminoquinolines were able to block channel formation in vitro and intoxication of living cells. In this study, we extended our previous work to the use of different chloroquine analogs and demonstrate that positively charged aminoquinolinium salts are able to block channels formed in lipid bilayer membranes by the binding components of C2- and Iota-toxin. Similarly, these molecules protect cultured mammalian cells from intoxication with C2- and Iota-toxin. The aminoquinolinium salts did presumably not interfere with actin ADP-ribosylation or receptor binding but blocked the pores formed by C2IIa and Iota b in living cells and in vitro. The blocking efficiency of pores formed by Iota b and C2IIa by the chloroquine analogs showed interesting differences indicating structural variations between the types of protein-conducting nanochannels formed by Iota b and C2IIa. PMID:27517960

  2. Factors affecting the disintegration and dissolution of chloroquine phosphate/starch tablets.

    PubMed

    Pilpel, N; Otuyemi, S O; Kurup, T R

    1978-04-01

    A study has been made of the effects produced on the disintegration and dissolution times of chloroquine phosphate tablets by varying their moisture and starch contents and the distribution of the starch in the formulation. 3 to 5% w/w of moisture produces a maximum in the disintegration and dissolution times. Starch added externally as a powder acts only as a disintegrating agent for the tablets, but starch added internally as a paste during granulation acts both as a binding agent and a disintegrant.

  3. A four-year surveillance program for detection of Plasmodium falciparum chloroquine resistance in Honduras.

    PubMed

    Fontecha, Gustavo A; Sanchez, Ana L; Mendoza, Meisy; Banegas, Engels; Mejía-Torres, Rosa E

    2014-07-01

    Countries could use the monitoring of drug resistance in malaria parasites as an effective early warning system to develop the timely response mechanisms that are required to avert the further spread of malaria. Drug resistance surveillance is essential in areas where no drug resistance has been reported, especially if neighbouring countries have previously reported resistance. Here, we present the results of a four-year surveillance program based on the sequencing of the pfcrt gene of Plasmodium falciparum populations from endemic areas of Honduras. All isolates were susceptible to chloroquine, as revealed by the pfcrt "CVMNK" genotype in codons 72-76.

  4. A Critical Review of the Effects of Hydroxychloroquine and Chloroquine on the Eye.

    PubMed

    Costedoat-Chalumeau, Nathalie; Dunogué, Bertrand; Leroux, Gaëlle; Morel, Nathalie; Jallouli, Moez; Le Guern, Véronique; Piette, Jean-Charles; Brézin, Antoine P; Melles, Ronald B; Marmor, Michael F

    2015-12-01

    Hydroxychloroquine (HCQ) and chloroquine have been used for more than 50 years to treat systemic lupus erythematosus (SLE) and other rheumatic diseases. In general, these drugs are well tolerated and rarely need to be discontinued because of an adverse systemic reaction. However, both medications can be irreversibly toxic to the retina. A new study indicates that toxicity is not as rare as once believed, but depends critically on daily dosage and duration of use, as well as other risk factors. With attention to dosage and other factors, and with proper screening for early signs of toxicity, HCQ can be prescribed with relative safety even over long periods of time.

  5. Efficacy of Chloroquine for the Treatment of Vivax malaria in Northwest Ethiopia

    PubMed Central

    Beyene, Habtamu Bedimo; Beyene, Melkamu Bedimo; Ebstie, Yehenew Asmamaw; Desalegn, Zelalem

    2016-01-01

    Background Resistance to anti-malarials is a major challenge for effective malaria control in sub-Saharan Africa. This triggered a need for routine monitoring of the efficacy of the antimalarial drugs every two years in all malaria endemic countries. Chloroquine remained the drug of choice for the treatment of vivax malaria in Ethiopia. Though, a strong scientific evidence of chloroquine resistance to P.vivax that could have brought change of treatment regimen is yet to be established in Ethiopia, continuous and regular monitoring of drug’s efficacy is critical for establishing rational anti-malarial drug policies. This study therefore, assessed the therapeutic efficacy of Chloroquine (CQ) for the treatment of Plasmodium vivax infections in Northwestern Ethiopia. Methods An observational, 28- day therapeutic clinical efficacy study was conducted from August to December, 2014, in Northwest Ethiopia. Patients confirmed to have monoinfection of vivax malaria, aged above 6 months were included. All subjects were treated with standard chloroquine dose of 25 mg/kg for three (3) days. Parasitological and clinical outcomes of treated patients were then evaluated on days 1, 2, 3, 7, 14, 21, and 28 during the entire 28-day follow-up period. A portable spectrophotometer (HemoCue Hb 301 System, Sweden) was used to estimate hemoglobin concentration. Results A total of 69 subjects had completed follow up. Some 57/69 (82.6%) had fever at enrolment and the rest 12 patients 48 hours before enrollment. Out of total, 65/69 (94.2%) and 66/69 (95.6%) of the study subjects were free of fever by day 1 and day 2 respectively but fever was cleared in all subjects by day 3. At base line the mean asexual parasitemia was 3540 parasites/μL of blood. Parasite carriage on day 3 was 3%. The overall cure rate (an adequate and clinical parasitological response) was very high (97%) [(95% CI = 93.1–99.4)]. The time to parasite, fever and gametocyte clearance as expressed in mean (SD) was 35 (3

  6. Current clinical efficacy of chloroquine for the treatment of Plasmodium falciparum infections in urban Dar es Salaam, United Republic of Tanzania.

    PubMed Central

    Premji, Z.; Makwaya, C.; Minjas, J. N.

    1999-01-01

    Reported is the use of a 14-day WHO protocol, which takes into account the clinical, parasitological and haematological responses to antimalarial drugs, to determine the efficacy of chloroquine in the treatment of uncomplicated malaria in young children (n = 200) in urban Dar es Salaam. Chloroquine failure was found in 43% of the children. Of these, 12.5% were considered to be early treatment failures and were given a single dose of sulfadoxine-pyrimethamine. Fever subsided in all children treated with sulfadoxine-pyrimethamine and there were no parasitological failures. In addition, children treated with sulfadoxine-pyrimethamine because of early treatment failure with chloroquine had better haematological recovery than the chloroquine-sensitive group. It is concluded that chloroquine can no longer be considered an effective therapy for P. falciparum malaria in young children in Dar es Salaam. PMID:10534897

  7. Dihydroartemisinin-piperaquine versus chloroquine to treat vivax malaria in Afghanistan: an open randomized, non-inferiority, trial

    PubMed Central

    2010-01-01

    Background Afghanistan's national guidelines recommend chloroquine for the treatment of Plasmodium vivax infection, the parasite responsible for the majority of its malaria burden. Chloroquine resistance in P. vivax is emerging in Asia. Therapeutic responses across Afghanistan have not been evaluated in detail. Methods Between July 2007 and February 2009, an open-label, randomized controlled trial of chloroquine and dihydroartemisinin-piperaquine in patients aged three months and over with slide-confirmed P. vivax mono-infections was conducted. Consistent with current national guidelines, primaquine was not administered. Subjects were followed up daily during the acute phase of illness (days 0-3) and weekly until day 56. The primary endpoint was the overall cumulative parasitological failure rate at day 56 after the start of treatment, with the hypothesis being that dihydroartemisinin-piperaquine was non-inferior compared to chloroquine (Δ = 5% difference in proportion of failures). Results Of 2,182 individuals with positive blood films for P. vivax, 536 were enrolled in the trial. The day 28 cure rate was 100% in both treatment groups. Parasite clearance was more rapid with dihydroartemisinin-piperaquine than chloroquine. At day 56, there were more recurrent infections in the chloroquine arm (8.9%, 95% CI 6.0-13.1%) than the dihydroartemisinin-piperaquine arm (2.8%, 95% CI 1.4-5.8%), a difference in cumulative recurrence rate of 6.1% (2-sided 90%CI +2.6 to +9.7%). The log-rank test comparing the survival curves confirmed the superiority of dihydroartemisinin-piperaquine over chloroquine (p = 0.003). Multivariate analysis showed that a lower initial haemoglobin concentration was also independently associated with recurrence. Both regimens were well tolerated and no serious adverse events were reported. Conclusions Chloroquine remains an efficacious treatment for the treatment of vivax malaria in Afghanistan. In a setting where radical therapy cannot be

  8. Regulation of autophagy and chloroquine sensitivity by oncogenic RAS in vitro is context-dependent.

    PubMed

    Morgan, Michael J; Gamez, Graciela; Menke, Christina; Hernandez, Ariel; Thorburn, Jacqueline; Gidan, Freddi; Staskiewicz, Leah; Morgan, Shellie; Cummings, Christopher; Maycotte, Paola; Thorburn, Andrew

    2014-10-01

    Chloroquine (CQ) is an antimalarial drug and late-stage inhibitor of autophagy currently FDA-approved for use in the treatment of rheumatoid arthritis and other autoimmune diseases. Based primarily on its ability to inhibit autophagy, CQ and its derivative, hydroxychloroquine, are currently being investigated as primary or adjuvant therapy in multiple clinical trials for cancer treatment. Oncogenic RAS has previously been shown to regulate autophagic flux, and cancers with high incidence of RAS mutations, such as pancreatic cancer, have been described in the literature as being particularly susceptible to CQ treatment, leading to the hypothesis that oncogenic RAS makes cancer cells dependent on autophagy. This autophagy "addiction" suggests that the mutation status of RAS in tumors could identify patients who would be more likely to benefit from CQ therapy. Here we show that RAS mutation status itself is unlikely to be beneficial in such a patient selection because oncogenic RAS does not always promote autophagy addiction. Moreover, oncogenic RAS can have opposite effects on both autophagic flux and CQ sensitivity in different cells. Finally, for any given cell type, the positive or negative effect of oncogenic RAS on autophagy does not necessarily predict whether RAS will promote or inhibit CQ-mediated toxicity. Thus, although our results confirm that different tumor cell lines display marked differences in how they respond to autophagy inhibition, these differences can occur irrespective of RAS mutation status and, in different contexts, can either promote or reduce chloroquine sensitivity of tumor cells.

  9. Short report: therapeutic efficacy of chloroquine combined with primaquine against Plasmodium falciparum in northeastern Papua, Indonesia.

    PubMed

    Baird, J Kevin; Wiady, Iwa; Sutanihardja, Awalludin; Suradi; Purnomo; Basri, Hasan; Sekartuti; Ayomi, Ester; Fryauff, David J; Hoffman, Stephen L

    2002-06-01

    Chloroquine combined with primaquine was evaluated for therapy of uncomplicated malaria caused by Plasmodium falciparum in nonimmune Javanese migrants to northeastern Papua, Indonesia. Subjects were randomized to treatment with standard chloroquine therapy (25 mg/kg in 3 doses over the course of 48 hours) with 30 mg primaquine administered daily for 28 days (n = 25) or a placebo of primaquine (n = 28). The 14-day cumulative incidence of therapeutic failure was 56% with primaquine and 79% with placebo (odds ratio [OR], 0.35; 95% confidence interval [CI], 0.1-1.3; P = 0.08). Primaquine administered daily created a marginally significant improvement in therapeutic efficacy at day 14, but not at day 7 (20% versus 36%; OR, 0.2; 95% CI, 0.1-1.8; P = 0.2) or day 28 (82% versus 93%; OR, 0.31; 95% Cl, 0.04-2.1; P = 0.23). This report corroborates studies suggesting that therapeutic doses of primaquine exert no discernible effect on parasitemia by P. falciparum.

  10. Chloroquine or pyrimethamine in salt as a suppressive against sporozoite-induced vivax malaria (Chesson strain)*

    PubMed Central

    Coatney, G. Robert; Mickelsen, Olaf; Burgess, Robert W.; Young, Martin D.; Pirkle, Carl I.

    1958-01-01

    The authors present the results of a study carried out to determine the efficacy of chloroquine- and pyrimethamine-salt mixtures as a suppressive against sporozoite-induced vivax malaria (Chesson strain). The test subjects used in this study were volunteers of military age in the US Penitentiary at Atlanta, Ga. The subjects chosen were all in good physical condition and had no previous history of malaria. Both drug-salt mixtures were entirely acceptable to the volunteers, were indistinguishable in taste and appearance from ordinary salt, and remained stable under the conditions of food preparation. The weekly dosage of the drugs (300 mg of chloroquine base or 25 mg of pyrimethamine per 50 g of salt) had in each case been adjusted to the average salt consumption. Suppression of malaria was found to be complete throughout the salt-drug regimen and for 28-43 days thereafter, even though the subjects were exposed to repeated heavy doses of sporozoites. In contrast, the control subjects, exposed to the same infective doses, all exhibited parasitaemia 13-15 days after exposure. The procedures for preparing the drug-salt mixtures are described in detail and a simple method for determining the salt consumption by measurement of the urinary chloride excretion is outlined. PMID:13585060

  11. Evaluation of Crimean-Congo hemorrhagic fever virus in vitro inhibition by chloroquine and chlorpromazine, two FDA approved molecules.

    PubMed

    Ferraris, O; Moroso, M; Pernet, O; Emonet, S; Ferrier Rembert, A; Paranhos-Baccalà, G; Peyrefitte, C N

    2015-06-01

    Crimean-Congo hemorrhagic virus (CCHFV) causes hemorrhagic fever with high case mortality rates and is endemic in south-eastern Europe, Africa, and Asia. The limited catalog of specific treatment, highlight the necessity to look for additional therapeutic solutions. Previous experiments suggested that CCHFV enters the cells via a clathrin dependent pathway. Therefore, we have evaluated the potential anti-CCHFV activity of several molecules targeting this entry possibility. We identified two molecules chloroquine and chlorpromazine. Neutralization and virus yield reduction assays were tested in Vero E6 and Huh7 cells on two different CCHFV strains. Several combinations, including ribavirin, were assayed to test a potential synergistic effect. The two molecules inhibited CCHFV, and depending on the virus and the cell lines, the 50% inhibitory concentration (IC50) values for chloroquine and chlorpromazine ranged from 28 to 43 and 10.8-15.7 μM, respectively. Time-of-addition studies demonstrated that these molecules had a direct effect on CCHFV infectivity and spread. The antiviral activity of the two molecules was still effective even when added up to 6h post-infection and up to 24h. The selectivity index ranging from 3 to 35 lead us to evaluate combinations with ribavirin. Combinations of ribavirin and chloroquine or chlorpromazine were synergistic against CCHFV. Though the low chlorpromazine selectivity index suggests the need for a chemical improvement, our present study highlights chloroquine as the main drug having the potential for drug repurposing.

  12. Inhibition of autophagy with chloroquine potentiates carfilzomib-induced apoptosis in myeloma cells in vitro and in vivo.

    PubMed

    Jarauta, Vidal; Jaime, Paula; Gonzalo, Oscar; de Miguel, Diego; Ramírez-Labrada, Ariel; Martínez-Lostao, Luis; Anel, Alberto; Pardo, Julián; Marzo, Isabel; Naval, Javier

    2016-11-01

    The proteasome inhibitor bortezomib is now the cornerstone of combination therapy of multiple myeloma (MM). Carfilzomib, a second-generation inhibitor, has shown a substantial benefit vs bortezomib in combination regimes. Here we have analyzed in detail the mechanism of cell death induced by carfilzomib and its crosstalk with autophagy and applied the results to the in vivo treatment of MM in a mouse model. Carfilzomib induced apoptosis essentially by the intrinsic pathway, through the up-regulation of Puma and Noxa proteins followed by the interaction of Puma, Noxa and Bim with Bax and of Noxa with Bak. Carfilzomib also produces an increase in the formation of autophagosomes but, as apoptosis progresses, autophagy is disrupted, probably owing to Beclin 1 and p62 inactivation. Cotreatment with chloroquine, which blocks autophagy, strongly potentiated apoptosis in vitro and in vivo. Accordingly, combination therapy with carfilzomib plus chloroquine was highly effective in the treatment of MM in a mouse xenograft model. Chloroquine also enhanced carfilzomib-induced calreticulin exposure in MM cells undergoing apoptosis, increasing the immunogenic ability of carfilzomib. These results support design of trials combining carfilzomib with chloroquine to improve MM therapy.

  13. The effect of chloroquine on the distribution of newly synthesized and old β-hexosaminidase in fibroblasts

    PubMed Central

    Vladutiu, Georgirene D.

    1982-01-01

    Most of the newly synthesized β-N-acetyl-d-glucosaminidase (EC 3.2.1.30; β-hexosaminidase) in normal fibroblast cultures is excreted during 24h incubation with serum-free medium. In this study, this new enzyme only comprises about one-half of the excreted pool as determined by a near total inhibition of [14C]leucine incorporation into the excreted enzyme in the presence of cycloheximide, with only a 46% reduction in enzyme activity. These data indicate that nearly equal fractions of new and old enzyme are normally excreted by fibroblasts. Incubation of normal fibroblast cultures with chloroquine (25 μm) for 24h doubled the amount of extracellular β-hexosaminidase activity from 15% to 37% of total culture activity while reducing the incorporation of [14C]leucine into intra- and extracellular enzyme by 66 and 29% of control, respectively. Therefore, it appears that chloroquine inhibited enzyme synthesis while enhancing the excretion of old as well as newly synthesized enzyme. Chloroquine and cycloheximide together reduced the [14C]leucine incorporation into intracellular enzyme by more than either agent alone, indicating a combined effect on enzyme synthesis and/or degradation. β-Hexosaminidase-deficient fibroblasts that contained endocytosed enzyme spontaneously excreted 10% of their enzyme during 24h incubation with serum-free medium and 18% in the presence of mannose 6-phosphate (2 mm). These results indicated that about one-half of the excreted enzyme still possessed its phosphomannosyl recognition residues and actually re-entered the cells. Chloroquine stimulated the excretion of an addition 15% of the total endocytosed enzyme at 48 and 72h after endocytosis. These data suggest that new, old and endocytosed β-hexosaminidase are all excreted by fibroblasts, that this excretion is enhanced by chloroquine, and that a fraction of the excreted enzyme retains its phosphomannosylated residues needed for re-uptake and transport inside the cells. ImagesFig. 1. PMID

  14. Chiral Platinum(II) Complexes Featuring Phosphine and Chloroquine Ligands as Cytotoxic and Monofunctional DNA-Binding Agents.

    PubMed

    Villarreal, Wilmer; Colina-Vegas, Legna; Rodrigues de Oliveira, Clayton; Tenorio, Juan C; Ellena, Javier; Gozzo, Fábio C; Cominetti, Marcia Regina; Ferreira, Antonio G; Ferreira, Marco Antonio Barbosa; Navarro, Maribel; Batista, Alzir A

    2015-12-21

    Chiral molecules in nature are involved in many biological events; their selectivity and specificity make them of great interest for understanding the behavior of bioactive molecules, by providing information about the chiral discrimination. Inspired by these conformational properties, we present the design and synthesis of novel chiral platinum(II) complexes featuring phosphine and chloroquine ligands with the general formula [PtCl(P)2(CQ)]PF6 (where (P)2 = triphenylphosphine (PPh3) (5), 1,3-bis(diphenylphosphine)propane (dppp) (6), 1,4-bis(diphenylphosphine)butane (dppb) (7), 1,1'-bis(diphenylphosphine)ferrocene (dppf) (8), and CQ = chloroquine] and their precursors of the type [PtCl2(P)2] are described. The complexes were characterized by elemental analysis, absorption spectroscopy in the infrared and ultraviolet-visible (UV-vis) regions, multinuclear ((1)H, (13)C, (31)P, (15)N, and (195)Pt) NMR spectroscopy, cyclic voltammetry, and mass spectrometry (in the case of chloroquine complexes). The interactions of the new platinum-chloroquine complexes with both albumin (BSA), using fluorescence spectroscopy, and DNA, by four widely reported methods were also evaluated. These experiments showed that these Pt-CQ complexes interact strongly with DNA and have high affinities for BSA, in contrast to CQ and CQDP (chloroquine diphosphate), which interact weakly with these biomolecules. Additional assays were performed in order to investigate the cytotoxicity of the platinum complexes against two healthy cell lines (mouse fibroblasts (L929) and the Chinese hamster lung (V79-4)) and four tumor cell lines (human breast (MDA-MB-231 and MCF-7), human lung (A549), and human prostate (DU-145)). The results suggest that the Pt-CQ complexes are generally more cytotoxic than the free CQ, showing that they are promising as anticancer drugs.

  15. Efficacy of chloroquine for the treatment of uncomplicated Plasmodium falciparum malaria in Honduras.

    PubMed

    Mejia Torres, Rosa Elena; Banegas, Engels Ilich; Mendoza, Meisy; Diaz, Cesar; Bucheli, Sandra Tamara Mancero; Fontecha, Gustavo A; Alam, Md Tauqeer; Goldman, Ira; Udhayakumar, Venkatachalam; Zambrano, Jose Orlinder Nicolas

    2013-05-01

    Chloroquine (CQ) is officially used for the primary treatment of Plasmodium falciparum malaria in Honduras. In this study, the therapeutic efficacy of CQ for the treatment of uncomplicated P. falciparum malaria in the municipality of Puerto Lempira, Gracias a Dios, Honduras was evaluated using the Pan American Health Organization-World Health Organization protocol with a follow-up of 28 days. Sixty-eight patients from 6 months to 60 years of age microscopically diagnosed with uncomplicated P. falciparum malaria were included in the final analysis. All patients who were treated with CQ (25 mg/kg over 3 days) cleared parasitemia by day 3 and acquired no new P. falciparum infection within 28 days of follow-up. All the parasite samples sequenced for CQ resistance mutations (pfcrt) showed only the CQ-sensitive genotype (CVMNK). This finding shows that CQ remains highly efficacious for the treatment of uncomplicated P. falciparum malaria in Gracias a Dios, Honduras.

  16. Membrane fusion inducers, chloroquine and spermidine increase lipoplex-mediated gene transfection

    SciTech Connect

    Wong-Baeza, Carlos; Bustos, Israel; Serna, Manuel; Tescucano, Alonso; Alcantara-Farfan, Veronica; Ibanez, Miguel; Montanez, Cecilia; Wong, Carlos; Baeza, Isabel

    2010-05-28

    Gene transfection into mammalian cells can be achieved with viral and non-viral vectors. Non-viral vectors, such as cationic lipids that form lipoplexes with DNA, are safer and more stable than viral vectors, but their transfection efficiencies are lower. Here we describe that the simultaneous treatment with a membrane fusion inducer (chlorpromazine or procainamide) plus the lysosomotropic agent chloroquine increases lipoplex-mediated gene transfection in human (HEK293 and C-33 A) and rat (PC12) cell lines (up to 9.2-fold), as well as in situ in BALB/c mice spleens and livers (up to 6-fold); and that the polyamine spermidine increases lipoplex-mediated gene transfection and expression in cell cultures. The use of these four drugs provides a novel, safe and relatively inexpensive way to considerably increase lipoplex-mediated gene transfection efficiency.

  17. Plasmodium falciparum chloroquine resistance transporter is a H+-coupled polyspecific nutrient and drug exporter

    PubMed Central

    Juge, Narinobu; Moriyama, Sawako; Miyaji, Takaaki; Kawakami, Mamiyo; Iwai, Haruka; Fukui, Tomoya; Nelson, Nathan; Omote, Hiroshi; Moriyama, Yoshinori

    2015-01-01

    Extrusion of chloroquine (CQ) from digestive vacuoles through the Plasmodium falciparum CQ resistance transporter (PfCRT) is essential to establish CQ resistance of the malaria parasite. However, the physiological relevance of PfCRT and how CQ-resistant PfCRT gains the ability to transport CQ remain unknown. We prepared proteoliposomes containing purified CQ-sensitive and CQ-resistant PfCRTs and measured their transport activities. All PfCRTs tested actively took up tetraethylammonium, verapamil, CQ, basic amino acids, polypeptides, and polyamines at the expense of an electrochemical proton gradient. CQ-resistant PfCRT exhibited decreased affinity for CQ, resulting in increased CQ uptake. Furthermore, CQ competitively inhibited amino acid transport. Thus, PfCRT is a H+-coupled polyspecific nutrient and drug exporter. PMID:25733858

  18. Chloroquine and sulphadoxine-pyrimethamine sensitivity of Plasmodium falciparum parasites in a Brazilian endemic area

    PubMed Central

    Gama, Bianca Ervatti; de Oliveira, Natália K Almeida; Zalis, Mariano G; de Souza, José Maria; Santos, Fátima; Daniel-Ribeiro, Cláudio Tadeu; Ferreira-da-Cruz, Maria de Fátima

    2009-01-01

    Background The goal of the present study was the characterization of Plasmodium falciparum genes associated to malaria drug resistance (pfcrt, pfdhfr and pfdhps), in samples from two Brazilian localities. Methods Parasites from 65 P. falciparum samples were genotyped using nested-PCR and direct DNA sequencing. Results Six resistant sulphadoxine-pyrimethamine (SP) pfdhfr genotypes and one haplotype associated to SP sensitivity were detected. For pfcrt gene, SVMNT chloroquine (CQ)-resistant genotype was detected as well as the CVMNK CQ-sensitive haplotype in the same sample from Paragominas, that showed a SP-sensitive genotype. Conclusion This study is the first to document the sensitivity of P. falciparum parasites to CQ and SP in Brazilian field samples. The importance of these findings is discussed. PMID:19602248

  19. In vivo and in vitro analysis of chloroquine resistance in Plasmodium falciparum isolates from Senegal.

    PubMed

    Sarr, Ousmane; Myrick, Alissa; Daily, Johanna; Diop, Bernard M; Dieng, Therese; Ndir, Omar; Sow, Pape Salif; Mboup, Souleymane; Wirth, Dyann F

    2005-09-01

    To determine the predictive value of chloroquine (CQ) resistance markers in Senegal, Plasmodium falciparum DNA polymorphisms in pfmdr1and pfcrt were examined in relation to clinical outcome. Despite CQ treatment, 17% of patients had parasitemia after 28 days. Examination of molecular markers of CQ resistance revealed that 64% of all isolates had the T76 resistant allele at the pfcrt locus, while 30% carried the Y86 resistant allele at the pfmdr1 locus. The pfcrt T76 allele was present not only in all in vivo resistant isolates, 89% of in vitro resistant isolates, but also in 35% of in vitro sensitive isolates. The pfmdr1 N86Y polymorphism did not correlate with in vitro or in vivo CQ resistance. Our data suggest that the pfcrt T76 allele alone is required but not a sufficient predictor for in vivo CQ resistance.

  20. Enhanced combination therapy effect on paclitaxel-resistant carcinoma by chloroquine co-delivery via liposomes

    PubMed Central

    Gao, Menghua; Xu, Yuzhen; Qiu, Liyan

    2015-01-01

    A novel composite liposomal system co-encapsulating paclitaxel (PTX) with chloroquine phosphate (CQ) was designed for treating PTX-resistant carcinoma. It was confirmed that liposomal CQ can sensitize PTX by means of autophagy inhibition and competitively binding with multidrug-resistance transporters. Furthermore, according to the in vitro cytotoxicity and apoptosis assay, real-time observation of cellular uptake, and in vivo tissue distribution study, co-encapsulation of PTX and CQ in liposomes was validated as superior to the mixture of PTX liposome plus CQ liposome due to the simultaneous delivery and synergetic effect of the two drugs. Consequently, this composite liposome achieved significantly stronger anticancer efficacy in vivo than the PTX liposome plus CQ liposome mixture. This study helps to guide and enlighten ongoing and future clinical trials about the optimal administration modes for drug combination therapy. PMID:26543365

  1. Enhanced combination therapy effect on paclitaxel-resistant carcinoma by chloroquine co-delivery via liposomes.

    PubMed

    Gao, Menghua; Xu, Yuzhen; Qiu, Liyan

    2015-01-01

    A novel composite liposomal system co-encapsulating paclitaxel (PTX) with chloroquine phosphate (CQ) was designed for treating PTX-resistant carcinoma. It was confirmed that liposomal CQ can sensitize PTX by means of autophagy inhibition and competitively binding with multidrug-resistance transporters. Furthermore, according to the in vitro cytotoxicity and apoptosis assay, real-time observation of cellular uptake, and in vivo tissue distribution study, co-encapsulation of PTX and CQ in liposomes was validated as superior to the mixture of PTX liposome plus CQ liposome due to the simultaneous delivery and synergetic effect of the two drugs. Consequently, this composite liposome achieved significantly stronger anticancer efficacy in vivo than the PTX liposome plus CQ liposome mixture. This study helps to guide and enlighten ongoing and future clinical trials about the optimal administration modes for drug combination therapy.

  2. Lymphocyte proliferative response and subset profiles during extended periods of chloroquine or primaquine prophylaxis.

    PubMed Central

    Fryauff, D J; Richards, A L; Baird, J K; Richie, T L; Mouzin, E; Tjitra, E; Sutamihardja, M A; Ratiwayanto, S; Hadiputranto, H; Larasati, R P; Pudjoprawoto, N; Subianto, B; Hoffman, S L

    1996-01-01

    Immune suppression and disturbances of normal leukocyte populations are side effects attributed to many antimalarial drugs and were concerns during a recent year-long placebo-controlled trial that compared daily primaquine (0.5 mg of base per kg of body weight per day) with weekly chloroquine (300 mg of base one time per week) for malaria prophylaxis. The study took place in Irian Jaya, Indonesia, from July 1994 to August 1995 and enrolled 129 Javanese men with normal glucose-6-phosphate dehydrogenase function. Tests for lymphocyte function and subset composition were conducted blindly on a cross-section of subjects during weeks 10 (n = 42) and 48 (n = 72) of supervised prophylaxis. Lymphocyte function, measured as the proliferative response of peripheral blood mononuclear cells to a panel of mitogens (pokeweed mitogen, phytohemagglutinin, and concanavalin A) and antigens (purified protein derivative of Mycobacterium tuberculosis and Clostridium tetani toxoid) and expressed as a stimulation index, allowed for statistical comparison between groups and sampling times. The lymphocyte subset composition for each group and time point was based on flow cytometry profiling, and the results were expressed as the mean percentages of CD3 (total T cells), CD19 (total B cells), CD4+ (T-helper and inducer cells), and CD8+ (T suppressor and cytotoxic cells), CD3/CD16+ CD56 (natural killer cells), CD3/anti-HLA-DR (activated T cells) cells and the CD4+/CD8+ ratios. Lymphocyte stimulation indices were statistically comparable among the placebo, primaquine, and chloroquine groups at both time points, although the primaquine group was distinguished by having repeatedly greater proportions of subjects with high ( > 3.0) stimulation indices. The lymphocyte subset profiles of these groups at both time points were also similar and undistorted relative to those of healthy reference populations matched for age, sex, and ethnicity. The results provide quantitative support for the safety of

  3. Localized permanent epidemics: the genesis of chloroquine resistance in Plasmodium falciparum.

    PubMed

    Verdrager, J

    1995-03-01

    Localized permanent epidemics occur when, for an indefinite period of time, there is a temporary but continuous introduction of unprotected non-immunes into the same locality of a hyperendemic area. The main epidemiological factors involved in the genesis of localized permanent epidemics were encountered in Pailin (Cambodia) the epicenter of drug resistance in Southeast Asia: a very efficient vector, Anopheles dirus, exophilic and of limited distribution with, therefore, adjacent hyperendemic and non-endemic areas; a permanent pole of attraction in the hyperendemic area: Pailin's sapphires and rubies; a temporary but continuous influx of non-immunes into the pole of attraction: continuous influx of non-immunes into the Pailin gem mining area. In the gem-mining Pailin village drug pressure was considerable: mass drug administration, a medicated salt project and permanent self-medication with very high doses, much higher doses being required to cure non-immunes with heavy infections and severe clinical attacks in epidemic situations. It appears, therefore, that the emergence of chloroquine resistance in Southeast Asia was the consequence of the localized permanent epidemics in Païlin. High level resistance was the result of continuous and intensive serial passages of P. falciparum in the non-immune subjects, large numbers of parasites being exposed to a high level of drug pressure at each passage. Similar epidemiological conditions are encountered in some parts of South America where the exophilic vector is An. nuneztovari. In Colombia, whose eastern mountains bordering Venezuela yield the most highly prized emeralds in the world, chloroquine resistance was detected at about the same time as in Southeast Asia.(ABSTRACT TRUNCATED AT 250 WORDS)

  4. Therapeutic responses of Plasmodium vivax malaria to chloroquine and primaquine treatment in northeastern Myanmar.

    PubMed

    Yuan, Lili; Wang, Ying; Parker, Daniel M; Gupta, Bhavna; Yang, Zhaoqing; Liu, Huaie; Fan, Qi; Cao, Yaming; Xiao, Yuping; Lee, Ming-chieh; Zhou, Guofa; Yan, Guiyun; Baird, J Kevin; Cui, Liwang

    2015-02-01

    Chloroquine-primaquine (CQ-PQ) continues to be the frontline therapy for radical cure of Plasmodium vivax malaria. Emergence of CQ-resistant (CQR) P. vivax parasites requires a shift to artemisinin combination therapies (ACTs), which imposes a significant financial, logistical, and safety burden. Monitoring the therapeutic efficacy of CQ is thus important. Here, we evaluated the therapeutic efficacy of CQ-PQ for P. vivax malaria in northeast Myanmar. We recruited 587 patients with P. vivax monoinfection attending local malaria clinics during 2012 to 2013. These patients received three daily doses of CQ at a total dose of 24 mg of base/kg of body weight and an 8-day PQ treatment (0.375 mg/kg/day) commencing at the same time as the first CQ dose. Of the 401 patients who finished the 28-day follow-up, the cumulative incidence of recurrent parasitemia was 5.20% (95% confidence interval [CI], 3.04% to 7.36%). Among 361 (61%) patients finishing a 42-day follow-up, the cumulative incidence of recurrent blood-stage infection reached 7.98% (95% CI, 5.20% to 10.76%). The cumulative risk of gametocyte carriage at days 28 and 42 was 2.21% (95% CI, 0.78% to 3.64%) and 3.93% (95% CI, 1.94% to 5.92%), respectively. Interestingly, for all 15 patients with recurrent gametocytemia, this was associated with concurrent asexual stages. Genotyping of recurrent parasites at the merozoite surface protein 3α gene locus from 12 patients with recurrent parasitemia within 28 days revealed that 10 of these were the same genotype as at day 0, suggesting recrudescence or relapse. Similar studies in 70 patients in the same area in 2007 showed no recurrent parasitemias within 28 days. The sensitivity to chloroquine of P. vivax in northeastern Myanmar may be deteriorating.

  5. Autophagy inhibitor chloroquine increases sensitivity to cisplatin in QBC939 cholangiocarcinoma cells by mitochondrial ROS

    PubMed Central

    Qu, Xianzhi; Sheng, Jiyao; Shen, Luyan; Su, Jing; Xu, Yunjie; Xie, Qi; Wu, Yao; Zhang, Xuewen; Sun, Liankun

    2017-01-01

    The tumor cells have some metabolic characteristics of the original tissues, and the metabolism of the tumor cells is closely related to autophagy. However, the mechanism of autophagy and metabolism in chemotherapeutic drug resistance is still poorly understood. In this study, we investigated the role and mechanism of autophagy and glucose metabolism in chemotherapeutic drug resistance by using cholangiocarcinoma QBC939 cells with primary cisplatin resistance and hepatocellular carcinoma HepG2 cells. We found that QBC939 cells with cisplatin resistance had a higher capacity for glucose uptake, consumption, and lactic acid generation, and higher activity of the pentose phosphate pathway compared with HepG2 cells, and the activity of PPP was further increased after cisplatin treatment in QBC939 cells. It is suggested that there are some differences in the metabolism of glucose in hepatocellular carcinoma and cholangiocarcinoma cells, and the activation of PPP pathway may be related to the drug resistance. Through the detection of autophagy substrates p62 and LC3, found that QBC939 cells have a higher flow of autophagy, autophagy inhibitor chloroquine can significantly increase the sensitivity of cisplatin in cholangiocarcinoma cells compared with hepatocellular carcinoma HepG2 cells. The mechanism may be related to the inhibition of QBC939 cells with higher activity of the PPP, the key enzyme G6PDH, which reduces the antioxidant capacity of cells and increases intracellular ROS, especially mitochondrial ROS. Therefore, we hypothesized that autophagy and the oxidative stress resistance mediated by glucose metabolism may be one of the causes of cisplatin resistance in cholangiocarcinoma cells. It is suggested that according to the metabolism characteristics of tumor cells, inhibition of autophagy lysosome pathway with chloroquine may be a new route for therapeutic agents against cholangiocarcinoma. PMID:28301876

  6. Comparative study of interactions between chloroquine and chlorpheniramine or promethazine in healthy volunteers: a potential combination-therapy phenomenon for resuscitating chloroquine for malaria treatment in Africa.

    PubMed

    Gbotosho, G O; Happi, C T; Sijuade, A; Ogundahunsi, O A T; Sowunmi, A; Oduola, A M J

    2008-01-01

    Although, in in-vitro and limited in-vivo studies, chlorpheniramine (CP) and promethazine (PR) have each been shown to reverse chloroquine (CQ) resistance, the pharmacokinetic basis of this reversal has not been fully elucidated. In the present study, 15 healthy volunteers were randomly allotted to receive standard doses of CQ alone or in combination with CP or PR. Blood samples were collected from each volunteer at 21 time-points, from immediately before to 168 h after the initial dose. These samples were used to follow the changes in the plasma and erythrocytic concentrations of CQ. The ratio between the mean maximum CQ concentration in the erythrocytes and that in the plasma was 4.2 for the volunteers given CQ alone, 7.3 in those given CQ-CP, and 3.2 in those given CQ-PR. CP significantly enhanced the erythrocytic accumulation of CQ, increasing the maximum CQ concentration observed in the erythrocytes by 24% (P = 0.02). The bio-availability of CQ was also significantly increased in the presence of CP, with the mean value for the area under the curve, of erythrocytic concentration v. time, increasing from 99,921 to 214,516 ng/ml.h (P=0.001). The mean half-life of CQ in the erythrocytes also increased when CP was used, from 51 to 100 h, but this change was not statistically significant (P=0.83). In contrast to CP, PR had no statistically significant effect on the disposition of CQ. As CP clearly enhances disposition of CQ, a combination of CQ with CP may be useful in the management of CQ-resistant infections. Detailed toxicological studies are required to understand the full clinical implications of CP's elevation of erythrocytic CQ concentrations.

  7. Effect of chloroquine phosphate and toxic concentrations of lead acetate on Ca2+-ATPase activity in isolates and clones of Plasmodium falciparum.

    PubMed

    Bolaji, O M; Happi, T C; Oduola, A M J; Babafunmi, E A

    2011-12-20

    The basal activity of Ca2+-ATPase in two isolates (NL56, UNC) and two clones (D6, W2) of P.falciparum was assessed. The effects of various concentrations of chloroquine phosphate and toxic concentrations of lead acetate were also evaluated in the clones and strains of P.falciparum. The Ca2+-ATPase activity was measured by monitoring the rate of release of inorganic phosphate from the gamma-position of ATP on spectrophotometer at 820nm wavelength. The various concentrations of chloroquine (3, 6, 9, 12, 18µg/ml) and lead acetate (5, 10, 20, 30, 40µg/ml) on Ca2+-ATPase activity were measured respectively. Chloroquine phosphate inhibited Ca2+-ATPase activity in both the isolates and the cloned strains of P.falciparum in concentration dependent manner. Median Inhibitory concentration of chloroquine (MIC50) estimated from the plot of activity against chloroquine concentration was found to be 2.6mg/ml at pH 7.4 for both the isolates and cloned strains examined. Lead acetate at concentrations 5-20µg/ml inhibited Ca2+-ATPase activity in concentration dependent manner in clone W2 (Chloroquine resistant strain) while the same range of concentrations of lead acetate stimulated the activity of the enzyme in clone D6 (Chloroquine sensitive strain).The inhibitory effect of lead acetate on the enzyme in clone D6 was observed at concentrations above 20µg/ml. The result also suggests that lead ions could modulate and moderate calcium ion homeostasis in P. falciparum via its effect on Ca2+-ATPase activity. Also sufficient influx of lead ions into P. falciparum may transform the biochemical or bioenergetics nature of chloroquine sensitive strain of P. falciparum (D6) to that similar to chloroquine resistant strain (W2). In conclusion, inhibition of Ca2+-ATPase activity of P.falciparum may be part of the mechanism of action of chloroquine in its use as chemotherapy for malaria. The study implies that populations simultaneously exposed to lead pollution and malaria infection may

  8. Rapid Selection of Plasmodium falciparum Chloroquine Resistance Transporter Gene and Multidrug Resistance Gene-1 Haplotypes Associated with Past Chloroquine and Present Artemether-Lumefantrine Use in Inhambane District, Southern Mozambique

    PubMed Central

    Thomsen, Thomas T.; Madsen, Laura B.; Hansson, Helle H.; Tomás, Elsa V. E.; Charlwood, Derek; Bygbjerg, Ib C.; Alifrangis, Michael

    2013-01-01

    Chloroquine (CQ) use in Mozambique was stopped in 2002 and artemether-lumefantrine (AL) was implemented in 2008. In light of no use of CQ and extensive use of AL, we determined the frequency of molecular markers of Plasmodium falciparum drug resistance/tolerance to CQ and AL in persons living in Linga-Linga, an isolated peninsula and in Furvela village, which is located 8 km inland. The P. falciparum chloroquine resistance transporter gene CVMNK wild type increased in frequency from 43.9% in 2009 to 66.4% in 2010 (P ≤ 0.001), and combined P. falciparum multidrug resistance gene 1 N86-184F-D1246 haplotype increased significantly between years (P = 0.039). The combination of P. falciparum chloroquine resistance transporter gene CVMNK and P. falciparum multidrug resistance gene NFD increased from 24.3% (2009) to 45.3% in (2010, P = 0.017). The rapid changes observed may largely be caused by decreased use of CQ and large-scale use of AL. In the absence of a clear AL-resistance marker and the (almost) continent-wide use of AL in sub-Saharan Africa, and when considering CQ reintroduction, continued monitoring of these markers is needed. PMID:23382159

  9. Defining Plasmodium falciparum Treatment in South West Asia: A Randomized Trial Comparing Artesunate or Primaquine Combined with Chloroquine or SP

    PubMed Central

    Kolaczinski, Kate; Leslie, Toby; Ali, Iftikhar; Durrani, Naeem; Lee, Sue; Barends, Marion; Beshir, Khalid; Ord, Rosalynn; Hallett, Rachel; Rowland, Mark

    2012-01-01

    Introduction Antimalarial resistance has led to a global policy of artemisinin-based combination therapy. Despite growing resistance chloroquine (CQ) remained until recently the official first-line treatment for falciparum malaria in Pakistan, with sulfadoxine-pyrimethamine (SP) second-line. Co-treatment with the gametocytocidal primaquine (PQ) is recommended for transmission control in South Asia. The relative effect of artesunate (AS) or primaquine, as partner drugs, on clinical outcomes and gametocyte carriage in this setting were unknown. Methods A single-blinded, randomized trial among Afghan refugees in Pakistan compared six treatment arms: CQ; CQ+(single-dose)PQ; CQ+(3 d)AS; SP; SP+(single-dose)PQ, and SP+(3 d)AS. The objectives were to compare treatment failure rates and effect on gametocyte carriage, of CQ or SP monotherapy against the respective combinations (PQ or AS). Outcomes included trophozoite and gametocyte clearance (read by light microscopy), and clinical and parasitological failure. Findings A total of 308 (87%) patients completed the trial. Failure rates by day 28 were: CQ 55/68 (81%); CQ+AS 19/67 (28%), SP 4/41 (9.8%), SP+AS 1/41 (2.4%). The addition of PQ to CQ or SP did not affect failure rates (CQ+PQ 49/67 (73%) failed; SP+PQ 5/33 (16%) failed). AS was superior to PQ at clearing gametocytes; gametocytes were seen on d7 in 85% of CQ, 40% of CQ+PQ, 21% of CQ+AS, 91% of SP, 76% of SP+PQ and 23% of SP+AS treated patients. PQ was more effective at clearing older gametocyte infections whereas AS was more effective at preventing emergence of mature gametocytes, except in cases that recrudesced. Conclusions CQ is no longer appropriate by itself or in combination. These findings influenced the replacement of CQ with SP+AS for first-line treatment of uncomplicated falciparum malaria in the WHO Eastern Mediterranean Region. The threat of SP resistance remains as SP monotherapy is still common. Three day AS was superior to single-dose PQ for reducing

  10. Inhibition of the peroxidative degradation of haem as the basis of action of chloroquine and other quinoline antimalarials.

    PubMed Central

    Loria, P; Miller, S; Foley, M; Tilley, L

    1999-01-01

    The malaria parasite feeds by degrading haemoglobin in an acidic food vacuole, producing free haem moieties as a by-product. The haem in oxyhaemoglobin is oxidized from the Fe(II) state to the Fe(III) state with the consequent production of an equimolar concentration of H2O2. We have analysed the fate of haem molecules in Plasmodium falciparum-infected erythrocytes and have found that only about one third of the haem is polymerized to form haemozoin. The remainder appears to be degraded by a non-enzymic process which leads to an accumulation of iron in the parasite. A possible route for degradation of the haem is by reacting with H2O2, and we show that, under conditions designed to resemble those found in the food vacuole, i.e., at pH5.2 in the presence of protein, free haem undergoes rapid peroxidative decomposition. Chloroquine and quinacrine are shown to be efficient inhibitors of the peroxidative destruction of haem, while epiquinine, a quinoline compound with very low antimalarial activity, has little inhibitory effect. We also show that chloroquine enhances the association of haem with membranes, while epiquinine inhibits this association, and that treatment of parasitized erythrocytes with chloroquine leads to a build-up of membrane-associated haem in the parasite. We suggest that chloroquine exerts its antimalarial activity by causing a build-up of toxic membrane-associated haem molecules that eventually destroy the integrity of the malaria parasite. We have further shown that resistance-modulating compounds, such as chlorpromazine, interact with haem and efficiently inhibit its degradation. This may explain the weak antimalarial activities of these compounds. PMID:10191268

  11. A Translational Approach to Validate in Vivo Anti-tumor Effects of Chloroquine on Breast Cancer Risk

    DTIC Science & Technology

    2014-05-01

    comply with a collection of information if it does not display a currently valid OMB control number. PLEASE DO NOT RETURN YOUR FORM TO THE ABOVE... genetically programmed rats by 37%. METHODS & SCOPE: About 65% of Peace Corps volunteers received chloroquine prophylactically between 1965 and 1990...patent anti-malarial drug with a 60-year history of use by millions, reduces the incidence of breast cancer in genetically programmed rats by 37

  12. Molecular Mechanisms for Drug Hypersensitivity Induced by the Malaria Parasite’s Chloroquine Resistance Transporter

    PubMed Central

    Baker, Eileen S.; Webster, Michael W.; Lehane, Adele M.; Shafik, Sarah H.; Martin, Rowena E.

    2016-01-01

    Mutations in the Plasmodium falciparum ‘chloroquine resistance transporter’ (PfCRT) confer resistance to chloroquine (CQ) and related antimalarials by enabling the protein to transport these drugs away from their targets within the parasite’s digestive vacuole (DV). However, CQ resistance-conferring isoforms of PfCRT (PfCRTCQR) also render the parasite hypersensitive to a subset of structurally-diverse pharmacons. Moreover, mutations in PfCRTCQR that suppress the parasite’s hypersensitivity to these molecules simultaneously reinstate its sensitivity to CQ and related drugs. We sought to understand these phenomena by characterizing the functions of PfCRTCQR isoforms that cause the parasite to become hypersensitive to the antimalarial quinine or the antiviral amantadine. We achieved this by measuring the abilities of these proteins to transport CQ, quinine, and amantadine when expressed in Xenopus oocytes and complemented this work with assays that detect the drug transport activity of PfCRT in its native environment within the parasite. Here we describe two mechanistic explanations for PfCRT-induced drug hypersensitivity. First, we show that quinine, which normally accumulates inside the DV and therewithin exerts its antimalarial effect, binds extremely tightly to the substrate-binding site of certain isoforms of PfCRTCQR. By doing so it likely blocks the normal physiological function of the protein, which is essential for the parasite’s survival, and the drug thereby gains an additional killing effect. In the second scenario, we show that although amantadine also sequesters within the DV, the parasite’s hypersensitivity to this drug arises from the PfCRTCQR-mediated transport of amantadine from the DV into the cytosol, where it can better access its antimalarial target. In both cases, the mutations that suppress hypersensitivity also abrogate the ability of PfCRTCQR to transport CQ, thus explaining why rescue from hypersensitivity restores the parasite

  13. Comparative efficacy and safety of chloroquine and alternative antimalarial drugs: a meta-analysis from six African countries.

    PubMed

    Mengesha, T; Makonnen, E

    1999-06-01

    A meta-analysis study evaluating the efficacy and safety of chloroquine and alternative antimalarial drugs used in six African countries including Ethiopia, Kenya, Uganda, Cote D'Ivoire, Gambia and Nigeria is presented. Findings from the six countries showed a higher efficacy of amodiaquine and quinine (over 90%) in malaria treatment compared to chloroquine, which was found to be 70% or more effective. The efficacy of amodiaquine can also be compared to other antimalarial drugs such as mefloquine and halofantrine. Data showed that fever clearance time of these drugs was less than 2 days, but parasite clearance time ranged from 2.5 days to 1 week. Recrudescence rate also varied among the different drugs. This is a very important indicator in determining which drug can be used for prophylactic or suppressive treatment of malaria. Pharmacokinetic profile demonstrates that all these drugs have similar therapeutic effects, but differ in their adverse reactions, contraindications, and half-life. A significant difference was also noted in the cost of these antimalarial drugs; chloroquine was the cheapest, while halofantrine was the most expensive among the drugs. Based on these results, the study recommends that different aspects of antimalarial drugs have to be considered before deciding which drug is the best alternative treatment.

  14. Neuronal Analogues of Conditioning Paradigms

    DTIC Science & Technology

    1984-04-24

    Although the mechanisms of interneuronal communication have been well established, the changes underlying most forms of learning have thus far eluded...stimulating electrodes on one of the connectives was adjusted so as to produce a small excitatory postsynaptic potential ( EPSP ) in the impaled cell...two stimuli would constitute a neuronal analogue of conditioning by producing an increased EPSP in response to the test stimulus alone. If so, then

  15. Substrate analogues for isoprenoid enzymes

    SciTech Connect

    Stremler, K.E.

    1987-01-01

    Diphosphonate analogues of geranyl diphosphate, resistant to degradation by phosphatases, were found to be alternate substrates for the reaction with farnesyl diphosphate synthetase isolated from avian liver. The difluoromethane analogue was shown to be the better alternate substrate, in agreement with solvolysis results which indicate that the electronegativity of the difluoromethylene unit more closely approximates that of the normal bridging oxygen. The usefulness of the C/sub 10/ difluoro analogue, for detecting low levels of isoprenoid enzymes in the presence of high levels of phosphatase activity, was demonstrated with a cell-free preparation from lemon peel. A series of C/sub 5/ through C/sub 15/ homoallylic and allylic diphosphonates, as well as two 5'-nucleotide diphosphonates, was prepared in high overall yield using the activation-displacement sequence. Radiolabeled samples of several of the allylic diphosphonates were prepared with tritium located at C1. A series of geraniols, stereospecifically deuterated at C1, was prepared. The enantiomeric purities and absolute configurations were determined by derivatization as the mandelate esters for analysis by /sup 1/H NMR. The stereochemistry of the activation-displacement sequence was examined using C1-deuterated substrates.

  16. Antiviral Activity of Chloroquine Against Dengue Virus Type 2 Replication in Aotus Monkeys

    PubMed Central

    Machado, Paula Renata Lima; Muniz, José Augusto Pereira Carneiro; Imbeloni, Aline Amaral; da Fonseca, Benedito Antônio Lopes

    2015-01-01

    Abstract Dengue virus (DENV) of the Flaviviridae family is a single positive-stranded RNA virus that is transmitted by Aedes aegypti and Aedes albopictus mosquitoes. The objective of this study was to investigate the use of chloroquine (CLQ) as an antiviral drug against dengue virus in monkeys. To analyze the action of the drug in vivo, nonhuman primates groups (Aotus azarai infulatus) were inoculated with a subcutaneous injection of a virulent strain of DENV-2, treated and untreated CLQ. Blood hematological, viremia, and serum biochemical values were obtained from 16 DENV-2-inoculated, treated and untreated; four received only CLQ and one mock-infected Aotus monkeys. Monkey serum samples (day 0–10 post-inoculation) were assayed by reverse transcription polymerase chain reaction and Cytometric Bead Array for determination of viremia and inflammatory cytokines, respectively. Additionally, body temperature and activity levels were determined. In the present work, CLQ was effective on replication of DENV-2 in Aotus monkeys; a time viremia reduction was observed compared with the controls. The concentration of tumor necrosis factor alpha and interferon gamma in the serum of the animals had a statistically significant reduction in the groups treated with CLQ after infection compared with the controls. A significant decrease in systemic levels of the liver enzyme aspartate aminotransferase (AST) was also observed in the animals treated with CLQ after infection compared with the controls. These results suggest that CLQ interferes in DENV-2 replication in Aotus monkeys. PMID:25664975

  17. A Whole Cell Pathway Screen Reveals Seven Novel Chemosensitizers to Combat Chloroquine Resistant Malaria

    PubMed Central

    Ch'ng, Jun-Hong; Mok, Sachel; Bozdech, Zbynek; Lear, Martin James; Boudhar, Aicha; Russell, Bruce; Nosten, Francois; Tan, Kevin Shyong-Wei

    2013-01-01

    Due to the widespread prevalence of resistant parasites, chloroquine (CQ) was removed from front-line antimalarial chemotherapy in the 1990s despite its initial promise of disease eradication. Since then, resistance-conferring mutations have been identified in transporters such as the PfCRT, that allow for the efflux of CQ from its primary site of action, the parasite digestive vacuole. Chemosensitizing/chemoreversing compounds interfere with the function of these transporters thereby sensitizing parasites to CQ once again. However, compounds identified thus far have disappointing in vivo efficacy and screening for alternative candidates is required to revive this strategy. In this study, we propose a simple and direct means to rapidly screen for such compounds using a fluorescent-tagged CQ molecule. When this screen was applied to a small library, seven novel chemosensitizers (octoclothepin, methiothepin, metergoline, loperamide, chlorprothixene, L-703,606 and mibefradil) were quickly elucidated, including two which showed greater potency than the classical chemosensitizers verapamil and desipramine. PMID:23615863

  18. Evaluation of starches obtained from four Dioscorea species as binding agent in chloroquine phosphate tablet formulations

    PubMed Central

    Okunlola, Adenike; Odeku, Oluwatoyin A.

    2011-01-01

    Starches obtained from four Dioscorea species namely Dioscorea dumetorum (Bitter), Dioscorea oppositifolia (Chinese), Dioscorea alata (Water), and Dioscorea rotundata (White) have been evaluated as binding agents in chloroquine phosphate tablet formulations in comparison with official corn starch. The compressional properties of the formulations were analyzed using density measurements and the Heckel and Kawakita equations. The mechanical properties of the tablets were assessed using tensile strength, brittle fracture index (BFI), and friability tests while the drug release properties of the tablets were assessed using disintegration and dissolution times. The results indicate that the four starches vary considerably in their physicochemical properties. The ranking for the tensile strength and the disintegration and dissolution times for the formulations was Chinese > Bitter > Corn > White > Water while the ranking was reversed for BFI and friability. The results suggest that Water, White, and Corn could be useful when faster disintegration time of tablets is desired while Chinese and Bitter could be more useful when bond strength is of concern and in minimizing the problems of lamination and capping in tablet formulation. PMID:23960747

  19. Chloroquine and Hydroxychloroquine Are Novel Inhibitors of Human Organic Anion Transporting Polypeptide 1A2.

    PubMed

    Xu, Chenghao; Zhu, Ling; Chan, Ting; Lu, Xiaoxi; Shen, Weiyong; Madigan, Michele C; Gillies, Mark C; Zhou, Fanfan

    2016-02-01

    Chloroquine (CQ) and hydroxychloroquine (HCQ) are widely used to treat malaria and inflammatory diseases, long-term usage of which often causes severe side effects, especially retinopathy. Solute carrier transporters (SLCs) are important proteins responsible for the cellular uptake of endogenous and exogenous substances. Inhibitors competing with transporter substrates for SLCs often results in unfavorable toxicities and unsatisfactory therapeutic outcomes. We investigated the inhibitory effect of CQ and HCQ on substrate uptake mediated through a range of important SLC transporters in overexpressing human embryonic kidney (HEK293) cells. Our data revealed that both CQ and HCQ potently inhibit the uptake activity of organic anion transporting polypeptide 1A2 (OATP1A2). We recently reported OATP1A2 to be expressed in human retinal pigment epithelium (RPE), where it mediates cellular uptake of all-trans-retinol (atROL), a key step in the classical visual cycle. In this study, we demonstrate that CQ and HCQ could markedly impair atROL uptake in OATP1A2-expressing HEK293 cells and more importantly, in primary human RPE cells. Our study shows that CQ and HCQ are novel inhibitors of OATP1A2 and significantly impair OATP1A2-mediated substrate uptake, particularly transport of atROL into the RPE. This effect may compromise the function of the classic visual cycle leading to vision impairment and contribute to the retinopathy observed clinically in patients using CQ or HCQ.

  20. [Current view on chloroquine derivative treatment from rheumatologist perspective and possible ocular side effects].

    PubMed

    Pawlak-Buś, Katarzyna; Gaca-Wysocka, Magdalena; Grzybowski, Andrzej; Leszczyński, Piotr

    2016-03-01

    Anti-malarial drugs specifically hydroxychloroquine (HCQ) or chloroquine (CQ) are very effective in treating and preventing the symptoms of systemic lupus erythematosus and other connective tissue diseases. These medications have shown to improve joint and muscle pain and arthritis, skin rashes, fatique, fever and also to control systemic signs of lupus as pericarditis or pleuritis. Shortterm and long-term treatment reduce cholesterol and have anti-platelet effect with decreasing risk of cardiovascular disease. The lupus patients on anti-malarials have also lower risk of cumulative organ damage due to reduce the amount of steroids. They may help to decrease lupus flares, mortality and are the key to controlling lupus long term outcome. Some lupus patients should be on anti-malarials for the rest of their life. For this reason, the key question is weather these drugs are absolutely safe and can be long term used in all lupus patients as a background therapy? Potential non-specific side effects occur very rare and are usually minor and last for short period. The major concerns are retinal deposits damage which could be potential reversible especially during hydroxychloroquine treatment. Nevertheless, ophthalmologist examination is still needed before starting to take HCQ or CQ and at to follow-up visits every 6-12 months. In conclusion it seems that anti-malarials are safe and have more clinical benefits than risks and from rheumatologist point of view should be more widely use in all lupus patients.

  1. Synthesis, Antiplasmodial Activity, and β-Hematin Inhibition of Hydroxypyridone–Chloroquine Hybrids

    PubMed Central

    2013-01-01

    A series of noncytotoxic 4-aminoquinoline-3-hydroxypyridin-4-one hybrids were synthesized on the basis of a synergistic in vitro combination of a precursor N-alkyl-3-hydroxypyridin-4-one with chloroquine (CQ) and tested in vitro against CQ resistant (K1 and W2) and sensitive (3D7) strains of Plasmodium falciparum. In vitro antiplasmodial activity of the precursors was negated by blocking the chelator moiety via complexation with gallium(III) or benzyl protection. None of the precursors inhibited β-hematin formation. Most hybrids were more potent inhibitors of β-hematin formation than CQ, and a correlation between antiplasmodial activity and inhibition of β-hematin formation was observed. Potent hybrids against K1, 3D7, and W2, respectively, were 8c (0.13, 0.004, and 0.1 μM); 8d (0.08, 0.01, and 0.02 μM); and 7g (0.07, 0.03, and 0.08 μM). PMID:24900724

  2. The Potential of β Carbolin Alkaloids to Hinder Growth and Reverse Chloroquine Resistance in Plasmodium falciparum

    PubMed Central

    IBRAHEEM, Zaid O; ABDUL MAJID, Roslaini; MOHD NOOR, Sabariah; MOHD SIDEK, Hasidah; BASIR, Rusliza

    2015-01-01

    Background: Nowadays, scourge of malaria as a fatalistic disease has increased due to emergence of drug resistance and tolerance among different strains of Plasmodium falciparum. Emergence of chloroquine (CQ) resistance has worsened the calamity as CQ is still considered the most efficient, safe and cost effective drug among other antimalarials. This urged the scientists to search for other alternatives or sensitizers that may be able to augment CQ action and reverse its resistance. Method: Three β-carbolin derivatives, namely, harmalin, harmol and harmalol were tested for their anti-plasmodial and CQ resistance reversal effects against P. falciparum 3D7 and K1. SYBRE Green-1 based drug sensitivity assay and isobologram analysis were used to screen the mentioned effects respectively. Results: All of them showed moderate anti-plasmodium effect and harmalin was the most effective as compared to the others in reversing CQ resistance and tolerance. Conclusion: The mentioned phytochemicals are not ideal to be used as conventional antimalarials and only harmalin can be suggested to reverse CQ resistance in P. falciparum K1. PMID:26811724

  3. Adverse Reactions to Chloroquine and Amodiaquine as Used for Malaria Prophylaxis: A Review of the Literature

    PubMed Central

    Wittes, Robert

    1987-01-01

    This paper reviews the published material on adverse reactions to chloroquine (CQ) and amodiaquine (ADQ) as used for anti-malarial chemophrophylaxis. Dermatologic reactions, including pruritus and photosensitivity, appear to be rather common. Ophthalmologic reactions include difficulty in visual accommodation, corneal deposits, and retinopathy, the last a serious condition that is reversible in its early stage by drug withdrawal, and that generally will not occur with less than four years of weekly CQ use. Neuromyopathy is a rare and serious reaction that may develop idiosyncratically after a small cumulative dose; it, too, is reversible by drug withdrawal. Seizures, syndromes of involuntary movements, psychosis, and ototoxicity have been reported occasionally. Fatal toxic overdoses may occur, especially following accidental ingestion by children. ADQ should not be used for anti-malarial prophylaxis because of associated agranulocytosis. Rabies vaccine given intradermally is less effective for pre-exposure prophylaxis while the patient is taking CQ. Care should be taken when prescribing prophylactic CQ to patients with heart block. In spite of its adverse effects, however, CQ is generally an extremely safe drug. Cq prophylaxis is recommended for pregnant women in CQ-sensitive malarial areas. PMID:21264010

  4. Screening for chloroquine maculopathy in populations with uncertain reliability in outcomes of automatic visual field testing

    PubMed Central

    Kunavisarut, Paradee; Chavengsaksongkram, Pimploy; Rothova, Aniki; Pathanapitoon, Kessara

    2016-01-01

    Purpose: The purpose of this study was to compare screening methods for the early detection of maculopathy in patients treated with chloroquine (CQ) or hydroxychloroquine (HCQ) and to identify the risk factors for the development of toxic maculopathy. Methods: We performed a prospective study of all 217 patients taking CQ and/or HCQ and seen in our center between July 2011 and December 2013. All subjects underwent a complete ocular examination, as well as spectral domain optical coherence tomography (SD-OCT), fundus autofluorescence (FAF), and 10-2 Humphrey visual field (10-2 HVF). Results: The median age of patients was 51 years, median CQ/HCQ duration was 40 months, and median cumulative dose was 180 g. The prevalence of at least two abnormal tests was 7.4% (16/217). SD-OCT had the highest sensitivity, specificity, predictive values and accuracy while 10-2 HVF showed in 30% of nonreliable results and had the lowest specificity and positive predictive value. In multivariate analysis, an age of older than 60 years (P = 0.002), CQ duration of more than 5 years (P < 0.001), and CQ dose more than 3 mg/kg/day (P = 0.005) were associated with toxicity. Conclusions: In patients with unreliable outcomes of 10-2 HVF testing, SD-OCT in combination with FAF might represent a suitable alternative screening tool for toxic maculopathy. PMID:27905330

  5. Degrees of chloroquine resistance in Plasmodium – Is the redox system involved?

    PubMed Central

    Lehane, Adele M.; McDevitt, Christopher A.; Kirk, Kiaran; Fidock, David A.

    2011-01-01

    Chloroquine (CQ) was once a very effective antimalarial drug that, at its peak, was consumed in the hundreds of millions of doses per year. The drug acts against the Plasmodium parasite during the asexual intra-erythrocytic phase of its lifecycle. Unfortunately, clinical resistance to this drug is now widespread. Questions remain about precisely how CQ kills malaria parasites, and by what means some CQ-resistant (CQR) parasites can withstand much higher concentrations of the drug than others that also fall in the CQR category. In this review we investigate the evidence for and against the proposal that CQ kills parasites by generating oxidative stress. Further, we examine a long-held idea that the glutathione system of malaria parasites plays a role in CQ resistance. We conclude that there is strong evidence that glutathione levels modulate CQ response in the rodent malaria species Plasmodium berghei, but that a role for redox in contributing to the degree of CQ resistance in species infectious to humans has not been firmly established. PMID:22773965

  6. Chloroquine-induced inhibition of the production of TNF, but not of IL-6, is affected by disruption of iron metabolism.

    PubMed Central

    Picot, S; Peyron, F; Donadille, A; Vuillez, J P; Barbe, G; Ambroise-Thomas, P

    1993-01-01

    There is now considerable evidence that cerebral malaria may be related to the over-production of tumour necrosis factor (TNF). Nevertheless, our knowledge is very poor concerning the biological events which lead up to this TNF over-production. Furthermore, interleukin-6 (IL-6) is produced in large amounts during malaria infection and seems to have inhibitory action on TNF production. Anti-malarial drugs were investigated for their ability to interfere with TNF and IL-6 secretion by human non-immune macrophages stimulated by lipopolysaccharides (LPS) or Plasmodium falciparum culture supernatant. Macrophages were pretreated with chloroquine, quinine, proguanil, mefloquine or halofantrine before stimulation. TNF and IL-6 production were suppressed in a dose-dependent manner when macrophages were treated with chloroquine, but not with other anti-malarial drugs. Considering that chloroquine probably acts via lysosomotropic mechanisms, and that iron metabolism may interfere with the non-specific immune response, we focused our attention on these biochemical events in order to investigate the mechanisms by which chloroquine inhibits cytokine production. Our results demonstrated that chloroquine-induced inhibition of TNF and IL-6 production is not mediated through a lysosomotropic mechanism, and that chloroquine probably acts on TNF secretion by disrupting iron homeostasis. Inhibition of IL-6 production seems not to be mediated through these pathways. These observations suggest that chloroquine may help to prevent cerebral malaria whatever the drug sensitivity of the parasite strain, and may provide new tools for an anti-disease therapy regardless of the emergence of parasite multi-drug resistance. PMID:8244453

  7. Space Analogue Environments: Are the Populations Comparable?

    NASA Astrophysics Data System (ADS)

    Sandal, G. M.

    Background: Much of our present understanding about psychology in space is based on studies of groups operating in so-called analogue environments where personnel are exposed to many of the same stressors as those experienced by astronauts in space. One possible problem with extrapolating results is that personnel operating in various hazardous and confined environments might differ in characteristics influencing coping, interaction, and performance. The object of this study was to compare the psychological similarity of these populations in order to get a better understanding of whether this extrapolation is justifiable. The samples investigated include polar crossings (N= 22), personnel on Antarctic research stations (N= 183), several military occupations (N= 187), and participants in space simulation studies (N=20). Methods: Personnel in each of these environments were assessed using the Personality Characteristic Inventory (PCI) and Utrecht Coping List (UCL). The PCI is a multidimensional trait assessment battery that measures various aspects of achievement orientation and social competence. The UCL is a questionnaire designed to assess habitual coping strategies when encountering stressful or demanding situations. Results: Only minor differences in use of habitual coping strategies were evident across the different samples. In relation to personality scores, the military subjects and participants in space simulation studies indicated higher competitiveness and negative instrumentality compared to both the personnel on Antarctic research stations and participants in polar expedition. Among the personnel on Antarctic research stations, significant gender differences were found with women scoring lower on competitiveness, negative instrumentality and impatience/irritability. Compared to the other samples, the participants in polar expeditions were found to be more homogeneous in personality and no significant gender differences were evident on the traits that

  8. Current european regulatory perspectives on insulin analogues

    PubMed Central

    2011-01-01

    Insulin analogues are increasingly considered as an alternative to human insulin in the therapy of diabetes mellitus. Insulin analogues (IAs) are chemically different from human insulin and may have different pharmacokinetic or pharmacodynamic properties. The significance of the modifications of the insulin molecule for the safety profile of IAs must be considered. This review describes the regulatory procedure and the expectations for the scientific content of European marketing authorization applications for innovative IAs submitted to the European Medicines Agency. Particular consideration is given to a potential cancer hazard. Specific regulatory guidance on how to address a possible carcinogenic or tumor promoting effect of innovative IAs in non-clinical studies is available. After marketing authorization, the factual access of patients to the new product will be determined to great extent by health technology assessment bodies, reimbursement decisions and the price. Whereas the marketing authorization is a European decision, pricing and reimbursement are national or regional responsibilities. The assessment of benefit and risk by the European Medicines Agency is expected to influence future decisions on price and reimbursement on a national or regional level. Collaborations between regulatory agencies and health technology assessment bodies have been initiated on European and national level to facilitate the use of the European Medicines Agency's benefit risk assessment as basis on which to build the subsequent health technology assessment. The option for combined or joint scientific advice procedures with regulators and health technology assessment bodies on European level or on a national level in several European Member States may help applicants to optimize their development program and dossier preparation in regard of both European marketing authorization application and reimbursement decisions. PMID:21736748

  9. Ecstasy analogues found in cacti.

    PubMed

    Bruhn, Jan G; El-Seedi, Hesham R; Stephanson, Nikolai; Beck, Olof; Shulgin, Alexander T

    2008-06-01

    Human interest in psychoactive phenethylamines is known from the use of mescaline-containing cacti and designer drugs such as Ecstasy. From the alkaloid composition of cacti we hypothesized that substances resembling Ecstasy might occur naturally. In this article we show that lophophine, homopiperonylamine and lobivine are new minor constituents of two cactus species, Lophophora williamsii (peyote) and Trichocereus pachanoi (San Pedro). This is the first report of putatively psychoactive phenethylamines besides mescaline in these cacti. A search for further biosynthetic analogues may provide new insights into the structure-activity relationships of mescaline. An intriguing question is whether the new natural compounds can be called "designer drugs."

  10. FUNCTION GENERATOR FOR ANALOGUE COMPUTERS

    DOEpatents

    Skramstad, H.K.; Wright, J.H.; Taback, L.

    1961-12-12

    An improved analogue computer is designed which can be used to determine the final ground position of radioactive fallout particles in an atomic cloud. The computer determines the fallout pattern on the basis of known wind velocity and direction at various altitudes, and intensity of radioactivity in the mushroom cloud as a function of particle size and initial height in the cloud. The output is then displayed on a cathode-ray tube so that the average or total luminance of the tube screen at any point represents the intensity of radioactive fallout at the geographical location represented by that point. (AEC)

  11. Template polymerization of nucleotide analogues

    NASA Technical Reports Server (NTRS)

    Orgel, L. E.

    1991-01-01

    Recent work on the template-directed reactions of the natural D-nucleotides has made it clear that l-nucleotides and nucleotide-like derivatives of other sugars would strongly inhibit the formation of long oligonucleotides. Consequently, attention is focusing on molecules simpler than nucleotides that might have acted as monomers of an information transfer system. We have begun a general exploration of the template directed reactions of diverse peptide analogues. I will present work by Dr. Taifeng Wu on oxidative oligomerization of phosphorothioates and of Dr. Mary Tohidi on the cyclic polymerization of nucleoside and related cyclic pyrophosphates.

  12. Choline Analogues in Malaria Chemotherapy

    PubMed Central

    Peyrottes, Suzanne; Caldarelli, Sergio; Wein, Sharon; Périgaud, Christian; Pellet, Alain; Vial, Henri

    2012-01-01

    Emerging resistance against well-established anti-malaria drugs warrants the introduction of new therapeutic agents with original mechanisms of action. Inhibition of membrane-based phospholipid biosynthesis, which is crucial for the parasite, has thus been proposed as a novel and promising therapeutic strategy. This review compiles literature concerning the design and study of choline analogues and related cation derivatives as potential anti-malarials. It covers advances achieved over the last two decades and describes: the concept validation, the design and selection of a clinical candidate (Albitiazolium), back-up derivatives while also providing insight into the development of prodrug approaches. PMID:22607139

  13. Autophagy is dispensable for Kmt2a/Mll-Mllt3/Af9 AML maintenance and anti-leukemic effect of chloroquine.

    PubMed

    Chen, Xiaoyi; Clark, Jason; Wunderlich, Mark; Fan, Cuiqing; Davis, Ashley; Chen, Song; Guan, Jun-Lin; Mulloy, James C; Kumar, Ashish; Zheng, Yi

    2017-02-15

    Recently, macroautophagy/autophagy has emerged as a promising target in various types of solid tumor treatment. However, the impact of autophagy on acute myeloid leukemia (AML) maintenance and the validity of autophagy as a viable target in AML therapy remain unclear. Here we show that Kmt2a/Mll-Mllt3/Af9 AML (MA9-AML) cells have high autophagy flux compared with normal bone marrow cells, but autophagy-specific targeting, either through Rb1cc1-disruption to abolish autophagy initiation, or via Atg5-disruption to prevent phagophore (the autophagosome precursor) membrane elongation, does not affect the growth or survival of MA9-AML cells, either in vitro or in vivo. Mechanistically, neither Atg5 nor Rb1cc1 disruption impairs endolysosome formation or survival signaling pathways. The autophagy inhibitor chloroquine shows autophagy-independent anti-leukemic effects in vitro but has no efficacy in vivo likely due to limited achievable drug efficacy in blood. Further, vesicular exocytosis appears to mediate chloroquine resistance in AML cells, and exocytotic inhibition significantly enhances the anti-leukemic effect of chloroquine. Thus, chloroquine can induce leukemia cell death in vitro in an autophagy-independent manner but with inadequate efficacy in vivo, and vesicular exocytosis is a possible mechanism of chloroquine resistance in MA9-AML. This study also reveals that autophagy-specific targeting is unlikely to benefit MA9-AML therapy.

  14. Chloroquine inhibits Rhodococcus equi replication in murine and foal alveolar macrophages by iron-starvation.

    PubMed

    Gressler, Leticia T; Bordin, Angela I; McQueen, Cole M; Cohen, Noah D; de Vargas, Agueda Castagna

    2016-05-30

    Rhodococcus equi preferentially infects macrophages causing pyogranulomatous pneumonia in young foals. Both the vapA and rhbC genes are up-regulated in an iron (Fe)-deprived environment, such as that found within macrophages. Chloroquine (CQ) is a drug widely used against malaria that suppresses the intracellular availability of Fe in eukaryotic cells. The main objective of this study was to evaluate the ability of CQ to inhibit replication of virulent R. equi within murine (J774A.1) and foal alveolar macrophages (AMs) and to verify whether the mechanism of inhibition could be Fe-deprivation-dependent. CQ effect on R. equi extracellular survival and toxicity to J774A.1 were evaluated. R. equi survival within J774A.1 and foal AMs was evaluated under CQ (10 and 20μM), bovine saturated transferrin (bHTF), and bovine unsaturated transferrin (bATF) exposure. To explore the action mechanism of CQ, the superoxide anion production, the lysozyme activity, as well as the relative mRNA expression of vapA and rhbC were examined. CQ at≤20μM had no effect on R. equi extracellular multiplication and J774A.1 viability. Exposure to CQ significantly and markedly reduced survival of R. equi within J774A.1 and foal AMs. Treatment with bHTF did not reverse CQ effect on R. equi. Exposure to CQ did not affected superoxide anion production or lysozyme activity, however vapA and rhbC expression was significantly increased. Our results reinforce the hypothesis that intracellular availability of Fe is required for R. equi survival, and our initial hypothesis that CQ can limit replication of R. equi in J774A.1 and foal AMs, most likely by Fe starvation.

  15. Chloroquine blocks the Kir4.1 channels by an open-pore blocking mechanism.

    PubMed

    Marmolejo-Murillo, Leticia G; Aréchiga-Figueroa, Iván A; Moreno-Galindo, Eloy G; Navarro-Polanco, Ricardo A; Rodríguez-Menchaca, Aldo A; Cui, Meng; Sánchez-Chapula, José A; Ferrer, Tania

    2017-04-05

    Kir4.1 channels have been implicated in various physiological processes, mainly in the K(+) homeostasis of the central nervous system and in the control of glial function and neuronal excitability. Even though, pharmacological research of these channels is very limited. Chloroquine (CQ) is an amino quinolone derivative known to inhibit Kir2.1 and Kir6.2 channels with different action mechanism and binding site. Here, we employed patch-clamp methods, mutagenesis analysis, and molecular modeling to characterize the molecular pharmacology of Kir4.1 inhibition by CQ. We found that this drug inhibits Kir4.1 channels heterologously expressed in HEK-293 cells. CQ produced a fast-onset voltage-dependent pore-blocking effect on these channels. In inside-out patches, CQ showed notable higher potency (IC50 ≈0.5μM at +50mV) and faster onset of block when compared to whole-cell configuration (IC50 ≈7μM at +60mV). Also, CQ showed a voltage-dependent unblock with repolarization. These results suggest that the drug directly blocks Kir4.1 channels by a pore-plugging mechanism. Moreover, we found that two residues (Thr128 and Glu158), facing the central cavity and located within the transmembrane pore, are particularly important structural determinants of CQ block. This evidence was similar to what was previously reported with Kir6.2, but distinct from the interaction site (cytoplasmic pore) CQ-Kir2.1. Thus, our findings highlight the diversity of interaction sites and mechanisms that underlie amino quinolone inhibition of Kir channels.

  16. Chloroquine-induced autophagic vacuole accumulation and cell death in glioma cells is p53 independent

    PubMed Central

    Geng, Ying; Kohli, Latika; Klocke, Barbara J.; Roth, Kevin A.

    2010-01-01

    Glioblastoma (GBM) is a high-grade central nervous system malignancy and despite aggressive treatment strategies, GBM patients have a median survival time of just 1 year. Chloroquine (CQ), an antimalarial lysosomotropic agent, has been identified as a potential adjuvant in the treatment regimen of GBMs. However, the mechanism of CQ-induced tumor cell death is poorly defined. We and others have shown that CQ-mediated cell death may be p53-dependent and at least in part due to the intrinsic apoptotic death pathway. Here, we investigated the effects of CQ on 5 established human GBM lines, differing in their p53 gene status. CQ was found to induce a concentration-dependent death in each of these cell lines. Although CQ treatment increased caspase-3–like enzymatic activity in all 5 cell lines, a broad-spectrum caspase inhibitor did not significantly attenuate death. Moreover, CQ caused an accumulation of autophagic vacuoles in all cell lines and was found to affect the levels and subcellular distribution of cathepsin D, suggesting that altered lysosomal function may also play a role in CQ-induced cell death. Thus, CQ can induce p53-independent death in gliomas that do not require caspase-mediated apoptosis. To potentially identify more potent chemotherapeutics, various CQ derivatives and lysosomotropic compounds were tested on the GBM cells. Quinacrine and mefloquine were found to be more potent than CQ in killing GBM cells in vitro and given their superior blood–brain barrier penetration compared with CQ may prove more efficacious as chemotherapeutic agents for GBM patients. PMID:20406898

  17. Ursolic acid and resveratrol synergize with chloroquine to reduce melanoma cell viability.

    PubMed

    Junco, Jacob J; Mancha-Ramirez, Anna; Malik, Gunjan; Wei, Sung-Jen; Kim, Dae Joon; Liang, Huiyun; Slaga, Thomas J

    2015-04-01

    Malignant melanoma is associated with a 5-year survival rate of less than 20% once metastasized. Malignant melanoma cells exhibit increased levels of autophagy, a process of intracellular digestion that allows cells to survive various stresses including chemotherapies, resulting in reduced patient survival. Autophagy can be inhibited by chemicals like chloroquine (CQ), which prevents fusion of autophagosomes to lysosomes, resulting in autophagosome accumulation in most systems. Here, we describe how tested CQ to see whether it could sensitize B16F10 metastatic mouse melanoma cells to the anticancer activities of the natural compounds ursolic acid (UA) and resveratrol (RES). CQ with UA or RES strongly and synergistically reduced the viability of B16F10 mouse melanoma and A375 human melanoma cells. Surprisingly, flow cytometry of acridine orange-stained cells showed that UA or RES in combination with CQ significantly reduced autophagosome levels. Western blotting analysis revealed that CQ plus UA or RES paradoxically increased LC3II, indicative of autophagosome accumulation. In addition, CQ plus RES synergistically decreased the levels of both autophagy initiator beclin-1 and autophagy supporter p62. These results indicate that CQ with UA or RES strongly and synergistically reduces the viability of B16F10 and A375 melanoma cells. However, studies on B16F10 cells have shown that the synergistic effect was not mediated by inhibition of autophagy induced by UA or RES. These compounds are well-tolerated in humans, and CQ has shown promise as an adjuvant therapy. These combinations may be valuable treatment strategies for melanoma.

  18. Chloroquine enhances the efficacy of cisplatin by suppressing autophagy in human adrenocortical carcinoma treatment

    PubMed Central

    Qin, Liang; Xu, Tianyuan; Xia, Leilei; Wang, Xianjin; Zhang, Xiang; Zhang, Xiaohua; Zhu, Zhaowei; Zhong, Shan; Wang, Chuandong; Shen, Zhoujun

    2016-01-01

    Background It has been demonstrated that chloroquine (CQ) enhances the efficacy of chemotherapy. However, little is known about whether CQ could enhance the efficacy of cisplatin (DDP) in the treatment of adrenocortical carcinoma (ACC). In this study, we explore the efficacy and mechanism by which CQ affects DDP sensitivity in human ACC in vitro and in vivo. Methods The autophagic gene Beclin-1 expression was detected by immunohistochemistry, and the protein levels were analyzed using immunoblotting assays of ACC tissues and normal adrenal cortex tissues. The ACC SW13 cells were treated with DDP and/or CQ. The cell viability assay was performed using the MTT method. Qualitative autophagy detection was performed by monodansylcadaverine staining of autophagic vacuoles. Annexin V-fluorescein isothiocyanate/propidium iodide double staining was used to count cell apoptosis by flow cytometry. The autophagy-related protein (Beclin-1, LC3, and p62) and apoptosis relative protein (Bax and Bcl-2) levels were evaluated with Western blot analysis. Furthermore, a murine model of nude BALB/c mice bearing SW13 cell xenografts was established to evaluate the efficacy of concomitant therapy. Results The expression of the autophagic gene Beclin-1 was significantly downregulated in ACC tissues compared to normal adrenal cortex tissues. The Beclin-1 protein level in ACC tissues was lower than that in normal adrenal cortex tissues (P<0.05). In vitro concomitant therapy (DDP and CQ) was more effective in restraining SW13 cell proliferation. DDP could promote cell apoptosis and induce autophagy in SW13 cells. Concomitant therapy further promoted cell apoptosis by inhibiting autophagy. In vivo, we found that concomitant therapy was more potent than DDP monotherapy in inhibiting the growth of xenografted tumors and prolonging the survival of tumor-bearing mice. Conclusion The antitumor ability of DDP was related to autophagy activity, and the concomitant therapy (DDP and CQ) could be an

  19. Sulphamoylated 2-Methoxyestradiol Analogues Induce Apoptosis in Adenocarcinoma Cell Lines

    PubMed Central

    Visagie, Michelle; Theron, Anne; Mqoco, Thandi; Vieira, Warren; Prudent, Renaud; Martinez, Anne; Lafanechère, Laurence; Joubert, Annie

    2013-01-01

    2-Methoxyestradiol (2ME2) is a naturally occurring estradiol metabolite which possesses antiproliferative, antiangiogenic and antitumor properties. However, due to its limited biological accessibility, synthetic analogues have been synthesized and tested in attempt to develop drugs with improved oral bioavailability and efficacy. The aim of this study was to evaluate the antiproliferative effects of three novel in silico-designed sulphamoylated 2ME2 analogues on the HeLa cervical adenocarcinoma cell line and estrogen receptor-negative breast adenocarcinoma MDA-MB-231 cells. A dose-dependent study (0.1–25 μM) was conducted with an exposure time of 24 hours. Results obtained from crystal violet staining indicated that 0.5 μM of all 3 compounds reduced the number of cells to 50%. Lactate dehydrogenase assay was used to assess cytotoxicity, while the mitotracker mitochondrial assay and caspase-6 and -8 activity assays were used to investigate the possible occurrence of apoptosis. Tubulin polymerization assays were conducted to evaluate the influence of these sulphamoylated 2ME2 analogues on tubulin dynamics. Double immunofluorescence microscopy using labeled antibodies specific to tyrosinate and detyrosinated tubulin was conducted to assess the effect of the 2ME2 analogues on tubulin dynamics. An insignificant increase in the level of lactate dehydrogenase release was observed in the compounds-treated cells. These sulphamoylated compounds caused a reduction in mitochondrial membrane potential, cytochrome c release and caspase 3 activation indicating apoptosis induction by means of the intrinsic pathway in HeLa and MDA-MB-231 cells. Microtubule depolymerization was observed after exposure to these three sulphamoylated analogues. PMID:24039728

  20. Electrostatic evaluation of isosteric analogues

    NASA Astrophysics Data System (ADS)

    Sayle, Roger; Nicholls, Anthony

    2006-04-01

    A method is presented for enumerating a large number of isosteric analogues of a ligand from a known protein-ligand complex structure and then rapidly calculating an estimate of their binding energies. This approach takes full advantage of the observed crystal structure, by reusing the atomic co-ordinates determined experimentally for one ligand, to approximate those of similar compounds that have approximately the same shape. By assuming that compounds with similar shapes adopt similar binding poses, and that entropic and protein flexibility effects are approximately constant across such an isosteric series ("the frozen ligand approximation"), it is possible to order their binding affinities relatively accurately. Additionally, the constraint that the atomic coordinates are invariant allows for a dramatic simplification in the Poisson-Boltzmann method used to calculation the electrostatic component of the binding energy. This algorithmic improvement allows for the calculation of tens of thousands of binding energies per second for drug-like molecules, enabling this technique to be used in screening large virtual libraries of isosteric analogues. Most significantly, this procedure is shown to be able to reproduce SAR effects of subtle medicinal chemistry substitutions. Finally, this paper reports the results of the proposed methodology on␣seven model systems; dihydrofolate reductase, Lck␣kinase, ribosome inactivating protein, l-arabinose binding protein, neuraminidase, HIV-1 reverse transcriptase and COX-2.

  1. The Valles natural analogue project

    SciTech Connect

    Stockman, H.; Krumhansl, J.; Ho, C.; McConnell, V.

    1994-12-01

    The contact between an obsidian flow and a steep-walled tuff canyon was examined as an analogue for a highlevel waste repository. The analogue site is located in the Valles Caldera in New Mexico, where a massive obsidian flow filled a paleocanyon in the Battleship Rock tuff. The obsidian flow provided a heat source, analogous to waste panels or an igneous intrusion in a repository, and caused evaporation and migration of water. The tuff and obsidian samples were analyzed for major and trace elements and mineralogy by INAA, XRF, X-ray diffraction; and scanning electron microscopy and electron microprobe. Samples were also analyzed for D/H and {sup 39}Ar/{sup 4O} isotopic composition. Overall,the effects of the heating event seem to have been slight and limited to the tuff nearest the contact. There is some evidence of devitrification and migration of volatiles in the tuff within 10 meters of the contact, but variations in major and trace element chemistry are small and difficult to distinguish from the natural (pre-heating) variability of the rocks.

  2. Heteroatom-Containing Porphyrin Analogues.

    PubMed

    Chatterjee, Tamal; Shetti, Vijayendra S; Sharma, Ritambhara; Ravikanth, Mangalampalli

    2017-02-22

    The heteroatom-containing porphyrin analogues or core-modified porphyrins that resulted from the replacement of one or two pyrrole rings with other five-membered heterocycles such as furan, thiophene, selenophene, tellurophene, indene, phosphole, and silole are highly promising macrocycles and exhibit quite different physicochemical properties compared to regular azaporphyrins. The properties of heteroporphyrins depend on the nature and number of different heterocycle(s) present in place of pyrrole ring(s). The heteroporphyrins provide unique and unprecedented coordination environments for metals. Unlike regular porphyrins, the monoheteroporphyrins are known to stabilize metals in unusual oxidation states such as Cu and Ni in +1 oxidation states. The diheteroporphyrins, which are neutral macrocycles without ionizable protons, also showed interesting coordination chemistry. Thus, significant progress has been made in last few decades on core-modified porphyrins in terms of their synthesis, their use in building multiporphyrin arrays for light-harvesting applications, their use as ligands to form interesting metal complexes, and also their use for several other studies. The synthetic methods available in the literature allow one to prepare mono- and diheteroporphyrins and their functionalized derivatives, which were used extensively to prepare several covalent and noncovalent heteroporphyrin-based multiporphyrin arrays. The methods are also developed to synthesize different hetero analogues of porphyrin derivatives such as heterocorroles, heterochlorins, heterocarbaporphyrinoids, heteroatom-substituted confused porphyrins, and so on. This Review summarizes the key developments that have occurred in heteroporphyrin chemistry over the last four decades.

  3. Transition States and transition state analogue interactions with enzymes.

    PubMed

    Schramm, Vern L

    2015-04-21

    Enzymatic transition states have lifetimes of a few femtoseconds (fs). Computational analysis of enzyme motions leading to transition state formation suggests that local catalytic site motions on the fs time scale provide the mechanism to locate transition states. An experimental test of protein fs motion and its relation to transition state formation can be provided by isotopically heavy proteins. Heavy enzymes have predictable mass-altered bond vibration states without altered electrostatic properties, according to the Born-Oppenheimer approximation. On-enzyme chemistry is slowed in most heavy proteins, consistent with altered protein bond frequencies slowing the search for the transition state. In other heavy enzymes, structural changes involved in reactant binding and release are also influenced. Slow protein motions associated with substrate binding and catalytic site preorganization are essential to allow the subsequent fs motions to locate the transition state and to facilitate the efficient release of products. In the catalytically competent geometry, local groups move in stochastic atomic motion on the fs time scale, within transition state-accessible conformations created by slower protein motions. The fs time scale for the transition state motions does not permit thermodynamic equilibrium between the transition state and stable enzyme states. Isotopically heavy enzymes provide a diagnostic tool for fast coupled protein motions to transition state formation and mass-dependent conformational changes. The binding of transition state analogue inhibitors is the opposite in catalytic time scale to formation of the transition state but is related by similar geometries of the enzyme-transition state and enzyme-inhibitor interactions. While enzymatic transition states have lifetimes as short as 10(-15) s, transition state analogues can bind tightly to enzymes with release rates greater than 10(3) s. Tight-binding transition state analogues stabilize the rare but

  4. Survey of chloroquine-resistant mutations in the Plasmodium falciparum pfcrt and pfmdr-1 genes in Hadhramout, Yemen.

    PubMed

    Bamaga, Omar A A; Mahdy, Mohammed A K; Lim, Yvonne A L

    2015-09-01

    Malaria is still a major public health problem in Yemen. More than 95% of the malaria cases are due to Plasmodium ‎falciparum‎. Recently in Yemen, the antimalarial treatment policy was changed from chloroquine (CQ) to artemisinin combination therapy (ACTs). However, CQ is still available and prescribed in the Yemeni market. The persistence of CQ resistance will be prolonged if the shift to ACT and the simultaneous withdrawal of CQ are not rigorously implemented. The aim of the current survey is to detect chloroquine-resistant mutations in P. falciparum chloroquine-resistance transporter (pfcrt) and P. falciparum multi-drug resistance-1 (pfmdr1) genes. These data will be important for future monitoring and assessment of antimalarial drug policy in Yemen. Blood specimens were collected from 735 individuals from different districts of the Hadhramout province, Yemen by house-to-house visit. Mutation-specific nested polymerase chain reaction (PCR) and restriction fragment length polymorphism (PCR-RFLP) methods were used to investigate the mutations in the pfmdr1(codons 86 and 1246) and pfcrt (codons 76, 271, 326, 356 and 371) genes. The overall prevalence of pfcrt mutations at codons 76, 271, 326 and 371 were 50.4%, 58.7%, 54.3% and 44.9%, respectively. All isolates had wild-type pfcrt 356 allele. The majority of pfmdr1 86 alleles (83.3%) and all pfmdr1 1246 alleles were wild type. There was no association between pfcrt mutations and symptomatology, gender and age groups. In conclusion, point mutations in codons 76, 271, 326 and 371 of pfcrt of P. falciparum are high suggesting a sustained high CQ resistance even after 4 years of shifting to ACTs. These findings warrant complete withdrawal of CQ use from the Yemeni market for P. falciparum and careful usage of CQ for treating Plasmodium vivax.

  5. Quality of shrimp analogue product as affected by addition of modified potato starch.

    PubMed

    Remya, S; Basu, S; Venkateshwarlu, G; Mohan, C O

    2015-07-01

    The present study was aimed to investigate the effects of addition of modified potato starch on the biochemical and textural properties of shrimp analogue/imitation shrimp, a popular value-added product prepared from surimi. Three batches of shrimp analogues were prepared with 0 % (NPS), 50 % (CPS) and 100 % (MPS) of modified starch incorporation and various quality attributes were monitored at regular intervals during frozen storage (-20 °C). Loss of myofibrillar protein was least for the shrimp analogue sample added with 100 % modified potato starch. The expressible moisture content of MPS (2.48 %) was less affected by long term storage compared to CPS (3.38 %) and NPS (3.99 %). During extended low temperature storage, the textural quality of sea food analogue was highly influenced by the type of starch added to it. The percentage of modified potato starch added to shrimp analogue significantly (p ≤ 0.05) affected its hardness and fracturability. MPS samples did not show significant changes in hardness during storage as compared to other two samples. Springiness of shrimp analogue increased 2.57, 1.5 and 1.77 times with the storage period for samples with NPS, CPS and MPS, respectively. Addition of modified potato starch improved the sensory quality and textural properties of shrimp analogue and reduced the quality degradation during frozen storage as compared to NPS which contained only native potato starch.

  6. Effect of chloroquine and leupeptin on intracellular accumulation of amyloid-beta (A beta) 1-42 peptide in a murine N9 microglial cell line.

    PubMed

    Chu, T; Tran, T; Yang, F; Beech, W; Cole, G M; Frautschy, S A

    1998-10-09

    Murine N9 microglia accumulated A beta from media containing 0.67 microM A beta within 6 h. In N9 and in primary rat microglia, chloroquine, which disrupts lysosomal pH, increased A beta-induced accumulation of A beta, particularly A beta1-42. Leupeptin similarly enhanced A beta accumulation. The scavenger receptor antagonist fucoidan did not affect acute chloroquine-dependent A beta1-42 accumulation, demonstrating uptake of non-aggregated A beta. After prolonged incubations, chloroquine enhanced A beta multimer (8-12 kDa) accumulation, an effect inhibited by fucoidan. Disruptions of the lysosomal system enhance A beta and its multimer formation. Despite negligible effects of fucoidan on initial A beta uptake, chronic exposure inhibits multimer accumulation, demonstrating a role for scavenger receptor in multimer accumulation.

  7. Analysis of Chloroquine and Metabolites Directly from Whole-body Animal Tissue Sections by Liquid Extraction Surface Analysis (LESA) and Tandem Mass Spectrometry

    SciTech Connect

    Parson, Whitney B; Koeniger, Stormy L; Johnson, Robert W; Erickson, Jamie; Tian, Yu; Stedman, Christopher A.; Schwartz, Annette; Tarcsa, Edit; Cole, Roderic; Van Berkel, Gary J

    2012-01-01

    The rapid and direct analysis of the amount and spatial distribution of exogenous chloroquine and chloroquine metabolites from tissue sections by liquid extraction surface sampling analysis coupled with tandem mass spectrometry (LESA-MS) was demonstrated. LESA-MS results compared well with previously published chloroquine quantification data collected by organ excision, extraction and fluorescent detection. The ability to directly sample and analyze spatially-resolved exogenous molecules from tissue sections with minimal sample preparation and analytical method development has the potential to facilitate the assessment of target tissue penetration of pharmaceutical compounds, to establish pharmacokinetic/pharmacodynamic (PK/PD) relationships, and to complement established pharmacokinetic methods used in the drug discovery process during tissue distribution assessment.

  8. Insulin analogues may accelerate progression of diabetic retinopathy after impairment of inner blood-retinal barrier.

    PubMed

    Kaya, Abdullah; Kar, Taner; Aksoy, Yakup; Özalper, Veysel; Başbuğ, Barbaros

    2013-12-01

    pigment epitelium (RPE) and mullerian cells. Mullerian cells also support inner blood-retinal barrier. Insulin analogues may cause proliferation in glial cells and generate traction force in RPE and mullerian cells by stimulating IGF-1 receptor. These effects of analogues may increase after deterioration of inner blood-retinal barrier and cause structural changes in retinal tissue. Deterioration of cellular structure may contribute to impairment of inner blood-retinal barrier, facilitate anjiogenesis and influence vitreoretinal interface. Therefore we suggest that insulin analogues should be used carefully after impairment of inner blood-retinal barrier. Analogues that bind with lesser affinity to IGF-1 receptor should be chosen after impairment. Pharmacologic agents may be developed to antagonize effect of insulin analogues on IGF-1 receptors.

  9. CO2 Capture with Enzyme Synthetic Analogue

    SciTech Connect

    Cordatos, Harry

    2010-11-08

    Overview of an ongoing, 2 year research project partially funded by APRA-E to create a novel, synthetic analogue of carbonic anhydrase and incorporate it into a membrane for removal of CO2 from flue gas in coal power plants. Mechanism background, preliminary feasibility study results, molecular modeling of analogue-CO2 interaction, and program timeline are provided.

  10. Macrolactam analogues of macrolide natural products.

    PubMed

    Hügel, Helmut M; Smith, Andrew T; Rizzacasa, Mark A

    2016-12-07

    The chemical modification of macrolide natural products into aza- or lactam analogues is a strategy employed to improve their metabolic stability and biological activity. The methods for the synthesis of several lactam analogues of macrolide natural products are highlighted and aspects of their biological properties presented.

  11. The effects of chloroquine and hydroxychloroquine on nitric oxide production in RAW 264.7 and bone marrow-derived macrophages.

    PubMed

    Perečko, T; Kassab, R B; Vašíček, O; Pekarová, M; Jančinová, V; Lojek, A

    2014-01-01

    Chloroquine, an antimalarial drug, can also be used in the regulation of the immune system, e.g. it is used in the treatment of autoimmune diseases. In this study we investigated the effects of chloroquine and its hydroxy-derivative on nitric oxide (NO) production in two different cell types: (i) immortalized mouse macrophage cell line RAW 264.7 and (ii) mouse bone marrow-derived macrophages (BMDM). The cells were treated with different concentrations (1-100 μM) of chloroquine or hydroxychloroquine and stimulated with lipopolysaccharide for 24 h to induce NO production. Measurement of nitrites by the Griess reaction was used to evaluate the production of NO. Expression of inducible NO synthase was evaluated with Western blot and ATPcytotoxicity test was used to measure the viability of the cells. Our results showed that both chloroquine and its hydroxy-derivative inhibited NO production in both cell types. However, based on the results of LD50 these inhibitory effects of both derivatives were due to their cytotoxicity. The LD50 values for chloroquine were 24.77 μM (RAW 264.7) and 24.86 μM (BMDM), the LD50 for hydroxychloroquine were 13.28 μM (RAW 264.7) and 13.98 μM (BMDM). In conclusion, hydroxychloroquine was more cytotoxic than its parent molecule. Comparing the two cell types tested, our data suggest that there are no differences in cytotoxicity of chloroquine or hydroxychloroquine for primary cells (BMDM) or immortalized cell line (RAW 264.7).

  12. The future of somatostatin analogue therapy.

    PubMed

    Stewart, P M; James, R A

    1999-10-01

    Since its discovery almost 30 years ago, the mode of action and therapeutic applications of somatostatin have been defined. In particular the cloning and characterization of somatostatin receptor subtypes has facilitated the development of high affinity analogues. In the context of pituitary disease, long-acting somatostatin analogues (octreotide, lanreotide) have been used to treat a variety of pituitary tumours but are most efficacious for the treatment of GH and TSH-secreting adenomas. In patients with acromegaly, depot preparations of these analogues are administered intramuscularly every 10-28 days and provide consistent suppression of GH levels to < 5 mU/l in approximately 50-65% of all cases. Even more specific somatostatin receptor analogues are under development. Finally, radiolabelled somatostatin analogue scintigraphy and, in larger doses, therapy, are now established tools in the evaluation and treatment of neuroendocrine tumours.

  13. Continuous analogues of matrix factorizations

    PubMed Central

    Townsend, Alex; Trefethen, Lloyd N.

    2015-01-01

    Analogues of singular value decomposition (SVD), QR, LU and Cholesky factorizations are presented for problems in which the usual discrete matrix is replaced by a ‘quasimatrix’, continuous in one dimension, or a ‘cmatrix’, continuous in both dimensions. Two challenges arise: the generalization of the notions of triangular structure and row and column pivoting to continuous variables (required in all cases except the SVD, and far from obvious), and the convergence of the infinite series that define the cmatrix factorizations. Our generalizations of triangularity and pivoting are based on a new notion of a ‘triangular quasimatrix’. Concerning convergence of the series, we prove theorems asserting convergence provided the functions involved are sufficiently smooth. PMID:25568618

  14. Fully analogue photonic reservoir computer.

    PubMed

    Duport, François; Smerieri, Anteo; Akrout, Akram; Haelterman, Marc; Massar, Serge

    2016-03-03

    Introduced a decade ago, reservoir computing is an efficient approach for signal processing. State of the art capabilities have already been demonstrated with both computer simulations and physical implementations. If photonic reservoir computing appears to be promising a solution for ultrafast nontrivial computing, all the implementations presented up to now require digital pre or post processing, which prevents them from exploiting their full potential, in particular in terms of processing speed. We address here the possibility to get rid simultaneously of both digital pre and post processing. The standalone fully analogue reservoir computer resulting from our endeavour is compared to previous experiments and only exhibits rather limited degradation of performances. Our experiment constitutes a proof of concept for standalone physical reservoir computers.

  15. Fully analogue photonic reservoir computer

    PubMed Central

    Duport, François; Smerieri, Anteo; Akrout, Akram; Haelterman, Marc; Massar, Serge

    2016-01-01

    Introduced a decade ago, reservoir computing is an efficient approach for signal processing. State of the art capabilities have already been demonstrated with both computer simulations and physical implementations. If photonic reservoir computing appears to be promising a solution for ultrafast nontrivial computing, all the implementations presented up to now require digital pre or post processing, which prevents them from exploiting their full potential, in particular in terms of processing speed. We address here the possibility to get rid simultaneously of both digital pre and post processing. The standalone fully analogue reservoir computer resulting from our endeavour is compared to previous experiments and only exhibits rather limited degradation of performances. Our experiment constitutes a proof of concept for standalone physical reservoir computers. PMID:26935166

  16. Polymorphism in Plasmodium falciparum Drug Transporter Proteins and Reversal of In Vitro Chloroquine Resistance by a 9,10-Dihydroethanoanthracene Derivative

    PubMed Central

    Millet, Julie; Alibert, Sandrine; Torrentino-Madamet, Marylin; Rogier, Christophe; Santelli-Rouvier, Christiane; Bigot, Patricia; Mosnier, Joel; Baret, Eric; Barbe, Jacques; Parzy, Daniel; Pradines, Bruno

    2004-01-01

    BG958 reverses resistance in chloroquine-resistant isolates from different countries. Five mutations in the Plasmodium falciparum crt (pfcrt) gene resulting in the amino acid changes K76T, M74I, N75E, A220S, and R371I are systematically identified in resistance-reversed Asian, African, and Brazilian parasites which possess the pfcrt (CIET) haplotype. In combination with BG958, the activity of chloroquine is increased in parasites with the N86Y mutation in pfmdr1. PMID:15561869

  17. Chloroquine potentiates the anti-cancer effect of 5-fluorouracil on colon cancer cells

    PubMed Central

    2010-01-01

    Background Chloroquine (CQ), the worldwide used anti-malarial drug, has recently being focused as a potential anti-cancer agent as well as a chemosensitizer when used in combination with anti-cancer drugs. It has been shown to inhibit cell growth and/or to induce cell death in various types of cancer. 5-Fluorouracil (5-FU) is the chemotherapeutic agent of first choice in colorectal cancer, but in most cases, resistance to 5-FU develops through various mechanisms. Here, we focused on the combination of CQ as a mechanism to potentiate the inhibitory effect of 5-FU on human colon cancer cells. Methods HT-29 cells were treated with CQ and/or 5-FU, and their proliferative ability, apoptosis and autophagy induction effects, and the affection of the cell cycle were evaluated. The proliferative ability of HT-29 was analyzed by the MTS assay. Apoptosis was quantified by flow-cytometry after double-staining of the cells with AnnexinV/PI. The cell cycle was evaluated by flow-cytometry after staining of cells with PI. Autophagy was quantified by flow-cytometry and Western blot analysis. Finally, to evaluate the fate of the cells treated with CQ and/or 5-FU, the colony formation assay was performed. Results 5-FU inhibited the proliferative activity of HT-29 cells, which was mostly dependent on the arrest of the cells to the G0/G1-phase but also partially on apoptosis induction, and the effect was potentiated by CQ pre-treatment. The potentiation of the inhibitory effect of 5-FU by CQ was dependent on the increase of p21Cip1 and p27Kip1 and the decrease of CDK2. Since CQ is reported to inhibit autophagy, the catabolic process necessary for cell survival under conditions of cell starvation or stress, which is induced by cancer cells as a protective mechanism against chemotherapeutic agents, we also analyzed the induction of autophagy in HT-29. HT-29 induced autophagy in response to 5-FU, and CQ inhibited this induction, a possible mechanism of the potentiation of the anti

  18. Side Effects of Chloroquine and Primaquine and Symptom Reduction in Malaria Endemic Area (Mâncio Lima, Acre, Brazil)

    PubMed Central

    Braga, Cássio Braga e; Martins, Antonio Camargo; Cayotopa, Athaid David Escalante; Klein, Wagner Werner; Schlosser, Andreus Roberto; da Silva, Aline Ferreira; de Souza, Mardelson Nery; Andrade, Breno Wilson Benevides; Filgueira-Júnior, José Alcântara; Pinto, Wagner de Jesus; da Silva-Nunes, Mônica

    2015-01-01

    Side effects of antimalarial drug can overlap with malaria symptoms. We evaluated 50 patients with vivax malaria in Mâncio Lima, Acre, treated with chloroquine and primaquine. Patients were evaluated for the presence of 21 symptoms before and after treatment and for reported side effects of these drugs after treatment was started. The most frequent symptoms before medication were headache, fever, chills, sweating, arthralgia, back pain, and weakness, which were present in between 40% and 76% of respondents. The treatment reduced the occurrence of these symptoms and reduced the lack of appetite, but gastrointestinal symptoms and choluria increased in frequency. There were no reports of pale stools before medication, but 12% reported the occurrence of this symptom after treatment started. Other symptoms such as blurred vision (54%), pruritus (22%), paresthesia (6%), insomnia (46%), and “stings” into the skin (22%) were reported after chloroquine was taken. The antimalarial drugs used to treat P. vivax malaria reduce much of the systemic and algic symptoms but cause mainly gastrointestinal side effects that may lead to lack of adherence to drug treatment. It is important to guide the patient for the appearance and the transience of such side effects in order to avoid abandoning treatment. PMID:26357512

  19. In vitro evaluation of the antiplasmodial activity of Dendropanax morbifera against chloroquine-sensitive strains of Plasmodium falciparum.

    PubMed

    Chung, Ill-Min; Kim, Min-Young; Park, Sun-Dong; Park, Won-Hwan; Moon, Hyung-In

    2009-11-01

    Dendropanax morbifera Leveille (Araliaceae) is well known in Korea traditional medicine for a variety of diseases. The methanol extract of the lower stem parts of D. morbifera was investigated for its activity against chloroquine-sensitive strains of Plasmodium falciparum using the parasite lactate dehydrogenase assay method. Two cycloartane-type glycosides oleifoliosides A (1) and B (2), and dendropanoxide (3), beta-amyrin (4), alpha-amyrin (5) have been isolated from the stem parts of D. morbifera. All five compounds were evaluated for in vitro antiplasmodial activities as well as their cytotoxic potential on SK-OV-3 cancer cell lines. Compounds 2 and 3 showed notable growth inhibitory activity against chloroquine-sensitive strains of Plasmodium falciparum with IC(50) values of 6.2 and 5.3 microm. This compound showed no significant cytotoxicity (IC(50) > 150 microm) evaluated using SK-OV-3 cancer cell lines. This is the first report on the antiplasmodial activity of the compounds from D. morbifera.

  20. Adaptations of the Saker-Solomons test: simple, reliable colorimetric field assays for chloroquine and its metabolites in urine.

    PubMed Central

    Mount, D. L.; Nahlen, B. L.; Patchen, L. C.; Churchill, F. C.

    1989-01-01

    Two field-adapted colorimetric methods for measuring the antimalarial drug chloroquine in urine are described. Both are modifications of the method of Saker and Solomons for screening urine for phencyclidine and other drugs of abuse, using the colour reagent tetrabromophenolphthalein ethyl ester. One method is semiquantitative, detecting the presence of chloroquine (Cq) and its metabolites in urine with a 1 microgram/ml detection limit; it is more sensitive and reliable than the commonly used Dill-Glazko method and is as easy to apply in the field. The second method uses a hand-held, battery-operated filter photometer to quantify Cq and its metabolites with a 2 microgram/ml detection limit and a linear range up to 8 micrograms/ml. The first method was validated in the field using a published quantitative colorimetric method and samples from a malaria study in Nigeria. The second method was validated in the laboratory against high-performance liquid chromatographic results on paired samples from the Nigerian study. Both methods may be used in remote locations where malaria is endemic and no electricity is available. PMID:2766451

  1. Plant Volatile Analogues Strengthen Attractiveness to Insect

    PubMed Central

    Sun, Yufeng; Yu, Hao; Zhou, Jing-Jiang; Pickett, John A.; Wu, Kongming

    2014-01-01

    Green leaf bug Apolygus lucorum (Meyer-Dür) is one of the major pests in agriculture. Management of A. lucorum was largely achieved by using pesticides. However, the increasing population of A. lucorum since growing Bt cotton widely and the increased awareness of ecoenvironment and agricultural product safety makes their population-control very challenging. Therefore this study was conducted to explore a novel ecological approach, synthetic plant volatile analogues, to manage the pest. Here, plant volatile analogues were first designed and synthesized by combining the bioactive components of β-ionone and benzaldehyde. The stabilities of β-ionone, benzaldehyde and analogue 3 g were tested. The electroantennogram (EAG) responses of A. lucorum adult antennae to the analogues were recorded. And the behavior assay and filed experiment were also conducted. In this study, thirteen analogues were acquired. The analogue 3 g was demonstrated to be more stable than β-ionone and benzaldehyde in the environment. Many of the analogues elicited EAG responses, and the EAG response values to 3 g remained unchanged during seven-day period. 3 g was also demonstrated to be attractive to A. lucorum adults in the laboratory behavior experiment and in the field. Its attractiveness persisted longer than β-ionone and benzaldehyde. This indicated that 3 g can strengthen attractiveness to insect and has potential as an attractant. Our results suggest that synthetic plant volatile analogues can strengthen attractiveness to insect. This is the first published study about synthetic plant volatile analogues that have the potential to be used in pest control. Our results will support a new ecological approach to pest control and it will be helpful to ecoenvironment and agricultural product safety. PMID:24911460

  2. Natural analogue studies as supplements to biomineralization research

    SciTech Connect

    McNeil, M.B.

    1995-09-01

    Chemical reactions can alter the chemistry and crystal structure of solid objects over archeological or geological times, while preserving external physical shapes. The reactions resulting in these structures offer natural analogues to laboratory experiments in biomineralization and to biologically influenced alteration of nuclear waste packages, and thus, they offer the only available way of validating models that purport waste package behavior over archaeological or geological times. Potential uses of such analogues in the construction and validation of hypothetical mechanisms of microbiological corrosion and biomineralization are reviewed. Evidence from such analogues suggests that biofilms can control materials alteration in ways usually overlooked. The newly hypothesized mechanisms involve control by biofilms of the cation flow near the solid surface and offer plausible mechanisms for the formation of mixed-cation minerals under conditions that would lead to dealloying in abiotic experiments; they also account for the formation of unusual minerals [such as posnjakite, Cu{sub 4}SO{sub 4}(OH){sub 6{center_dot}}H{sub 2}O] and mineral morphologies unusual in corrosion [malachite, Cu{sub 2}CO{sub 3}(OH){sub 2}, rarely forms botryoidally under corrosion conditions and its occasional presence on archaeological objects that appear to have undergone microbiological corrosion may be related to biofilm phenomena].

  3. The UVB1 Vitamin D analogue inhibits colorectal carcinoma progression.

    PubMed

    Ferronato, María Julia; Alonso, Eliana Noelia; Gandini, Norberto Ariel; Fermento, María Eugenia; Villegas, María Emilia; Quevedo, Mario Alfredo; Arévalo, Julián; López Romero, Alejandro; Rivadulla, Marcos Lois; Gómez, Generosa; Fall, Yagamare; Facchinetti, María Marta; Curino, Alejandro Carlos

    2016-10-01

    Vitamin D has been shown to display a wide variety of antitumour effects, but their therapeutic use is limited by its severe side effects. We have designed and synthesized a Gemini vitamin D analogue of calcitriol (UVB1) which has shown to display antineoplastic effects on different cancer cell lines without causing hypercalcemia. The aim of this work has been to investigate, by employing in silico, in vitro, and in vivo assays, whether UVB1 inhibits human colorectal carcinoma progression. We demonstrated that UVB1 induces apoptotic cell death and retards cellular migration and invasion of HCT116 colorectal carcinoma cells. Moreover, the analogue reduced the tumour volume in vivo, and modulated the expression of Bax, E-cadherin and nuclear β-catenin in tumour animal tissues without producing toxic effects. In silico analysis showed that UVB1 exhibits greater affinity for the ligand binding domain of vitamin D receptor than calcitriol, and that several characteristics in the three-dimensional conformation of VDR may influence the biological effects. These results demonstrate that the Gemini vitamin D analogue affects the growth of the colorectal cancer and suggest that UVB1 is a potential chemotherapeutic agent for treatment of this disease.

  4. Spinal neurons that contain gastrin-releasing peptide seldom express Fos or phosphorylate extracellular signal-regulated kinases in response to intradermal chloroquine

    PubMed Central

    Gutierrez-Mecinas, Maria; Polgár, Erika; Todd, Andrew J

    2016-01-01

    Background Gastrin-releasing peptide (GRP) is thought to play a role in the itch evoked by intradermal injection of chloroquine. Although some early studies suggested that GRP was expressed in pruriceptive primary afferents, it is now thought that GRP in the spinal cord is derived mainly from a population of excitatory interneurons in lamina II, and it has been suggested that these are involved in the itch pathway. To test this hypothesis, we used the transcription factor Fos and phosphorylation of extracellular signal-regulated kinases (ERK) to look for evidence that interneurons expressing GRP were activated following intradermal injection of chloroquine into the calf, in mice that express enhanced green fluorescent protein (EGFP) in these cells. Results Injection of chloroquine resulted in numerous Fos- or phospho-ERK (pERK) positive cells in the somatotopically appropriate part of the superficial dorsal horn. The proportion of all neurons in this region that showed Fos or pERK was 18% and 21%, respectively. However, among the GRP–EGFP, only 7% were Fos-positive and 3% were pERK-positive. As such, GRP–EGFP cells were significantly less likely than other neurons to express Fos or to phosphorylate ERK. Conclusions Both expression of Fos and phosphorylation of ERK can be used to identify dorsal horn neurons activated by chloroquine injection. However, these results do not support the hypothesis that interneurons expressing GRP are critical components in the itch pathway. PMID:27270268

  5. Space analogue studies in Antarctica

    NASA Astrophysics Data System (ADS)

    Lugg, D.; Shepanek, M.

    1999-09-01

    Medical research has been carried out on the Australian National Antarctic Research Expeditions (ANARE) for 50 years. As an extension of this program collaborative Australian/United States research on immunology, microbiology, psychology and remote medicine has produced important data and insight on how humans adapt to the stress of extreme isolation, confinement and the harsh environment of Antarctica. An outstanding analogue for the isolation and confinement of space missions (especially planetary outposts), ANARE has been used as an international research platform by Australia and the United States since 1993. Collaborative research has demonstrated a lowered responsiveness of the immune system under the isolation and confinement of Antarctic winter-over; a reduction of almost 50% in T cell proliferation to mltogen phytohaemogglutinin, as well as changes in latent herpesvirus states and the expansion of the polyclonal latent Epstein-Barr virus infected B cell populations. Although no clinically significant disease has been found to result from these immune changes, research is currently assessing the effects of psychological factors on the immune system. This and associated research performed to date and its relevance to both organisations is discussed, and comment made on possible extensions to the program in both medical and other fields.

  6. Condensed matter analogues of cosmology

    NASA Astrophysics Data System (ADS)

    Kibble, Tom; Srivastava, Ajit

    2013-10-01

    It is always exciting when developments in one branch of physics turn out to have relevance in a quite different branch. It would be hard to find two branches farther apart in terms of energy scales than early-universe cosmology and low-temperature condensed matter physics. Nevertheless ideas about the formation of topological defects during rapid phase transitions that originated in the context of the very early universe have proved remarkably fruitful when applied to a variety of condensed matter systems. The mathematical frameworks for describing these systems can be very similar. This interconnection has led to a deeper understanding of the phenomena in condensed matter systems utilizing ideas from cosmology. At the same time, one can view these condensed matter analogues as providing, at least in a limited sense, experimental access to the phenomena of the early universe for which no direct probe is possible. As this special issue well illustrates, this remains a dynamic and exciting field. The basic idea is that when a system goes through a rapid symmetry-breaking phase transition from a symmetric phase into one with spontaneously broken symmetry, the order parameter may make different choices in different regions, creating domains that when they meet can trap defects. The scale of those domains, and hence the density of defects, is constrained by the rate at which the system goes through the transition and the speed with which order parameter information propagates. This is what has come to be known as the Kibble-Zurek mechanism. The resultant scaling laws have now been tested in a considerable variety of different systems. The earliest experiments illustrating the analogy between cosmology and condensed matter were in liquid crystals, in particular on the isotropic-to-nematic transition, primarily because it is very easy to induce the phase transition (typically at room temperature) and to image precisely what is going on. This field remains one of the

  7. Space analogue studies in Antarctica.

    PubMed

    Lugg, D; Shepanek, M

    1999-01-01

    Medical research has been carried out on the Australian National Antarctic Research Expeditions (ANARE) for 50 years. As an extension of this program collaborative Australian/United States research on immunology, microbiology, psychology and remote medicine has produced important data and insight on how humans adapt to the stress of extreme isolation, confinement and the harsh environment of Antarctica. An outstanding analogue for the isolation and confinement of space missions (especially planetary outposts), ANARE has been used as an international research platform by Australia and the United States since 1993. Collaborative research has demonstrated a lowered responsiveness of the immune system under the isolation and confinement of Antarctic winter-over; a reduction of almost 50% in T cell proliferation to mitogen phytohaemogglutinin, as well as changes in latent herpesvirus states and the expansion of the polyclonal latent Epstein-Barr virus infected B cell populations. Although no clinically significant disease has been found to result from these immune changes, research is currently assessing the effects of psychological factors on the immune system. This and associated research performed to date and its relevance to both organisations is discussed, and comment made on possible extensions to the program in both medical and other fields.

  8. Space analogue studies in Antarctica

    NASA Technical Reports Server (NTRS)

    Lugg, D.; Shepanek, M.

    1999-01-01

    Medical research has been carried out on the Australian National Antarctic Research Expeditions (ANARE) for 50 years. As an extension of this program collaborative Australian/United States research on immunology, microbiology, psychology and remote medicine has produced important data and insight on how humans adapt to the stress of extreme isolation, confinement and the harsh environment of Antarctica. An outstanding analogue for the isolation and confinement of space missions (especially planetary outposts), ANARE has been used as an international research platform by Australia and the United States since 1993. Collaborative research has demonstrated a lowered responsiveness of the immune system under the isolation and confinement of Antarctic winter-over; a reduction of almost 50% in T cell proliferation to mitogen phytohaemogglutinin, as well as changes in latent herpesvirus states and the expansion of the polyclonal latent Epstein-Barr virus infected B cell populations. Although no clinically significant disease has been found to result from these immune changes, research is currently assessing the effects of psychological factors on the immune system. This and associated research performed to date and its relevance to both organisations is discussed, and comment made on possible extensions to the program in both medical and other fields.

  9. Rapid detection of Pfcrt and Pfmdr1 mutations in Plasmodium falciparum isolates by FRET and in vivo response to chloroquine among children from Osogbo, Nigeria

    PubMed Central

    Ojurongbe, Olusola; Ogungbamigbe, Titus O; Fagbenro-Beyioku, Adetayo F; Fendel, Rolf; Kremsner, Peter G; Kun, Jürgen FJ

    2007-01-01

    Background Chloroquine (CQ) has been in use in Africa for a long time. Because of misuse, this drug has now lost its efficacy due to the emergence of resistance strains in most parts of Africa. Recently, it was shown that after chloroquine has been withdrawn from the market, chloroquine-sensitive Plasmodium falciparum re-emerged and chloroquine could again be used successfully as an antimalarial. Surveillance of parasite populations is, therefore, important to decide whether chloroquine could be re-introduced. Methods To estimate the prevalence of the most pivotal polymorphisms, including Pfcrt K76T, Pfmdr1 N86Y and Pfmdr1 Y184F mutations, and their contributions to the outcome of CQ treatment, isolates from Osogbo Western Nigeria were tested using the Fluorescence Resonance Energy Transfer (FRET) method on a real-time PCR instrument. Results 116 children with acute uncomplicated P. falciparum malaria infections were treated with the standard dosage of CQ and followed-up for 28 days. Blood samples were collected on filter paper at enrollment and during follow-up for identification of parasite carrying the chloroquine resistant transporter (pfcrt) and P. falciparum-multi drug resistance (pfmdr1) gene mutations. Parasitological assessment of response to treatment showed that 62% of the patients were cured and 38% failed the CQ treatment. The presence of single mutant pfcrt (T76) alleles (P = 0.003) and in combination with mutant pfmdr1 Y86 (P = 0.028) was significantly associated with in vivo CQR. No other mutation on its own or in combinations was significantly associated with treatment outcome. Mutant pfcrt was more prevalent in both pre- and post-treatment isolates. No association was observed between age or initial level of parasitaemia and chloroquine treatment outcome. Conclusion The result established the usefulness and accuracy of real time PCR in pfcrt and pfmdr1 mutation detection and also give further evidence to the reliability of the pfcrt T76 point

  10. Artesunate–mefloquine versus chloroquine for treatment of uncomplicated Plasmodium knowlesi malaria in Malaysia (ACT KNOW): an open-label, randomised controlled trial

    PubMed Central

    Grigg, Matthew J; William, Timothy; Menon, Jayaram; Dhanaraj, Prabakaran; Barber, Bridget E; Wilkes, Christopher S; von Seidlein, Lorenz; Rajahram, Giri S; Pasay, Cielo; McCarthy, James S; Price, Ric N

    2016-01-01

    Summary Background The zoonotic parasite Plasmodium knowlesi has become the most common cause of human malaria in Malaysia and is present throughout much of southeast Asia. No randomised controlled trials have been done to identify the optimum treatment for this emerging infection. We aimed to compare artesunate–mefloquine with chloroquine to define the optimum treatment for uncomplicated P knowlesi malaria in adults and children. Methods We did this open-label, randomised controlled trial at three district hospitals in Sabah, Malaysia. Patients aged 1 year or older with uncomplicated P knowlesi malaria were randomly assigned, via computer-generated block randomisation (block sizes of 20), to receive oral artesunate–mefloquine (target dose 12 mg/kg artesunate and 25 mg/kg mefloquine) or chloroquine (target dose 25 mg/kg). Research nursing staff were aware of group allocation, but allocation was concealed from the microscopists responsible for determination of the primary endpoint, and study participants were not aware of drug allocation. The primary endpoint was parasite clearance at 24 h. Analysis was by modified intention to treat. This study is registered with ClinicalTrials.gov, number NCT01708876. Findings Between Oct 16, 2012, and Dec 13, 2014, we randomly assigned 252 patients to receive either artesunate–mefloquine (n=127) or chloroquine (n=125); 226 (90%) patients comprised the modified intention-to-treat population. 24 h after treatment, we recorded parasite clearance in 97 (84% [95% CI 76–91]) of 115 patients in the artesunate–mefloquine group versus 61 (55% [45–64]) of 111 patients in the chloroquine group (difference in proportion 29% [95% CI 18·0–40·8]; p<0·0001). Parasite clearance was faster in patients given artesunate–mefloquine than in those given chloroquine (18·0 h [range 6·0–48·0] vs 24·0 h [6·0–60·0]; p<0·0001), with faster clearance of ring stages in the artesunate–mefloquine group (mean time to 50% clearance

  11. Surfactin analogues produced by Bacillus subtilis strains grown on rapeseed cake

    NASA Astrophysics Data System (ADS)

    Jajor, Paweł; Piłakowska-Pietras, Dorota; Krasowska, Anna; Łukaszewicz, Marcin

    2016-12-01

    Microbiologically produced surface acting compounds (biosurfactants) have very interesting properties with many potential industrial applications. Lipopeptides is a particularly promising group of biosurfactants in respect to the potentially huge number of various chemical structures. The chemical diversity results from fatty acid moiety (e.g. length, saturation, branching or hydroxylation) and type and sequence of the amino acids in the peptide chain. The limiting factor for the design and analysis of various lipopeptides is the ability of the targeted biosynthesis. Biosynthesis of particular lipopeptides may be potentially achieved by strain selection, culture conditions, or molecular engineering. The well-known lipopeptedes (surfactins, iturins, and fengycins) producer is B. subtilis. The aim of this study was to study targeted surfactin structural analogues biosynthesis in response to culture conditions in view of the design and production of tailor-made lipopeptides. Two B. subtilis strains (KB1 and #309) were tested for surfactin production. Both strains produced a mixture of five major surfactin analogues with the number of carbons in an alkyl chain ranging from 12 to 16. The two strains differed with respect to their oxygen demand for optimal surfactin biosynthesis (lower oxygen demand for KB1). The amount of air influenced the relative ratios of surfactin analogues. Lower oxygen amount decreased the share of C15 analogues while it increased the share of C12 analogues. Thus, the biosynthesis of a desired surfactin analogue may controlled by both strain and culture conditions.

  12. Nematic order-disorder state transition in a liquid crystal analogue formed by oriented and migrating amoeboid cells

    NASA Astrophysics Data System (ADS)

    Kemkemer, R.; Teichgräber, V.; Schrank-Kaufmann, S.; Kaufmann, D.; Gruler, H.

    2000-10-01

    In cell culture, liquid crystal analogues are formed by elongated, migrating, and interacting amoeboid cells. An apolar nematic liquid crystal analogue is formed by different cell types like human melanocytes (=pigment cells of the skin), human fibroblasts (=connective tissue cells), human osteoblasts (=bone cells), human adipocytes (=fat cells), etc. The nematic analogue is quite well described by i) a stochastic machine equation responsible for cell orientation and ii) a self-organized extracellular guiding signal, E_2, which is proportional to the orientational order parameter as well as to the cell density. The investigations were mainly made with melanocytes. The transition to an isotropic state analogue can be accomplished either by changing the strength of interaction (e.g. variation of the cell density) or by influencing the cellular machinery by an externally applied signal: i) An isotropic gaseous state analogue is observed at low cell density (ρ < 110melanocytes/mm^2) and a nematic liquid crystal state analogue at higher cell density. ii) The nematic state analogue disappears if the bipolar shaped melanocytes are forced to become a star-like shape (induced by colchicine or staurosporine). The analogy between nematic liquid crystal state analogue formed by elongated, migrating and interacting cells and the nematic liquid crystal phase formed by interacting elongated molecules is discussed.

  13. Organofluorine Isoselenocyanate Analogues of Sulforaphane: Synthesis and Anticancer Activity.

    PubMed

    Cierpiał, Tomasz; Łuczak, Jerzy; Kwiatkowska, Małgorzata; Kiełbasiński, Piotr; Mielczarek, Lidia; Wiktorska, Katarzyna; Chilmonczyk, Zdzisław; Milczarek, Małgorzata; Karwowska, Katarzyna

    2016-10-07

    A series of previously unknown sulforaphane analogues with organofluorine substituents bonded to the sulfinyl sulfur atom, an isoselenocyanate moiety in place of the isothiocyanate group, the central sulfur atom in various oxidation states, and different numbers of methylene groups in the central alkyl chain were synthesized and fully characterized. All new compounds were tested for their biological properties in vitro and demonstrated much higher anticancer activity against two breast cancer cell lines than that shown by native sulforaphane; at the same time, the compounds were less toxic for normal cells. The influence of the particular structural changes in the molecules on the cytotoxicity is discussed.

  14. Influence of pre-existing fabrics on fault kinematics and rift geometry of interacting segments: Analogue models based on the Albertine Rift (Uganda), Western Branch-East African Rift System

    NASA Astrophysics Data System (ADS)

    Aanyu, K.; Koehn, D.

    2011-02-01

    This study aims at showing how far pre-existing crustal weaknesses left behind by Proterozoic mobile belts, that pass around cratonic Archean shields (Tanzania Craton to the southeast and Congo Craton to the northwest), control the geometry of the Albertine Rift. Focus is laid on the development of the Lake Albert and Lake Edward/George sub-segments and between them the greatly uplifted Rwenzori Mountains, a horst block located within the rift and whose highest peak rises to >5000 m above mean sea level. In particular we study how the southward propagating Lake Albert sub-segment to the north interacts with the northward propagating Lake Edward/George sub-segment south of it, and how this interaction produces the structures and geometry observed in this section of the western branch of the East African Rift, especially within and around the Rwenzori horst. We simulate behaviour of the upper crust by conducting sandbox analogue experiments in which pre-cut rubber strips of varying overstep/overlap connected to a basal sheet and oriented oblique and/or orthogonal to the extension vector, are placed below the sand-pack. The points of connection present velocity discontinuities to localise deformation, while the rubber strips represent ductile domain affected by older mobile belts. From fault geometry of developing rift segments in plan view and section cuts, we study kinematics resulting from a given set of boundary conditions, and results are compared with the natural scenario. Three different basal model-configurations are used to simulate two parallel rifts that propagate towards each other and interact. Wider overstep (model SbR3) produces an oblique transfer zone with deep grabens (max. 7.0 km) in the adjoining segments. Smaller overlap (model SbR4) ends in offset rift segments without oblique transfer faults to join the two, and produces moderately deep grabens (max. 4.6 km). When overlap doubles the overstep (model SbR5), rifts propagate sub-orthogonal to the

  15. Adaptive evolution of malaria parasites in French Guiana: Reversal of chloroquine resistance by acquisition of a mutation in pfcrt.

    PubMed

    Pelleau, Stéphane; Moss, Eli L; Dhingra, Satish K; Volney, Béatrice; Casteras, Jessica; Gabryszewski, Stanislaw J; Volkman, Sarah K; Wirth, Dyann F; Legrand, Eric; Fidock, David A; Neafsey, Daniel E; Musset, Lise

    2015-09-15

    In regions with high malaria endemicity, the withdrawal of chloroquine (CQ) as first-line treatment of Plasmodium falciparum infections has typically led to the restoration of CQ susceptibility through the reexpansion of the wild-type (WT) allele K76 of the chloroquine resistance transporter gene (pfcrt) at the expense of less fit mutant alleles carrying the CQ resistance (CQR) marker K76T. In low-transmission settings, such as South America, drug resistance mutations can attain 100% prevalence, thereby precluding the return of WT parasites after the complete removal of drug pressure. In French Guiana, despite the fixation of the K76T allele, the prevalence of CQR isolates progressively dropped from >90% to <30% during 17 y after CQ withdrawal in 1995. Using a genome-wide association study with CQ-sensitive (CQS) and CQR isolates, we have identified a single mutation in pfcrt encoding a C350R substitution that is associated with the restoration of CQ susceptibility. Genome editing of the CQR reference strain 7G8 to incorporate PfCRT C350R caused a complete loss of CQR. A retrospective molecular survey on 580 isolates collected from 1997 to 2012 identified all C350R mutant parasites as being CQS. This mutation emerged in 2002 and rapidly spread throughout the P. falciparum population. The C350R allele is also associated with a significant decrease in piperaquine susceptibility in vitro, suggesting that piperaquine pressure in addition to potential fitness costs associated with the 7G8-type CQR pfcrt allele may have selected for this mutation. These findings have important implications for understanding the evolutionary dynamics of antimalarial drug resistance.

  16. Glucagonlike Peptide 2 Analogue Teduglutide

    PubMed Central

    Chaturvedi, Lakshmi S.; Basson, Marc D.

    2015-01-01

    IMPORTANCE Short bowel syndrome occurs when a shortened intestine cannot absorb sufficient nutrients or fluids. Teduglutide is a recombinant analogue of human glucagonlike peptide 2 that reduces dependence on parenteral nutrition in patients with short bowel syndrome by promoting enterocytic proliferation, increasing the absorptive surface area. However, enterocyte function depends not only on the number of cells that are present but also on differentiated features that facilitate nutrient absorption and digestion. OBJECTIVE To test the hypothesis that teduglutide impairs human intestinal epithelial differentiation. DESIGN AND SETTING We investigated the effects of teduglutide in the modulation of proliferation and differentiation in human Caco-2 intestinal epithelial cells at a basic science laboratory. This was an in vitro study using Caco-2 cells, a human-derived intestinal epithelial cell line commonly used to model enterocytic biology. EXPOSURE Cells were exposed to teduglutide or vehicle control. MAINOUTCOMESAND MEASURES We analyzed the cell cycle by bromodeoxyuridine incorporation or propidium iodide staining and flow cytometry and measured cell proliferation by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay. We used quantitative reverse transcription–polymerase chain reaction to assay the expression of the enterocytic differentiation markers villin, sucrase-isomaltase, glucose transporter 2 (GLUT2), and dipeptidyl peptidase 4 (DPP-4), as well as that of the putative differentiation signals schlafen 12 (SLFN12) and caudal-related homeobox intestine-specific transcription factor (Cdx2). Villin promoter activity was measured by a luciferase-based assay. RESULTS The MTS assay demonstrated that teduglutide increased cell numbers by a mean (SD) of 10% (2%) over untreated controls at a maximal 500nM (n = 6, P < .05). Teduglutide increased bromodeoxyuridine-positive cells vs untreated controls by a mean (SD

  17. On the mechanical analogue of DNA.

    PubMed

    Yakushevich, Ludmila

    2017-03-01

    The creation of mechanical analogues of biological systems is known as a useful instrument that helps to understand better the dynamical mechanisms of the functioning of living organisms. Mechanical analogues of biomolecules are usually constructed for imitation of their internal mobility, which is one of the most important properties of the molecules. Among the different types of internal motions, angular oscillations of nitrous bases are of special interest because they make a substantial contribution to the base pairs opening that in turn is an important element of the process of the DNA-protein recognition. In this paper, we investigate the possibility to construct a mechanical analogue for imitation of angular oscillations of nitrous bases in inhomogeneous DNA. It is shown that the analogue has the form of a mechanical chain of non-identical pendulums that oscillate in the gravitational field of the Earth and coupled by identical springs. The masses and lengths of pendulums, as well as the distances between neighboring pendulums and the rigidity of springs are calculated. To illustrate the approach, we present the result of construction of the mechanical analogue of the fragment of the sequence of bacteriophage T7D.

  18. Analogue Downscaling of Seasonal Rainfall Forecasts

    NASA Astrophysics Data System (ADS)

    Charles, A. N.; Timbal, B.; Hendon, H.

    2010-12-01

    We have taken an existing statistical downscaling model (SDM), based on meteorological analogues that was developed for downscaling climate change projections (Timbal et al 2009), and applied it in the seasonal forecasting context to produce downscaled rainfall hindcasts from a coupled model seasonal forecast system (POAMA). Downscaling of POAMA forecasts is required to provide seasonal climate information at local scales of interest. Analogue downscaling is a simple technique to generate rainfall forecasts appropriate to the local scale by conditioning on the large scale predicted GCM circulation and the local topography and climate. Analogue methods are flexible and have been shown to produce good results when downscaling 20th century South Eastern Australian rainfall output from climate models. A set of re-forecasts for three month rainfall at 170 observing stations in the South Murray Darling region of Australia were generated using predictors from the POAMA re-forecasts as input for the analogue SDM. The predictors were optimised over a number of different GCMS in previous climate change downscaling studies. Downscaling with the analogue SDM results in predicted rainfall with realistic variance while maintaining the modest predictive skill of the dynamical model. Evaluation of the consistency between the large scale mean of downscaled and direct GCM output precipitation is encouraging.

  19. Immunogenicity and Safety of a Booster Dose of an Investigational Adjuvanted Polyprotein HIV-1 Vaccine in Healthy Adults and Effect of Administration of Chloroquine

    PubMed Central

    Bourguignon, Patricia; Willekens, Julie; Janssens, Michel; Clement, Frédéric; Didierlaurent, Arnaud M.; Fissette, Laurence; Roman, François; Boutriau, Dominique

    2014-01-01

    This phase II study evaluated the effect of chloroquine on the specific CD8+ T-cell responses to and the safety of a booster dose of investigational human immunodeficiency virus type 1 (HIV-1) F4/AS01B vaccine containing 10 μg of recombinant fusion protein (F4) adjuvanted with the AS01B adjuvant system. Healthy adults aged 21 to 41 years, primed 3 years before with two F4/AS01B doses containing 10 or 30 μg of F4 (ClinicalTrials.gov registration number NCT00434512), were randomized (1:1) to receive the F4/AS01B booster administered alone or 2 days after chloroquine (300 mg). F4-specific CD8+/CD4+ T-cell responses were characterized by intracellular cytokine staining and lymphoproliferation assays and anti-F4 antibodies by enzyme-linked immunosorbent assays (ELISAs). No effect of chloroquine on CD4+/CD8+ T-cell and antibody responses and no vaccine effect on CD8+ T-cell responses (cytokine secretion or proliferation) were detected following F4/AS01B booster administration. In vitro, chloroquine had a direct inhibitory effect on AS01B adjuvant properties; AS01-induced cytokine production decreased upon coincubation of cells with chloroquine. In the pooled group of participants primed with F4/AS01B containing 10 μg of F4, CD4+ T-cell and antibody responses induced by primary vaccination persisted for at least 3 years. The F4/AS01B booster induced strong F4-specific CD4+ T-cell responses, which persisted for at least 6 months with similar frequencies and polyfunctional phenotypes as following primary vaccination, and high anti-F4 antibody concentrations, reaching higher levels than those following primary vaccination. The F4/AS01B booster had a clinically acceptable safety and reactogenicity profile. An F4/AS01B booster dose, administered alone or after chloroquine, induced robust antibody and F4-specific CD4+ T-cell responses but no significant CD8+ T-cell responses (cytokine secretion or proliferation) in healthy adults. (This study has been registered at Clinical

  20. Is a Combine Therapy of Aqueous Extract of Azadirachta Indica Leaf (Neem Leaf) and Chloroquine Sulphate Toxic to the Histology of the Rabbit Cerebellum?

    PubMed Central

    Ucheya, RE; Ochei, UM; Amiegheme, FE

    2011-01-01

    Background: Herbal medication is commonly employed in treatment of diseases. Aqueous extract of Azadirachta indica leaf (A. indica) is commonly used in treatment of malaria by Nigerians. Most often, aqueous extract of A. indica leaf is taken in combination with chloroquine in order to cure malaria infection without knowledge of the side effect especially by the rural dwellers in Nigeria. Objectives: This study is designed to investigate the effects of aqueous extract of A. indica leaf, and concomitant administration of chloroquine phosphate + aqueous extract of A. indica leaf on the Brain tissue (cerebellum) of rabbit. Methods: Eight adult male Rabbits with average weight range between 1.29kg – 1.52kg obtained from Department of Zoology University of Ekpoma, Edo state were used for this study. They were weighed at intervals of five days before and after the experiment. They were randomly divided into four groups (A– D) of two rabbits each. The chloroquine and aqueous extract of A. indica leaf was administered to the animals orally via a cannula inserted through the oral cavity. They were treated as follows; group A received (100mg ml-1 dry extract solution of aqueous extract of A. indica), group B received (15mg kg-1 of chloroquine sulphate), group C received (100mg ml-1 dry extract solution of aqueous extract of A. indica + 15mg kg-1 of chloroquine sulphate and the control animals (group D) were given normal saline. Both the treatment and control animals were sacrificed at the end of the experiment. The cerebellum was carefully dissected out and immediately fixed in Bouin's fluid for histological studies. Results: Groups A-C animals showed normal Cerebellar histoarchitecture and average weight gain of 2.1% (group A), 1.4% (group B), 0.7% (group C) and 1.4% (group D) respectively. When the average weight gain by the treated animals was compared to the average weight gain by the control animals, it was statistically not significant (P>0.06). Conclusion: Our

  1. Enantioseparation of citalopram analogues with sulfated β-cyclodextrin by capillary electrophoresis.

    PubMed

    Wang, Yadi; Zhang, Shusheng; Breitbach, Zachary S; Petersen, Hans; Ellegaard, Peter; Armstrong, Daniel W

    2016-03-01

    Capillary electrophoresis methods were developed for the enantiomeric separation of 27 citalopram analogues. Sulfated β-cyclodextrin was the most broadly selective and useful chiral selector. The separations of most of the citalopram analogue compounds reported in this work have not been reported previously. Excellent enantiomeric separations were obtained for 26 out of 27 compounds, and most of the separations were achieved within 10 min. The effects of chemical parameters such as chiral selector types, buffer types, chiral selector and buffer concentrations, buffer pH and organic modifiers on the separation were investigated. The influence of analyte structure on separation also was examined and discussed.

  2. GABAA Receptor Modulation by Etomidate Analogues

    PubMed Central

    Pejo, Ervin; Santer, Peter; Wang, Lei; Dershwitz, Philip; Husain, S. Shaukat; Raines, Douglas E.

    2015-01-01

    Background Etomidate is a highly potent anesthetic agent that is believed to produce hypnosis by enhancing γ-aminobutyric acid type A (GABAA) receptor function. We characterized the GABAA receptor and hypnotic potencies of etomidate analogues. We then used computational techniques to build statistical and graphical models that relate the potencies of these etomidate analogues to their structures in order to identify the specific molecular determinants of potency. Methods GABAA receptor potencies were defined with voltage-clamp electrophysiology using α1β3γ2 receptors harboring a channel mutation (α1(L264T)) that enhances anesthetic sensitivity (n = 36 – 60 measurements per concentration-response curve). The hypnotic potencies of etomidate analogues were defined using a loss of righting reflexes assay in Sprague Dawley rats (n = 9 – 21 measurements per dose-response curve). Three-dimensional quantitative structure-activity relationships were determined in silico using comparative molecular field analysis. Results The GABAA receptor and hypnotic potencies of etomidate and the etomidate analogues ranged by 91-fold and 53-fold, respectively. These potency measurements were significantly correlated (r2 = 0.72), but neither measurement correlated with drug hydrophobicity (r2 = 0.019 and 0.005, respectively). Statistically significant and predictive comparative molecular field analysis models were generated and a pharmacophore model was built that revealed both the structural elements in etomidate analogues associated with high potency and the interactions that these elements make with the etomidate binding site. Conclusion There are multiple specific structural elements in etomidate and etomidate analogues that mediate GABAA receptor modulation. Modifying any one element can alter receptor potency by an order of magnitude or more. PMID:26691905

  3. Classical Simulated Annealing Using Quantum Analogues

    NASA Astrophysics Data System (ADS)

    La Cour, Brian R.; Troupe, James E.; Mark, Hans M.

    2016-08-01

    In this paper we consider the use of certain classical analogues to quantum tunneling behavior to improve the performance of simulated annealing on a discrete spin system of the general Ising form. Specifically, we consider the use of multiple simultaneous spin flips at each annealing step as an analogue to quantum spin coherence as well as modifications of the Boltzmann acceptance probability to mimic quantum tunneling. We find that the use of multiple spin flips can indeed be advantageous under certain annealing schedules, but only for long anneal times.

  4. Insulin analogues: action profiles beyond glycaemic control.

    PubMed

    Eckardt, Kristin; Eckel, Jürgen

    2008-02-01

    A variety of studies have documented significant improvements in the treatment of type 1 and 2 diabetes after the introduction of artificial insulins. This review gives an overview of insulin analogues which are currently approved for therapeutical use. Clinical data regarding the efficiency to control blood glucose level as well as improving HbA1c level in comparison to conventional insulin preparations in type 1 and 2 diabetic patients are summarized. Furthermore, special features of insulin analogues regarding their signalling properties are discussed with focus on the proliferative effects of insulin glargine as well as some recent data of insulin detemir.

  5. Polymorphism of the Plasmodium falciparum multidrug resistance and chloroquine resistance transporter genes and in vitro susceptibility to aminoquinolines in isolates from the Peruvian Amazon.

    PubMed

    Huaman, Maria Cecilia; Roncal, Norma; Nakazawa, Shusuke; Long, Ton That Ai; Gerena, Lucia; Garcia, Coralith; Solari, Lely; Magill, Alan J; Kanbara, Hiroji

    2004-05-01

    In vitro drug sensitivity to chloroquine (CQ), mefloquine (MQ) and quinine was investigated in 60 culture-adapted Plasmodium falciparum isolates from malaria patients in Padrecocha, a village in the Amazonian Department of Loreto, Peru. All isolates showed resistance to CQ, decreased susceptibility to quinine, and sensitivity to MQ. These isolates were examined for mutations in the P. falciparum multidrug resistance 1 (pfmdr1) and chloroquine resistance transporter (pfcrt) genes previously linked to CQ resistance. The mutations N86Y and D1246Y, two of the five mutations commonly observed in the pfmdr1 gene of CQ-resistant clones, were not found. The pfcrt mutation K76T, associated with CQ resistance, was identified in all the isolates tested. Sequence analysis of codons 72-76 in the pfcrt gene showed the haplotypes SVMNT and CVMNT.

  6. [Mutant alleles associated to chloroquine and sulfadoxine-pyrimethanime resistance in Plasmodium falciparum of the Ecuador-Peru and Ecuador-Colombia borders].

    PubMed

    Arróspide, Nancy; Hijar-Guerra, Gisely; de Mora, Doménica; Diaz-Cortéz, César Eduardo; Veloz-Perez, Raúl; Gutierrez, Sonia; Cabezas-Sánchez, César

    2014-04-01

    The frequency of mutations in pfCRT and DHFR/DHPS genes of Plasmodium falciparum associated with resistance to chloroquine and sulfadoxine-pyrimethamine was evaluated in 83 strains from the districts of Esmeralda and Machala, located on the borders of Ecuador-Peru and Ecuador-Colombia in 2002. Polymerase chain reaction (PCR), conventional and its variants, was used. Mutations in the pfCRT gene were found in more than 90% of the samples from Esmeralda and Machala. For the DHFR gene, 90% of the strains were mutant samples from Esmeralda, 3 were double mutations and 1 was a triple mutation. In Machala, 25% were simple mutant forms and 75% mixed mutant forms (wild forms/mutant). In conclusion, resistance to chloroquine has been fixed in strains carrying K76T pfCRT mutation, whereas genetic imprinting for resistance to pyrimethamine is evolving, particularly in the district of Esmeralda.

  7. Properties of granular analogue model materials: A community wide survey

    NASA Astrophysics Data System (ADS)

    Klinkmüller, M.; Schreurs, G.; Rosenau, M.; Kemnitz, H.

    2016-08-01

    We report the material properties of 26 granular analogue materials used in 14 analogue modelling laboratories. We determined physical characteristics such as bulk density, grain size distribution, and grain shape, and performed ring shear tests to determine friction angles and cohesion, and uniaxial compression tests to evaluate the compaction behaviour. Mean grain size of the materials varied between c. 100 and 400 μm. Analysis of grain shape factors shows that the four different classes of granular materials (14 quartz sands, 5 dyed quartz sands, 4 heavy mineral sands and 3 size fractions of glass beads) can be broadly divided into two groups consisting of 12 angular and 14 rounded materials. Grain shape has an influence on friction angles, with most angular materials having higher internal friction angles (between c. 35° and 40°) than rounded materials, whereas well-rounded glass beads have the lowest internal friction angles (between c. 25° and 30°). We interpret this as an effect of intergranular sliding versus rolling. Most angular materials have also higher basal friction angles (tested for a specific foil) than more rounded materials, suggesting that angular grains scratch and wear the foil. Most materials have an internal cohesion in the order of 20-100 Pa except for well-rounded glass beads, which show a trend towards a quasi-cohesionless (C < 20 Pa) Coulomb-type material. The uniaxial confined compression tests reveal that rounded grains generally show less compaction than angular grains. We interpret this to be related to the initial packing density after sifting, which is higher for rounded grains than for angular grains. Ring-shear test data show that angular grains undergo a longer strain-hardening phase than more rounded materials. This might explain why analogue models consisting of angular grains accommodate deformation in a more distributed manner prior to strain localisation than models consisting of rounded grains.

  8. Molecular epidemiology of malaria in Cameroon. XXI. Baseline therapeutic efficacy of chloroquine, amodiaquine, and sulfadoxine-pyrimethamine monotherapies in children before national drug policy change.

    PubMed

    Basco, Leonardo K; Ngane, Vincent Foumane; Ndounga, Mathieu; Same-Ekobo, Albert; Youmba, Jean-Christian; Abodo, Raphael Therese Okalla; Soula, Georges

    2006-09-01

    The availability of epidemiologic data on drug-resistant malaria based on a standardized clinical and parasitological protocol is a prerequisite for a rational therapeutic strategy to control malaria. As part of the surveillance program on the therapeutic efficacy of the first-line (chloroquine and amodiaquine) and second-line (sulfadoxine-pyrimethamine) drugs for the management of uncomplicated Plasmodium falciparum infections, non-randomized studies were conducted in symptomatic children aged less than 10 years according to the World Health Organization protocol (14-day follow-up period) at 12 sentinel sites in Cameroon between 1999 and 2004. Of 1,407 children enrolled in the studies, 460, 444, and 503 were treated with chloroquine, amodiaquine, or sulfadoxine-pyrimethamine, respectively. Chloroquine treatment resulted in high failure rates (proportion of early and late failures, 48.6%). Amodiaquine was effective at all study sites (proportion of failures, 7.3%). Sulfadoxine-pyrimethamine therapy was less effective than amodiaquine (P < 0.05), with failures observed in 9.9% of patients. Chloroquine is no longer a viable option and has been withdrawn from the official drug outlets in Cameroon. Amodiaquine and, to a lesser extent, sulfadoxine-pyrimethamine monotherapies are still effective in Cameroon, but further development of resistance to these drugs should be delayed by the novel strategy using artemisinin-based combination therapy. Our findings indicate that amodiaquine is the most rational partner for artesunate. Studies on the efficacy of artesunate-amodiaquine combination are currently being undertaken at several sites in the country.

  9. [In vitro evaluation of the sensitivity of Plasmodium falciparum to chloroquine using the deli-microtest in region of Dakar, Senegal].

    PubMed

    Dieng, T; Bah, I B; Ndiaye, P M; Diallo, I; Diop, B M; Brasseur, P; Mboup, S; Wirth, D; Ndir, O

    2005-11-01

    This study was carried out between 2000 and 2001 in the peri-urban Pikine area located 15 km from Dakar, Senegal. The purpose was to evaluate the in vitro sensitivity of Plasmodium falciparum isolates to chloroquine, which was the recommended first-line drug for uncomplicated malaria treatment in Senegal. Testing was carried out using the double-site enzyme-linked lactate dehydrogenase imnunosorbent (DELI) microtest. The DELI-microtest is an ELISA method using 2 monoclonal antibodies against 2 antigenic sites of the specific P. falciparum lactate dehydrogenase (LDH) enzyme. The level of LDH is proportional to the extent of parasite growth. P. falciparum isolates were cultured in 96-well plates in RPMI 1640 medium supplemented with hypoxanthine and albumax, in the presence of chloroquine sulphate concentrations ranging from 5.6 nM/L to 2870.8 nM/L. Plates were incubated in a candle-jar for 48 hours at 37 degrees C and frozen at -20 degrees C. The DELI-microtest was performed using the supernatant of hemolysed cultures. The amount of pLDH released was evaluated based on optical density. The chloroquine sensitivity of the isolate was estimated based on IC50 with a cut-off of <100 nM/L. Geometric mean IC50 values were 41 nM/L (range: 4.8 nM/L to 1435 nM/L) and 135 nM/L (range: 8.63 nM/L to 2153 nM/L) in 2000 and 2001 respectively. This study demonstrated a dramatic increase in the in vitro resistance of P. falciparum to chloroquine from 30% in 2000 to 59.6% in 2001. These findings suggest that regular surveillance of in vitro drug resistance is important to predict in vivo drug resistance and allow timely changes in public health recommendations.

  10. Temporal and seasonal changes of genetic polymorphisms associated with altered drug susceptibility to chloroquine, lumefantrine, and quinine in Guinea-Bissau between 2003 and 2012.

    PubMed

    Jovel, Irina Tatiana; Kofoed, Poul-Erik; Rombo, Lars; Rodrigues, Amabelia; Ursing, Johan

    2015-02-01

    In 2008, artemether-lumefantrine was introduced in Guinea-Bissau, West Africa, but quinine has also been commonly prescribed for the treatment of uncomplicated Plasmodium falciparum malaria. An efficacious high-dose chloroquine treatment regimen was used previously. Temporal and seasonal changes of genetic polymorphisms associated with altered drug susceptibility to chloroquine, lumefantrine, and quinine have been described. P. falciparum chloroquine resistance transporter (pfcrt) K76T, pfmdr1 gene copy numbers, pfmdr1 polymorphisms N86Y and Y184F, and pfmdr1 sequences 1034 to 1246 were determined using PCR-based methods. Blood samples came from virtually all (n=1,806) children<15 years of age who had uncomplicated P. falciparum monoinfection and presented at a health center in suburban Bissau (from 2003 to 2012). The pfcrt K76T and pfmdr1 N86Y frequencies were stable, and seasonal changes were not seen from 2003 to 2007. Since 2007, the mean annual frequencies increased (P<0.001) for pfcrt 76T (24% to 57%), pfmdr1 N86 (72% to 83%), and pfcrt 76+pfmdr1 86 TN (10% to 27%), and pfcrt 76T accumulated during the high transmission season (P=0.001). The pfmdr1 86+184 NF frequency increased from 39% to 66% (from 2003 to 2011; P=0.004). One sample had two pfmdr1 gene copies. pfcrt 76T was associated with a lower parasite density (P<0.001). Following the discontinuation of an effective chloroquine regimen, probably highly artemether-lumefantrine-susceptible P. falciparum (with pfcrt 76T) accumulated, possibly due to suboptimal use of quinine and despite a fitness cost linked to pfcrt 76T. (The studies reported here were registered at ClinicalTrials.gov under registration no. NCT00137514 [PSB-2001-chl-amo], NCT00137566 [PSB-2004-paracetamol], NCT00426439 [PSB-2006-coartem], NCT01157689 [AL-eff 2010], and NCT01704508 [Eurartesim 2012].).

  11. Nonradioactive heteroduplex tracking assay for the detection of minority-variant chloroquine-resistant Plasmodium falciparum in Madagascar

    PubMed Central

    Juliano, Jonathan J; Randrianarivelojosia, Milijaona; Ramarosandratana, Benjamin; Ariey, Frédéric; Mwapasa, Victor; Meshnick, Steven R

    2009-01-01

    Background Strains of Plasmodium falciparum genetically resistant to chloroquine (CQ) due to the presence of pfcrt 76T appear to have been recently introduced to the island of Madagascar. The prevalence of such resistant genotypes is reported to be low (< 3%) when evaluated by conventional PCR. However, these methods are insensitive to low levels of mutant parasites present in patients with polyclonal infections. Thus, the current estimates may be an under representation of the prevalence of the CQ-resistant P. falciparum isolates on the island. Previously, minority variant chloroquine resistant parasites were described in Malawian patients using an isotopic heteroduplex tracking assay (HTA), which can detect pfcrt 76T-bearing P. falciparum minority variants in individual patients that were undetectable by conventional PCR. However, as this assay required a radiolabeled probe, it could not be used in many resource-limited settings. Methods This study describes a digoxigenin (DIG)-labeled chemiluminescent heteroduplex tracking assay (DIG-HTA) to detect pfcrt 76T-bearing minority variant P. falciparum. This assay was compared to restriction fragment length polymorphism (RFLP) analysis and to the isotopic HTA for detection of genetically CQ-resistant parasites in clinical samples. Results Thirty one clinical P. falciparum isolates (15 primary isolates and 16 recurrent isolates) from 17 Malagasy children treated with CQ for uncomplicated malaria were genotyped for the pfcrt K76T mutation. Two (11.7%) of 17 patients harboured genetically CQ-resistant P. falciparum strains after therapy as detected by HTA. RFLP analysis failed to detect any pfcrt K76T-bearing isolates. Conclusion These findings indicate that genetically CQ-resistant P. falciparum are more common than previously thought in Madagascar even though the fitness of the minority variant pfcrt 76T parasites remains unclear. In addition, HTAs for malaria drug resistance alleles are promising tools for the

  12. Multiple Origins of Mutations in the mdr1 Gene—A Putative Marker of Chloroquine Resistance in P. vivax

    PubMed Central

    Schousboe, Mette L.; Ranjitkar, Samir; Rajakaruna, Rupika S.; Amerasinghe, Priyanie H.; Morales, Francisco; Pearce, Richard; Ord, Rosalyn; Leslie, Toby; Rowland, Mark; Gadalla, Nahla B.; Konradsen, Flemming; Bygbjerg, Ib C.; Roper, Cally; Alifrangis, Michael

    2015-01-01

    Background Chloroquine combined with primaquine has been the recommended antimalarial treatment of Plasmodium vivax malaria infections for six decades but the efficacy of this treatment regimen is threatened by chloroquine resistance (CQR). Single nucleotide polymorphisms (SNPs) in the multidrug resistance gene, Pvmdr1 are putative determinants of CQR but the extent of their emergence at population level remains to be explored. Objective In this study we describe the prevalence of SNPs in the Pvmdr1 among samples collected in seven P. vivax endemic countries and we looked for molecular evidence of drug selection by characterising polymorphism at microsatellite (MS) loci flanking the Pvmdr1 gene. Methods We examined the prevalence of SNPs in the Pvmdr1 gene among 267 samples collected from Pakistan, Afghanistan, Sri Lanka, Nepal, Sudan, São Tomé and Ecuador. We measured and diversity in four microsatellite (MS) markers flanking the Pvmdr1 gene to look evidence of selection on mutant alleles. Results SNP polymorphism in the Pvmdr1 gene was largely confined to codons T958M, Y976F and F1076L. Only 2.4% of samples were wildtype at all three codons (TYF, n = 5), 13.3% (n = 28) of the samples were single mutant MYF, 63.0% of samples (n = 133) were double mutant MYL, and 21.3% (n = 45) were triple mutant MFL. Clear geographic differences in the prevalence of these Pvmdr mutation combinations were observed. Significant linkage disequilibrium (LD) between Pvmdr1 and MS alleles was found in populations sampled in Ecuador, Nepal and Sri Lanka, while significant LD between Pvmdr1 and the combined 4 MS locus haplotype was only seen in Ecuador and Sri Lanka. When combining the 5 loci, high level diversity, measured as expected heterozygosity (He), was seen in the complete sample set (He = 0.99), while He estimates for individual loci ranged from 0.00–0.93. Although Pvmdr1 haplotypes were not consistently associated with specific flanking MS alleles, there was significant

  13. Dumb holes: analogues for black holes.

    PubMed

    Unruh, W G

    2008-08-28

    The use of sonic analogues to black and white holes, called dumb or deaf holes, to understand the particle production by black holes is reviewed. The results suggest that the black hole particle production is a low-frequency and low-wavenumber process.

  14. CO2 Capture with Enzyme Synthetic Analogue

    SciTech Connect

    Cordatos, Harry

    2010-03-01

    Project overview provides background on carbonic anhydrase transport mechanism for CO2 in the human body and proposed approach for ARPA-E project to create a synthetic enzyme analogue and utilize it in a membrane for CO2 capture from flue gas.

  15. Solanapyrone analogues from a Hawaiian fungicolous fungus

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Four new solanayrone analogues (solanapyrones J-M; 1-4) have been isolated from an unidentified fungicolous fungus collected in Hawaii. The structures and relative configurations of these compounds were determined by analysis of ID NMR, 2D NMR, and MS data. Solanapyrone J(1) showed antifungal acti...

  16. [Dmt(1)]DALDA analogues modified with tyrosine analogues at position 1.

    PubMed

    Cai, Yunxin; Lu, Dandan; Chen, Zhen; Ding, Yi; Chung, Nga N; Li, Tingyou; Schiller, Peter W

    2016-08-01

    Analogues of [Dmt(1)]DALDA (H-Dmt-d-Arg-Phe-Lys-NH2; Dmt=2',6'-dimethyltyrosine), a potent μ opioid agonist peptide with mitochondria-targeted antioxidant activity were prepared by replacing Dmt with various 2',6'-dialkylated Tyr analogues, including 2',4',6'-trimethyltyrosine (Tmt), 2'-ethyl-6'-methyltyrosine (Emt), 2'-isopropyl-6'-methyltyrosine (Imt) and 2',6'-diethyltyrosine (Det). All compounds were selective μ opioid agonists and the Tmt(1)-, Emt(1) and Det(1)-analogues showed subnanomolar μ opioid receptor binding affinities. The Tmt(1)- and Emt(1)-analogues showed improved antioxidant activity compared to the Dmt(1)-parent peptide in the DPPH radical-scavenging capacity assay, and thus are of interest as drug candidates for neuropathic pain treatment.

  17. Tryptophan analogues. 1. Synthesis and antihypertensive activity of positional isomers.

    PubMed

    Safdy, M E; Kurchacova, E; Schut, R N; Vidrio, H; Hong, E

    1982-06-01

    A series of tryptophan analogues having the carboxyl function at the beta-position was synthesized and tested for antihypertensive activity. The 5-methoxy analogue 46 exhibited antihypertensive activity in the rat via the oral route and was much more potent than the normal tryptophan analogue. The methyl ester was found to be a critical structural feature for activity.

  18. PfCRT and the trans-vacuolar proton electrochemical gradient: regulating the access of chloroquine to ferriprotoporphyrin IX

    PubMed Central

    Bray, Patrick G.; Mungthin, Mathirut; Hastings, Ian M.; Biagini, Giancarlo A.; Saidu, Dauda K.; Lakshmanan, Viswanathan; Johnson, David J.; Hughes, Ruth H.; Stocks, Paul A.; O'Neill, Paul M.; Fidock, David A.; Warhurst, David C.; Ward, Stephen A.

    2010-01-01

    Summary It is accepted that resistance of Plasmodium falciparum to chloroquine (CQ) is caused primarily by mutations in the pfcrt gene. However, a consensus has not yet been reached on the mechanism by which resistance is achieved. CQ-resistant (CQR) parasite lines accumulate less CQ than do CQ-sensitive (CQS) parasites. The CQR phenotype is complex with a component of reduced energy-dependent CQ uptake and an additional component that resembles energy-dependent CQ efflux. Here we show that the required energy input is in the form of the proton electrochemical gradient across the digestive vacuole (DV) membrane. Collapsing the DV proton gradient (or starving the parasites of glucose) results in similar levels of CQ accumulation in CQS and CQR lines. Under these conditions the accumulation of CQ is stimulated in CQR parasite lines but is reduced in CQS lines. Energy deprivation has no effect on the rate of CQ efflux from CQR lines implying that mutant PfCRT does not function as an efflux pump or active carrier. Using pfcrt-modified parasite lines we show that the entire CQ susceptibility phenotype is switched by the single K76T amino acid change in PfCRT. The efflux of CQ in CQR lines is not directly coupled to the energy supply, consistent with a model in which mutant PfCRT functions as a gated channel or pore, allowing charged CQ species to leak out of the DV. PMID:16956382

  19. A dose-ranging study of the pharmacokinetics of hydroxy-chloroquine following intravenous administration to healthy volunteers.

    PubMed

    Tett, S E; Cutler, D J; Day, R O; Brown, K F

    1988-09-01

    1. The pharmacokinetics of hydroxychloroquine were studied in five healthy volunteers following an intravenous infusion of 155 mg (2.47 +/- 0.25 mg kg-1) racemic hydroxychloroquine. Four of these volunteers also received a further 310 mg (4.92 +/- 0.45 mg kg-1) infusion of hydroxychloroquine and evidence of nonlinearities in the pharmacokinetics of hydroxychloroquine were sought. 2. No nonlinear elimination or distribution processes appeared to be operating at the doses of hydroxychloroquine used in this study, supporting the hypothesis that in the therapeutic dosing range the pharmacokinetics of hydroxychloroquine are linear. 3. Half-life and mean residence time were long (around 40 days) and large volumes of distribution were calculated (5,522 l from blood, 44,257 l from plasma). Sequestration into the tissues is an important feature of the disposition of hydroxychloroquine. The persistence of hydroxychloroquine in the body is due primarily to this extensive tissue distribution, rather than to low clearance (667 ml min-1 based on plasma data, 96 ml min-1 based on blood data). 4. Plasma data were more variable than blood data. Blood to plasma concentration ratios were not constant (mean +/- s.d.: 7.2 +/- 4.2). The data indicate that it is preferable to measure whole blood concentrations of hydroxychloroquine, rather than plasma concentrations, in pharmacokinetic studies. 5. The pharmacokinetics of hydroxychloroquine are similar to those of chloroquine.

  20. Discovery of a selective, safe and novel anti-malarial compound with activity against chloroquine resistant strain of Plasmodium falciparum

    PubMed Central

    Agarwal, Ankita; Paliwal, Sarvesh; Mishra, Ruchi; Sharma, Swapnil; Kumar Dwivedi, Anil; Tripathi, Renu; Gunjan, Sarika

    2015-01-01

    In recent years the DNA minor groove has attracted much attention for the development of anti-malarial agents. In view of this we have attempted to discover novel DNA minor groove binders through in-silico and in-vitro workflow. A rigorously validated pharmacophore model comprising of two positive ionizable (PI), one hydrophobic (HY) and one ring aromatic (RA) features was used to mine NCI chemical compound database. This led to retrieval of many hits which were screened on the basis of estimated activity, fit value and Lipinski’s violation. Finally two compounds NSC639017 and NSC371488 were evaluated for their in-vitro anti-malarial activities against Plasmodium falciparum 3D7 (CQ sensitive) and K1 (CQ resistant) strains by SYBR green-I based fluorescence assay. The results revealed that out of two, NSC639017 posses excellent anti-malarial activity particularly against chloroquine resistant strain and moreover NSC639017 also appeared to be safe (CC50 126.04 μg/ml) and selective during cytotoxicity evaluation. PMID:26346444

  1. Low Prevalence of Pfcrt Resistance Alleles among Patients with Uncomplicated Falciparum Malaria in Niger Six Years after Chloroquine Withdrawal

    PubMed Central

    Salissou, Adamou; Zamanka, Halima; Biyghe Binze, Brigitte; Rivière, Taiana; Tichit, Magalie; Ibrahim, Maman Laminou; Fandeur, Thierry

    2014-01-01

    Chloroquine (CQ) resistance is widespread in Africa, but few data are available for Niger. Pfcrt haplotypes (aa 56–118) and ex vivo responses to CQ and amodiaquine were characterized for 26 isolates collected in South Niger from children under 15 years of age suffering from uncomplicated falciparum malaria, six years after the introduction of artemisinin-based combinations and the withdrawal of CQ. The wild-type Pfcrt haplotype CVMNK was found in 22 of the 26 isolates, with CVIET sequences observed in only three of the samples. We also describe for the first time a new CVINT haplotype. The ex vivo responses were better for CVMNK than for CVIET parasites. Pfcrt sequence data were compared with those obtained for 26 additional parasitized blood samples collected in Gabon, from an area of CQ resistance used as a control. Our findings suggest that there has been a significant decline in CQ-resistant genotypes since the previous estimates for Niger were obtained. No such decline in molecular resistance to CQ was observed in the subset of samples collected in similar conditions from Gabon. These results have important implications for public health and support the policy implemented in Niger since 2005, which aims to increase the efficacy and availability of antimalarial drugs whilst controlling the spread of resistance. PMID:25506465

  2. The Antimalarial Chloroquine Suppresses LPS-Induced NLRP3 Inflammasome Activation and Confers Protection against Murine Endotoxic Shock

    PubMed Central

    2017-01-01

    Activation of the NLRP3 inflammasome, which catalyzes maturation of proinflammatory cytokines like IL-1β and IL-18, is implicated and essentially involved in many kinds of inflammatory disorders. Chloroquine (CQ) is a traditional antimalarial drug and also possesses an anti-inflammatory property. In this study, we investigated whether CQ suppresses NLRP3 inflammasome activation and thereby confers protection against murine endotoxic shock. CQ attenuated NF-κB and MAPK activation and prohibited expression of IL-1β, IL-18, and Nlrp3 in LPS treated murine bone marrow-derived macrophages (BMDMs), demonstrating its inhibitory effect on the priming signal of NLRP3 activation. Then, CQ was shown to inhibit caspase-1 activation and ASC specks formation in BMDMs, which indicates that CQ also suppresses inflammasome assembly, the second signal for NLRP3 inflammasome activation. In a murine endotoxic shock model, CQ effectively improved survival and markedly reduced IL-1β and IL-18 production in serum, peritoneal fluid, and lung tissues. Moreover, CQ reduced protein levels of NLRP3 and caspases-1 p10 in lung homogenates of mice with endotoxic shock, which may possibly explain its anti-inflammatory activity and life protection efficacy in vivo. Overall, our results demonstrate a new role of CQ that facilitates negative regulation on NLRP3 inflammasome, which thereby confers protection against lethal endotoxic shock. PMID:28321151

  3. A metabolic synthetic lethal strategy with arginine deprivation and chloroquine leads to cell death in ASS1-deficient sarcomas

    PubMed Central

    Bean, Gregory R; Kremer, Jeff C; Prudner, Bethany C; Schenone, Aaron D; Yao, Juo-Chin; Schultze, Matthew B; Chen, David Y; Tanas, Munir R; Adkins, Douglas R; Bomalaski, John; Rubin, Brian P; Michel, Loren S; Van Tine, Brian A

    2016-01-01

    Sarcomas comprise a large heterogeneous group of mesenchymal cancers with limited therapeutic options. When treated with standard cytotoxic chemotherapies, many sarcomas fail to respond completely and rapidly become treatment resistant. A major problem in the investigation and treatment of sarcomas is the fact that no single gene mutation or alteration has been identified among the diverse histologic subtypes. We searched for therapeutically druggable targets that are common to a wide range of histologies and hence could provide alternatives to the conventional chemotherapy. Seven hundred samples comprising 45 separate histologies were examined. We found that almost 90% were arginine auxotrophs, as the expression of argininosuccinate synthetase 1 was lost or significantly reduced. Arginine auxotrophy confers sensitivity to arginine deprivation, leading temporarily to starvation and ultimately to cell survival or death under different circumstances. We showed that, in sarcoma, arginine deprivation therapy with pegylated arginine deiminase (ADI-PEG20) maintains a prolonged state of arginine starvation without causing cell death. However, when starvation was simultaneously prolonged by ADI-PEG20 while inhibited by the clinically available drug chloroquine, sarcoma cells died via necroptosis and apoptosis. These results have revealed a novel metabolic vulnerability in sarcomas and provided the basis for a well-tolerated alternative treatment strategy, potentially applicable to up to 90% of the tumors, regardless of histology. PMID:27735949

  4. Prospective Study of Plasmodium vivax Malaria Recurrence after Radical Treatment with a Chloroquine-Primaquine Standard Regimen in Turbo, Colombia

    PubMed Central

    Blair, Silvia; Akinyi Okoth, Sheila; Udhayakumar, Venkatachalam; Marcet, Paula L.; Escalante, Ananias A.; Alexander, Neal; Rojas, Carlos

    2016-01-01

    Plasmodium vivax recurrences help maintain malaria transmission. They are caused by recrudescence, reinfection, or relapse, which are not easily differentiated. A longitudinal observational study took place in Turbo municipality, Colombia. Participants with uncomplicated P. vivax infection received supervised treatment concomitantly with 25 mg/kg chloroquine and 0.25 mg/kg/day primaquine for 14 days. Incidence of recurrence was assessed over 180 days. Samples were genotyped, and origins of recurrences were established. A total of 134 participants were enrolled between February 2012 and July 2013, and 87 were followed for 180 days, during which 29 recurrences were detected. The cumulative incidence of first recurrence was 24.1% (21/87) (95% confidence interval [CI], 14.6 to 33.7%), and 86% (18/21) of these events occurred between days 51 and 110. High genetic diversity of P. vivax strains was found, and 12.5% (16/128) of the infections were polyclonal. Among detected recurrences, 93.1% (27/29) of strains were genotyped as genetically identical to the strain from the previous infection episode, and 65.5% (19/29) of infections were classified as relapses. Our results indicate that there is a high incidence of P. vivax malaria recurrence after treatment in Turbo municipality, Colombia, and that a large majority of these episodes are likely relapses from the previous infection. We attribute this to the primaquine regimen currently used in Colombia, which may be insufficient to eliminate hypnozoites. PMID:27185794

  5. Chloroquine enhances cobalt chloride-induced leukemic cell differentiation via the suppression of autophagy at the late phase.

    PubMed

    Yan, Zhao-Wen; Hou, Jia-Kai; He, Wei; Fan, Li; Huang, Ying

    2013-01-18

    We previously reported that moderate hypoxia and hypoxia-mimetic agents including cobalt chloride (CoCl(2)) induce differentiation of human acute myeloid leukemia (AML) cells through hypoxia-inducible factor-1 α (HIF-1 α), which interacts with and enhances transcriptional activity of CCAAT-enhancer binding factor alpha and Runx1/AML1, two important transcriptional factors for hematopoietic cell differentiation. Here, we show that autophagy inhibitor chloroquine (CQ) increases HIF-1 α accumulation, thus potentiating CoCl(2)-induced growth arrest and differentiation of leukemic cells. Furthermore, the increased effect of CQ on differentiation induction is dependent of the inhibition of autophagosome maturation and degradation, since this sensitization could be mimicked by the suppression of expression of both lysosome-associated membrane proteins 1 and 2 (LAMP1 and LAMP2). These findings not only provide the evidence that CQ is a sensitizer for CoCl(2)-induced differentiation of leukemic cells but also possibly propose the new therapeutic strategy for differentiation induction of AML.

  6. Retinal damage in chloroquine maculopathy, revealed by high resolution imaging: a case report utilizing adaptive optics scanning laser ophthalmoscopy.

    PubMed

    Bae, Eun Jin; Kim, Kyoung Rae; Tsang, Stephen H; Park, Sung Pyo; Chang, Stanley

    2014-02-01

    A 53-year-old Asian woman was treated with hydroxychloroquine and chloroquine for lupus erythematosus. Within a few years, she noticed circle-shaped shadows in her central vision. Upon examination, the patient's visual acuity was 20 / 25 in both eyes. Humphrey visual field (HVF) testing revealed a central visual defect, and fundoscopy showed a ring-shaped area of parafoveal retinal pigment epithelium depigmentation. Fundus autofluorescence imaging showed a hypofluorescent lesion consistent with bull's eye retinopathy. Adaptive optics scanning laser ophthalmoscope (AO-SLO) revealed patch cone mosaic lesions, in which cones were missing or lost. In addition, the remaining cones consisted of asymmetrical shapes and sizes that varied in brightness. Unlike previous studies employing deformable mirrors for wavefront aberration correction, our AO-SLO approach utilized dual liquid crystal on silicon spatial light modulators. Thus, by using AO-SLO, we were able to create a photographic montage consisting of high quality images. Disrupted cone AO-SLO images were matched with visual field test results and functional deficits were associated with a precise location on the montage, which allowed correlation of histological findings with functional changes determined by HVF. We also investigated whether adaptive optics imaging was more sensitive to anatomical changes compared with spectral-domain optical coherence tomography.

  7. Pre-erythrocytic antibody profiles induced by controlled human malaria infections in healthy volunteers under chloroquine prophylaxis

    PubMed Central

    Felgner, Philip L.; Roestenberg, Meta; Liang, Li; Hung, Christopher; Jain, Aarti; Pablo, Jozelyn; Nakajima-Sasaki, Rie; Molina, Douglas; Teelen, Karina; Hermsen, Cornelus C.; Sauerwein, Robert

    2013-01-01

    Complete sterile protection to Plasmodium falciparum (Pf) infection mediated by pre-erythrocytic immunity can be experimentally induced under chloroquine prophylaxis, through immunization with sporozoites from infected mosquitoes' bites (CPS protocol). To characterize the profile of CPS induced antibody (Ab) responses, we developed a proteome microarray containing 809 Pf antigens showing a distinct Ab profile with recognition of antigens expressed in pre-erythrocytic life-cycle stages. In contrast, plasma from naturally exposed semi-immune individuals from Kenya was skewed toward antibody reactivity against asexual blood stage antigens. CPS-immunized and semi-immune individuals generated antibodies against 192 and 202 Pf antigens, respectively, but only 60 antigens overlapped between the two groups. Although the number of reactive antigens varied between the CPS-immunized individuals, all volunteers reacted strongly against the pre-erythrocytic antigens circumsporozoite protein (CSP) and liver stage antigen 1 (LSA1). Well classified merozoite and erythrocytic antigens were strongly reactive in semi-immune individuals but lacking in the CPS immunized group. These data show that the antibody profile of CPS-immunized and semi-immune groups have quite distinct profiles reflecting their protective immunity; antibodies from CPS immunized individuals react strongly against pre-erythrocytic while semi-immune individuals mainly react against erythrocytic antigens. PMID:24351974

  8. Long-acting lipidated analogue of human pancreatic polypeptide is slowly released into circulation.

    PubMed

    Bellmann-Sickert, Kathrin; Elling, Christian E; Madsen, Andreas N; Little, Paul B; Lundgren, Karsten; Gerlach, Lars-Ole; Bergmann, Ralf; Holst, Birgitte; Schwartz, Thue W; Beck-Sickinger, Annette G

    2011-04-28

    The main disadvantages of peptide pharmaceuticals are their rapid degradation and excretion, their low hydrophilicity, and low shelf lifes. These bottlenecks can be circumvented by acylation with fatty acids (lipidation) or polyethylene glycol (PEGylation). Here, we describe the modification of a human pancreatic polypeptide analogue specific for the human (h)Y(2) and hY(4) receptor with PEGs of different size and palmitic acid. Receptor specificity was demonstrated by competitive binding studies. Modifications had only a small influence on binding affinities and no influence on secondary structure. Both modifications improved pharmacokinetic properties of the hPP analogue in vivo and in vitro, however, lipidation showed a greater resistance to degradation and excretion than PEGylation. Furthermore, the lipidated peptide is taken up and degraded solely by the liver but not the kidneys. Lipidation resulted in prolonged action of the hPP analogue in respect of reducing food intake in mice after subcutaneous administration. Therefore, the lipidated hPP analogue could constitute a potential new therapeutic agent against obesity.

  9. Optimization of propafenone analogues as antimalarial leads.

    PubMed

    Lowes, David J; Guiguemde, W Armand; Connelly, Michele C; Zhu, Fangyi; Sigal, Martina S; Clark, Julie A; Lemoff, Andrew S; Derisi, Joseph L; Wilson, Emily B; Guy, R Kiplin

    2011-11-10

    Propafenone, a class Ic antiarrythmic drug, inhibits growth of cultured Plasmodium falciparum. While the drug's potency is significant, further development of propafenone as an antimalarial would require divorcing the antimalarial and cardiac activities as well as improving the pharmacokinetic profile of the drug. A small array of propafenone analogues was designed and synthesized to address the cardiac ion channel and PK liabilities. Testing of this array revealed potent inhibitors of the 3D7 (drug sensitive) and K1 (drug resistant) strains of P. falciparum that possessed significantly reduced ion channel effects and improved metabolic stability. Propafenone analogues are unusual among antimalarial leads in that they are more potent against the multidrug resistant K1 strain of P. falciparum compared to the 3D7 strain.

  10. Enzymatic synthesis of lipid II and analogues.

    PubMed

    Huang, Lin-Ya; Huang, Shih-Hsien; Chang, Ya-Chih; Cheng, Wei-Chieh; Cheng, Ting-Jen R; Wong, Chi-Huey

    2014-07-28

    The emergence of antibiotic resistance has prompted active research in the development of antibiotics with new modes of action. Among all essential bacterial proteins, transglycosylase polymerizes lipid II into peptidoglycan and is one of the most favorable targets because of its vital role in peptidoglycan synthesis. Described in this study is a practical enzymatic method for the synthesis of lipid II, coupled with cofactor regeneration, to give the product in a 50-70% yield. This development depends on two key steps: the overexpression of MraY for the synthesis of lipid I and the use of undecaprenol kinase for the preparation of polyprenol phosphates. This method was further applied to the synthesis of lipid II analogues. It was found that MraY and undecaprenol kinase can accept a wide range of lipids containing various lengths and configurations. The activity of lipid II analogues for bacterial transglycolase was also evaluated.

  11. Polyamine analogues targeting epigenetic gene regulation.

    PubMed

    Huang, Yi; Marton, Laurence J; Woster, Patrick M; Casero, Robert A

    2009-11-04

    Over the past three decades the metabolism and functions of the polyamines have been actively pursued as targets for antineoplastic therapy. Interactions between cationic polyamines and negatively charged nucleic acids play a pivotal role in DNA stabilization and RNA processing that may affect gene expression, translation and protein activity. Our growing understanding of the unique roles that the polyamines play in chromatin regulation, and the discovery of novel proteins homologous with specific regulatory enzymes in polyamine metabolism, have led to our interest in exploring chromatin remodelling enzymes as potential therapeutic targets for specific polyamine analogues. One of our initial efforts focused on utilizing the strong affinity that the polyamines have for chromatin to create a backbone structure, which could be combined with active-site-directed inhibitor moieties of HDACs (histone deacetylases). Specific PAHAs (polyaminohydroxamic acids) and PABAs (polyaminobenzamides) polyamine analogues have demonstrated potent inhibition of the HDACs, re-expression of p21 and significant inhibition of tumour growth. A second means of targeting the chromatin-remodelling enzymes with polyamine analogues was facilitated by the recent identification of flavin-dependent LSD1 (lysine-specific demethylase 1). The existence of this enzyme demonstrated that histone lysine methylation is a dynamic process similar to other histone post-translational modifications. LSD1 specifically catalyses demethylation of mono- and di-methyl Lys4 of histone 3, key positive chromatin marks associated with transcriptional activation. Structural and catalytic similarities between LSD1 and polyamine oxidases facilitated the identification of biguanide, bisguanidine and oligoamine polyamine analogues that are potent inhibitors of LSD1. Cellular inhibition of LSD1 by these unique compounds led to the re-activation of multiple epigenetically silenced genes important in tumorigenesis. The use of

  12. Benchmarking analogue models of brittle thrust wedges

    NASA Astrophysics Data System (ADS)

    Schreurs, Guido; Buiter, Susanne J. H.; Boutelier, Jennifer; Burberry, Caroline; Callot, Jean-Paul; Cavozzi, Cristian; Cerca, Mariano; Chen, Jian-Hong; Cristallini, Ernesto; Cruden, Alexander R.; Cruz, Leonardo; Daniel, Jean-Marc; Da Poian, Gabriela; Garcia, Victor H.; Gomes, Caroline J. S.; Grall, Céline; Guillot, Yannick; Guzmán, Cecilia; Hidayah, Triyani Nur; Hilley, George; Klinkmüller, Matthias; Koyi, Hemin A.; Lu, Chia-Yu; Maillot, Bertrand; Meriaux, Catherine; Nilfouroushan, Faramarz; Pan, Chang-Chih; Pillot, Daniel; Portillo, Rodrigo; Rosenau, Matthias; Schellart, Wouter P.; Schlische, Roy W.; Take, Andy; Vendeville, Bruno; Vergnaud, Marine; Vettori, Matteo; Wang, Shih-Hsien; Withjack, Martha O.; Yagupsky, Daniel; Yamada, Yasuhiro

    2016-11-01

    We performed a quantitative comparison of brittle thrust wedge experiments to evaluate the variability among analogue models and to appraise the reproducibility and limits of model interpretation. Fifteen analogue modeling laboratories participated in this benchmark initiative. Each laboratory received a shipment of the same type of quartz and corundum sand and all laboratories adhered to a stringent model building protocol and used the same type of foil to cover base and sidewalls of the sandbox. Sieve structure, sifting height, filling rate, and details on off-scraping of excess sand followed prescribed procedures. Our analogue benchmark shows that even for simple plane-strain experiments with prescribed stringent model construction techniques, quantitative model results show variability, most notably for surface slope, thrust spacing and number of forward and backthrusts. One of the sources of the variability in model results is related to slight variations in how sand is deposited in the sandbox. Small changes in sifting height, sifting rate, and scraping will result in slightly heterogeneous material bulk densities, which will affect the mechanical properties of the sand, and will result in lateral and vertical differences in peak and boundary friction angles, as well as cohesion values once the model is constructed. Initial variations in basal friction are inferred to play the most important role in causing model variability. Our comparison shows that the human factor plays a decisive role, and even when one modeler repeats the same experiment, quantitative model results still show variability. Our observations highlight the limits of up-scaling quantitative analogue model results to nature or for making comparisons with numerical models. The frictional behavior of sand is highly sensitive to small variations in material state or experimental set-up, and hence, it will remain difficult to scale quantitative results such as number of thrusts, thrust spacing

  13. Antitumoral cyclic peptide analogues of chlamydocin.

    PubMed

    Bernardi, E; Fauchere, J L; Atassi, G; Viallefont, P; Lazaro, R

    1993-01-01

    A series of cyclic tetrapeptides bearing the bioactive alkylating group on an epsilon-amino-lysyl function have been examined for their antitumoral activity on L1210 and P388 murine leukemia cell lines. One analogue belonging to the chlamydocin family and bearing a beta-chloroethylnitrosourea group was found to be potent at inhibiting L1210 cell proliferation and had a higher therapeutic index than the reference compound bis-beta-chloroethylnitrosourea (BCNU) on the in vivo P388-induced leukemia model.

  14. Synthesis of constrained analogues of tryptophan

    PubMed Central

    Negrato, Marco; Abbiati, Giorgio; Dell’Acqua, Monica

    2015-01-01

    Summary A Lewis acid-catalysed diastereoselective [4 + 2] cycloaddition of vinylindoles and methyl 2-acetamidoacrylate, leading to methyl 3-acetamido-1,2,3,4-tetrahydrocarbazole-3-carboxylate derivatives, is described. Treatment of the obtained cycloadducts under hydrolytic conditions results in the preparation of a small library of compounds bearing the free amino acid function at C-3 and pertaining to the class of constrained tryptophan analogues. PMID:26664620

  15. The Brookhaven electron analogue, 1953--1957

    SciTech Connect

    Plotkin, M.

    1991-12-18

    The following topics are discussed on the Brookhaven electron analogue: L.J. Haworth and E.L. VanHorn letters; Original G.K. Green outline for report; General description; Parameter list; Mechanical Assembly; Alignment; Degaussing; Vacuum System; Injection System; The pulsed inflector; RF System; Ferrite Cavity; Pick-up electrodes and preamplifiers; Radio Frequency power amplifier; Lens supply; Controls and Power; and RF acceleration summary.

  16. Thymidine analogues for tracking DNA synthesis.

    PubMed

    Cavanagh, Brenton L; Walker, Tom; Norazit, Anwar; Meedeniya, Adrian C B

    2011-09-15

    Replicating cells undergo DNA synthesis in the highly regulated, S-phase of the cell cycle. Analogues of the pyrimidine deoxynucleoside thymidine may be inserted into replicating DNA, effectively tagging dividing cells allowing their characterisation. Tritiated thymidine, targeted using autoradiography was technically demanding and superseded by 5-bromo-2-deoxyuridine (BrdU) and related halogenated analogues, detected using antibodies. Their detection required the denaturation of DNA, often constraining the outcome of investigations. Despite these limitations BrdU alone has been used to target newly synthesised DNA in over 20,000 reviewed biomedical studies. A recent breakthrough in "tagging DNA synthesis" is the thymidine analogue 5-ethynyl-2'-deoxyuridine (EdU). The alkyne group in EdU is readily detected using a fluorescent azide probe and copper catalysis using 'Huisgen's reaction' (1,3-dipolar cycloaddition or 'click chemistry'). This rapid, two-step biolabelling approach allows the tagging and imaging of DNA within cells whilst preserving the structural and molecular integrity of the cells. The bio-orthogonal detection of EdU allows its application in more experimental assays than previously possible with other "unnatural bases". These include physiological, anatomical and molecular biological experimentation in multiple fields including, stem cell research, cancer biology, and parasitology. The full potential of EdU and related molecules in biomedical research remains to be explored.

  17. Blood Loss Estimation Using Gauze Visual Analogue

    PubMed Central

    Ali Algadiem, Emran; Aleisa, Abdulmohsen Ali; Alsubaie, Huda Ibrahim; Buhlaiqah, Noora Radhi; Algadeeb, Jihad Bagir; Alsneini, Hussain Ali

    2016-01-01

    Background Estimating intraoperative blood loss can be a difficult task, especially when blood is mostly absorbed by gauze. In this study, we have provided an improved method for estimating blood absorbed by gauze. Objectives To develop a guide to estimate blood absorbed by surgical gauze. Materials and Methods A clinical experiment was conducted using aspirated blood and common surgical gauze to create a realistic amount of absorbed blood in the gauze. Different percentages of staining were photographed to create an analogue for the amount of blood absorbed by the gauze. Results A visual analogue scale was created to aid the estimation of blood absorbed by the gauze. The absorptive capacity of different gauze sizes was determined when the gauze was dripping with blood. The amount of reduction in absorption was also determined when the gauze was wetted with normal saline before use. Conclusions The use of a visual analogue may increase the accuracy of blood loss estimation and decrease the consequences related to over or underestimation of blood loss. PMID:27626017

  18. The costal landslide from analogue experiments: perspectives and limitation

    NASA Astrophysics Data System (ADS)

    Del Ventisette, C.; Nolesini, T.; Moretti, S.; Fanti, R.

    2010-12-01

    Understanding the triggering mechanism of coastal landslides (triggered and/or developed at air-water interface) and their evolution is fundamental to evaluate their hazard and, predicting the energy, the associated tsunami risk. The aim of this work is to verify the suitability of analogue modelling to understand the triggering mechanism and the evolution of landslide along the costal line. As a starting case study the Sciara del Fuoco (SdF), northwest flank of the volcanic island of Stromboli (Italy), was chosen. The analogue modelling technique has been proven to represent an useful tool to understand many geological processes, as it allows studying the progressive deformation, providing also useful indications about the role of distinct factors controlling the final deformation pattern. The models simulated at a first approximation the geological geometries observed at Stromboli, a composite volcano forming the northernmost island of the Aeolian Archipelago (Tyrrhenian Sea). The activity of Stromboli volcano is characterized by a persistent mild explosive activity at the summit craters sporadically interrupted by episodes of lava effusion and violent paroxysmal explosions as in 2002-2003 and in 2007. During the 2002 effusion a large landslide occurred on the SdF. The landslide caused a tsunami, which produced severe damages along the island shores. A series of analogue models was performed to investigate the influence of two different types of triggering mechanism and the behaviour of landslides both in air and air-water interface: 1) surface bulging due to the intrusion of a dike; 2) accumulation of material due to an uppermost landslide or due to opening of a new vent. The models, constructed in a Plexiglas tank, were scaled to the natural prototype following the geometrical, rheological, kinematical and dynamical similarities (e.g. Hubbert, 1937; Ramberg, 1981). The modelling material (Fontainbleau sand and rice) was sieved on a slope, inclination of which

  19. Late Pleniglacial vegetation in eastern-central Europe: are there modern analogues in Siberia?

    NASA Astrophysics Data System (ADS)

    Magyari, Enikő Katalin; Kuneš, Petr; Jakab, Gusztáv; Sümegi, Pál; Pelánková, Barbora; Schäbitz, Frank; Braun, Mihály; Chytrý, Milan

    2014-07-01

    To characterize Late Pleniglacial (LPG: 26.5-15 ka cal BP) and particularly Last Glacial Maximum (LGM: 21 ± 2 ka cal BP) vegetation and climate, fossil pollen assemblages are often compared with modern pollen assemblages. Given the non-analogue climate of the LPG, a key question is how glacial pollen assemblages and thereby vegetation compare with modern vegetation. In this paper we present three LPG pollen records from the Carpathian Basin and the adjoining Carpathian Mountains to address this question and provide a concise compositional characterization of the LPG vegetation. Fossil pollen assemblages were compared with surface pollen spectra from the Altai-Sayan Mountains in southern Siberia. This area shows many similarities with the LPG vegetation of eastern-central Europe, and has long been considered as its best modern analogue. Ordination and analogue matching were used to characterize vegetation composition and find the best analogues. Our results show that few LPG pollen assemblages have statistically significant analogues in southern Siberia. When analogue pairings occur they suggest the predominance of wet and mesic grasslands and dry steppe in the studied region. Wooded vegetation types (continental and suboceanic hemiboreal forest, continental taiga) appear as significant analogues only in a few cases during the LGM and more frequently after 16 ka cal BP. These results suggest that the LPG landscape of the Carpathian Basin was dominated by dry steppe that occurred outside the river floodplains, while wet and mesic grasslands occurred in the floodplains and on other sites influenced by ground water. Woody vegetation mainly occurred in river valleys, on wet north-facing hillsides, and scattered trees were likely also present on the loess plateaus. The dominant woody species were Larix, Pinus sylvestris, Pinus mugo, Pinus cembra, Picea abies, Betula pendula/pubescens, Betula nana, Juniperus, Hippophaë rhamnoides, Populus, Salix and Alnus. The pollen

  20. Excitation and modulation of TRPA1, TRPV1, and TRPM8 channel-expressing sensory neurons by the pruritogen chloroquine.

    PubMed

    Than, Jonathan Y-X L; Li, Lin; Hasan, Raquibul; Zhang, Xuming

    2013-05-03

    The sensations of pain, itch, and cold often interact with each other. Pain inhibits itch, whereas cold inhibits both pain and itch. TRPV1 and TRPA1 channels transduce pain and itch, whereas TRPM8 transduces cold. The pruritogen chloroquine (CQ) was reported to excite TRPA1, leading to the sensation of itch. It is unclear how CQ excites and modulates TRPA1(+), TRPV1(+), and TRPM8(+) neurons and thus affects the sensations of pain, itch, and cold. Here, we show that only 43% of CQ-excited dorsal root ganglion neurons expressed TRPA1; as expected, the responses of these neurons were completely prevented by the TRPA1 antagonist HC-030031. The remaining 57% of CQ-excited neurons did not express TRPA1, and excitation was not prevented by either a TRPA1 or TRPV1 antagonist but was prevented by the general transient receptor potential canonical (TRPC) channel blocker BTP2 and the selective TRPC3 inhibitor Pyr3. Furthermore, CQ caused potent sensitization of TRPV1 in 51.9% of TRPV1(+) neurons and concomitant inhibition of TRPM8 in 48.8% of TRPM8(+) dorsal root ganglion neurons. Sensitization of TRPV1 is caused mainly by activation of the phospholipase C-PKC pathway following activation of the CQ receptor MrgprA3. By contrast, inhibition of TRPM8 is caused by a direct action of activated Gαq independent of the phospholipase C pathway. Our data suggest the involvement of the TRPC3 channel acting together with TRPA1 to mediate CQ-induced itch. CQ not only elicits itch by directly exciting itch-encoding neurons but also exerts previously unappreciated widespread actions on pain-, itch-, and cold-sensing neurons, leading to enhanced pain and itch.

  1. Co-delivery of docetaxel and chloroquine via PEO-PPO-PCL/TPGS micelles for overcoming multidrug resistance.

    PubMed

    Shi, Chunhuan; Zhang, Zhiqing; Shi, Jiaxing; Wang, Fang; Luan, Yuxia

    2015-11-30

    The combination of two or more drug is a promising strategy to suppress the multidrug resistance (MDR) through different action mechanisms. Co-delivery drugs via polymeric micelle can minimize the amount of each drug and reduce toxic side effects. Here we co-encapsulate anticancer drug docetaxel (DTX) and autophagy inhibitor chloroquine (CQ) in complex micelles based on poly(ethylene oxide)-block-poly(propylene oxide)-block-poly(ϵ-caprolactone) (PEO-PPO-PCL) and D-α-tocopheryl poly(ethylene glycol) (TPGS) for enhancing anticancer effects. Two series copolymer with different length of hydrophobic chain were synthesized (PEO68-PPO34-PCL18 and PEO68-PPO34-PCL36) in our lab. The dual-drug micelles possessed nanosize and sustained release profile in vitro. Drug-loaded micelles have low hemolysis rate (<5%), indicating that they are safe for use in vivo. Studies on cellular uptake demonstrate that the micelles can effectively accumulate in cancer cells. Furthermore, in vitro cytotoxicity with different DTX/CQ mass ratio are studied and the sample with a DTX/CQ ratio of 0.8/0.2 is found to have the strongest synergism effect. The co-delivery micelles have obviously higher therapeutic effects against MCF-7 and MCF-7/ADR cells than either free drug or individually DTX-loaded micelles. The IC50 values of DTX/CQ-loaded PEO68-PPO34-PCL18/TPGS and PEO68-PPO34-PCL36/TPGS micelles are 134.16 and 194.74 fold smaller than that of free DTX after 48 h treatment with MCF-7/ADR cells, respectively. Therefore, the as-prepared co-delivery of DTX and CQ based on PEO-PPO-PCL/TPGS micelles can provide a promising combined therapeutic strategy for enhanced antitumor therapy.

  2. Chloroquine attenuates LPS-mediated macrophage activation through miR-669n-regulated SENP6 protein translation

    PubMed Central

    Long, Yupeng; Liu, Xin; Wang, Ning; Zhou, Hong; Zheng, Jiang

    2015-01-01

    Chloroquine (CQ) has been shown to inhibit Toll-like receptor 4 (TLR4)-mediated monocyte and macrophage activation induced by lipopolysaccharide (LPS). However, the underlying mechanisms have not been completely elucidated. Recently, SUMO-specific protease 6 (SENP6) has been reported to suppress LPS-induced activation of macrophages through deSUMOlation of NF-κB essential modifier (NEMO). Here, we studied whether this molecular pathway may also be involved in CQ/LPS model. We found that CQ dose-dependently increased SENP6 protein, but not mRNA, in mouse macrophages, RAW264.7 cells. Overexpression of SENP6 in RAW264.7 cells significantly decreased the LPS-induced release of pro-inflammatory proteins, TNF-α, IL-6 and IFN-γ, while depletion of SENP6 in RAW264.7 cells significantly increased these proteins. Moreover, in LPS-treated RAW264.7 cells, CQ dose-dependently decreased the levels of microRNA-669n (miR-669n), which bound to 3’-UTR of SENP6 mRNA to inhibit its translation. Overexpression of miR-669n decreased SENP6, resulting in increased production of TNF-α, IL-6 and IFN-γ in RAW264.7 cells, while depletion of miR-669n increased SENP6, resulting in decreased production of TNF-α, IL-6 and IFN-γ in RAW264.7 cells. In vivo, delivery of miR-669n plasmids augmented the effects of LPS, while delivery of antisense of miR-669n (as-miR-669n) plasmids abolished the effects of LPS. Taken together, our data demonstrate a previously unappreciated molecular control of LPS-induced macrophage activation by CQ, through miR-669n-regulated SENP6 protein translation. PMID:26807181

  3. Mutant Plasmodium falciparum chloroquine resistance transporter in Hodeidah, Yemen: association with parasitologic indices and treatment-seeking behaviors.

    PubMed

    Abdul-Ghani, Rashad; Farag, Hoda F; Allam, Amal F; Shawky, Sherine M; Al-Mekhlafi, Abdulsalam M

    2013-12-01

    Malaria still represents a major health problem in Yemen, particularly in Hodeidah, despite continuing efforts to eliminate it. With the absence of clinically proven vaccines, chemotherapy with antimalarials is still greatly needed. Chloroquine (CQ) has been popular as the drug of choice for malaria control. However, Plasmodium falciparum resistance to CQ has been one of the main obstacles in malaria control and elimination. Although CQ is no longer the recommended antimalarial chemotherapy, it has remained the number one over-the-counter antimalarial drug in many endemic areas, including Yemen, and is still used for self-medication. In addition, promising reports on CQ efficacy reversal in many African countries brought it again into the scene. This has led to a growing interest in the possibility of its re-introduction, particularly with the concerns raised about the parasite resistance to artemisinin-based combination therapies. Therefore, the present study aimed at analyzing the CQ-associated pfcrt 76T mutation in P. falciparum isolates from patients with uncomplicated falciparum malaria in Hodeidah, west of Yemen. The association of treatment-seeking behaviors and antimalarial drug use with the pfcrt 76T mutant allele was also studied. It was revealed that there is still a sustained high frequency of this molecular marker among parasite isolates associated with younger age, decreased parasite density and the presence of gametocytes in blood. Delay in seeking treatment and frequent use of antimalarials were the behaviors significantly associated with the presence of the pfcrt 76T mutant allele among patients reporting a history of malaria treatment.

  4. Magnetic nanoparticles are highly toxic to chloroquine-resistant Plasmodium falciparum, dengue virus (DEN-2), and their mosquito vectors.

    PubMed

    Murugan, Kadarkarai; Wei, Jiang; Alsalhi, Mohamad Saleh; Nicoletti, Marcello; Paulpandi, Manickam; Samidoss, Christina Mary; Dinesh, Devakumar; Chandramohan, Balamurugan; Paneerselvam, Chellasamy; Subramaniam, Jayapal; Vadivalagan, Chithravel; Wei, Hui; Amuthavalli, Pandiyan; Jaganathan, Anitha; Devanesan, Sandhanasamy; Higuchi, Akon; Kumar, Suresh; Aziz, Al Thabiani; Nataraj, Devaraj; Vaseeharan, Baskaralingam; Canale, Angelo; Benelli, Giovanni

    2017-02-01

    A main challenge in parasitology is the development of reliable tools to prevent or treat mosquito-borne diseases. We investigated the toxicity of magnetic nanoparticles (MNP) produced by Magnetospirillum gryphiswaldense (strain MSR-1) on chloroquine-resistant (CQ-r) and sensitive (CQ-s) Plasmodium falciparum, dengue virus (DEN-2), and two of their main vectors, Anopheles stephensi and Aedes aegypti, respectively. MNP were studied by Fourier-transform infrared spectroscopy and transmission electron microscopy. They were toxic to larvae and pupae of An. stephensi, LC50 ranged from 2.563 ppm (1st instar larva) to 6.430 ppm (pupa), and Ae. aegypti, LC50 ranged from 3.231 ppm (1st instar larva) to 7.545 ppm (pupa). MNP IC50 on P. falciparum were 83.32 μg ml(-1) (CQ-s) and 87.47 μg ml(-1) (CQ-r). However, the in vivo efficacy of MNP on Plasmodium berghei was low if compared to CQ-based treatments. Moderate cytotoxicity was detected on Vero cells post-treatment with MNP doses lower than 4 μg ml(-1). MNP evaluated at 2-8 μg ml(-1) inhibited DEN-2 replication inhibiting the expression of the envelope (E) protein. In conclusion, our findings represent the first report about the use of MNP in medical and veterinary entomology, proposing them as suitable materials to develop reliable tools to combat mosquito-borne diseases.

  5. Rosiglitazone is a superior bronchodilator compared to chloroquine and β-adrenoceptor agonists in mouse lung slices

    PubMed Central

    2014-01-01

    Background Current therapy for relieving bronchoconstriction may be ineffective in severe asthma, particularly in the small airways. The aim of this study was to further characterise responses to the recently identified novel bronchodilators rosiglitazone (RGZ) and chloroquine (CQ) under conditions where β-adrenoceptor agonist efficacy was limited or impaired in mouse small airways within lung slices. Methods Relaxation to RGZ and CQ was assessed following submaximal methacholine (MCh) pre-contraction, in slices treated overnight with either RGZ, CQ or albuterol (ALB) (to induce β-adrenoceptor desensitization), and in slices treated with caffeine/ryanodine in which contraction is associated with increases in Ca2+ sensitivity in the absence of contractile agonist-induced Ca2+ oscillations. Furthermore, the effects of RGZ, CQ, ALB and isoproterenol (ISO) on the initiation and development of methacholine-induced contraction were also compared. Results RGZ and CQ, but not ALB or ISO, elicited complete relaxation with increasing MCh pre-contraction and maintained their potency and efficacy following β-adrenoceptor desensitization. RGZ, CQ and ALB maintained efficacy following overnight incubation with RGZ or CQ. Relaxation responses to all dilators were generally maintained but delayed after caffeine/ryanodine. Pre-treatment with RGZ, but not CQ, ALB or ISO, reduced MCh potency. Conclusions This study demonstrates the superior effectiveness of RGZ in comparison to CQ and β-adrenoceptor agonists as a dilator of mouse small airways. Further investigation of the mechanisms underlying the relatively greater efficacy of RGZ under these conditions are warranted and should be extended to include studies in human asthmatic airways. PMID:24621080

  6. Mode of inhibitory actions of acute and chronic chloroquine administration on the electrically stimulated mouse diaphragm in vitro.

    PubMed Central

    Okwuasaba, F. K.; Otubu, J. A.; Udoh, F. V.

    1990-01-01

    1. The effects of bath applied chloroquine (Chlo) and of acute and chronic Chlo administration on skeletal muscle reactivity to electrical stimulation and to drugs have been studied on mouse hemidiaphragm preparations in vitro. 2. Chlo (0.15-150 micrograms) produced a concentration-dependent inhibition twitch and tetanic contractions due to direct muscle stimulation (MS). Acute and chronic administration of Chlo (45 mg kg-1, i.p. daily, for 3-28 days) progressively shifted the concentration-response curve to bath-applied Chlo to the right, with maximum effect occurring from day 14 of Chlo pretreatment. 3. Acute and chronic administration of Chlo decreased the twitch and tetanus tension, raised the minimal fusion frequency (MFR) for tetanic contraction to occur and did not alter the twitch/tetanus tension ratio. Tetanus tension unlike twitch tension was not significantly decreased on day 3. 4. Caffeine (5-500 microM)--and isoprenaline (0.001-0.8 microM)-induced potentiations of twitch contraction were attenuated in a concentration-dependent manner by bath-applied Chlo and by acute and chronic administration of Chlo. Higher concentrations of caffeine (0.1-5 microM) and KCl (10 mM-130 mM) produced contracture of the muscle which was sensitive to inhibition by Chlo (50-150 microM). Moreover, the spike contractions superimposed on caffeine contracture were more sensitive to the inhibitory effect of Chlo than the contracture. 5. The inhibitory effects of dantrolene sodium and (+)-tubocurarine on MS and on indirectly stimulated hemidiaphragm respectively were not significantly altered by acute and chronic administration of Chlo. In contrast, the inhibitory concentration-response curve to procaine was shifted to the right.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:2282456

  7. The single crystal X-ray structure of β-hematin DMSO solvate grown in the presence of chloroquine, a β-hematin growth-rate inhibitor

    PubMed Central

    Gildenhuys, Johandie; le Roex, Tanya; Egan, Timothy J.; de Villiers, Katherine A.

    2012-01-01

    Single crystals of solvated β-hematin were grown from a DMSO solution containing the antimalarial drug chloroquine, a known inhibitor of β-hematin formation. In addition, a kinetics study employing biomimetic lipid-water emulsion conditions was undertaken to further investigate the effect of chloroquine and quinidine on the formation of β-hematin. Scanning electron microscopy shows that the external morphology of the β-hematin DMSO solvate crystals is almost indistinguishable from that of malaria pigment (hemozoin) and single crystal X-ray diffraction confirms the presence of μ-propionato coordination dimers of iron(III) protoporphyrin IX. The free propionic acid functional groups of adjacent dimers hydrogen bond to included DMSO molecules, rather than forming carboxylic acid dimers. The observed exponential kinetics were modeled using the Avrami equation, with an Avrami constant equal to 1. The decreased rate of β-hematin formation observed at low concentrations of both drugs could be accounted for by assuming a mechanism of drug adsorption to sites on the fastest growing face of β-hematin. This behavior was modeled using the Langmuir isotherm. Higher concentrations of drug resulted in decreased final yields of β-hematin, and an irreversible drug-induced precipitation of iron(III) protoporphyrin IX was postulated to account for this. The model permits determination of the equilibrium adsorption constant (Kads). The values for chloroquine (log Kads = 5.55 ± 0.03) and quinidine (log Kads = 4.92 ± 0.01) suggest that the approach may be useful as a relative probe of the mechanism of action of novel antimalarial compounds. PMID:23253048

  8. Chloroquine derivatives block the translocation pores and inhibit cellular entry of Clostridium botulinum C2 toxin and Bacillus anthracis lethal toxin.

    PubMed

    Kreidler, Anna-Maria; Benz, Roland; Barth, Holger

    2017-03-01

    The pathogenic bacteria Clostridium botulinum and Bacillus anthracis produce the binary protein toxins C2 and lethal toxin (LT), respectively. These toxins consist of a binding/transport (B7) component that delivers the separate enzyme (A) component into the cytosol of target cells where it modifies its specific substrate and causes cell death. The B7 components of C2 toxin and LT, C2IIa and PA63, respectively, are ring-shaped heptamers that bind to their cellular receptors and form complexes with their A components C2I and lethal factor (LF), respectively. After receptor-mediated endocytosis of the toxin complexes, C2IIa and PA63 insert into the membranes of acidified endosomes and form trans-membrane pores through which C2I and LF translocate across endosomal membranes into the cytosol. C2IIa and PA63 also form channels in planar bilayer membranes, and we used this approach earlier to identify chloroquine as a potent blocker of C2IIa and PA63 pores. Here, a series of chloroquine derivatives was investigated to identify more efficient toxin inhibitors with less toxic side effects. Chloroquine, primaquine, quinacrine, and fluphenazine blocked C2IIa and PA63 pores in planar lipid bilayers and in membranes of living epithelial cells and macrophages, thereby preventing the pH-dependent membrane transport of the A components into the cytosol and protecting cells from intoxication with C2 toxin and LT. These potent inhibitors of toxin entry underline the central role of the translocation pores for cellular uptake of binary bacterial toxins and as relevant drug targets, and might be lead compounds for novel pharmacological strategies against severe enteric diseases and anthrax.

  9. Swift heavy ion irradiation of interstellar dust analogues. Small carbonaceous species released by cosmic rays

    NASA Astrophysics Data System (ADS)

    Dartois, E.; Chabot, M.; Pino, T.; Béroff, K.; Godard, M.; Severin, D.; Bender, M.; Trautmann, C.

    2017-03-01

    Context. Interstellar dust grain particles are immersed in vacuum ultraviolet (VUV) and cosmic ray radiation environments influencing their physicochemical composition. Owing to the energetic ionizing interactions, carbonaceous dust particles release fragments that have direct impact on the gas phase chemistry. Aims: The exposure of carbonaceous dust analogues to cosmic rays is simulated in the laboratory by irradiating films of hydrogenated amorphous carbon interstellar analogues with energetic ions. New species formed and released into the gas phase are explored. Methods: Thin carbonaceous interstellar dust analogues were irradiated with gold (950 MeV), xenon (630 MeV), and carbon (43 MeV) ions at the GSI UNILAC accelerator. The evolution of the dust analogues is monitored in situ as a function of fluence at 40, 100, and 300 K. Effects on the solid phase are studied by means of infrared spectroscopy complemented by simultaneously recording mass spectrometry of species released into the gas phase. Results: Specific species produced and released under the ion beam are analyzed. Cross sections derived from ion-solid interaction processes are implemented in an astrophysical context.

  10. Molecular docking and QSAR of aplyronine A and analogues: potent inhibitors of actin

    NASA Astrophysics Data System (ADS)

    Hussain, Abrar; Melville, James L.; Hirst, Jonathan D.

    2010-01-01

    Actin-binding natural products have been identified as a potential basis for the design of cancer therapeutic agents. We report flexible docking and QSAR studies on aplyronine A analogues. Our findings show the macrolide `tail' to be fundamental for the depolymerisation effect of actin-binding macrolides and that it is the tail which forms the initial interaction with the actin rather than the macrocycle, as previously believed. Docking energy scores for the compounds were highly correlated with actin depolymerisation activity. The 3D-QSAR models were predictive, with the best model giving a q 2 value of 0.85 and a r 2 of 0.94. Results from the docking simulations and the interpretation from QSAR "coeff*stdev" contour maps provide insight into the binding mechanism of each analogue and highlight key features that influence depolymerisation activity. The results herein may aid the design of a putative set of analogues that can help produce efficacious and tolerable anti-tumour agents. Finally, using the best QSAR model, we have also made genuine predictions for an independent set of recently reported aplyronine analogues.

  11. Synthesis of novel tricyclic oxazolidinones by a tandem SN2 and SNAr reaction: SAR studies on conformationally constrained analogues of Linezolid.

    PubMed

    Selvakumar, N; Yadi Reddy, B; Sunil Kumar, G; Khera, Manoj Kumar; Srinivas, D; Sitaram Kumar, M; Das, Jagattaran; Iqbal, Javed; Trehan, Sanjay

    2006-08-15

    A series of conformationally constrained analogues of Linezolid were synthesised by employing a tandem SN(2) and SNAr reaction as the key step and tested for antibacterial activity. While the hexahydroazolo-quinoxaline compounds were inactive, the tetrahydroazolo-benzothiazine compounds exhibited interesting antibacterial activity. The introduction of fluorine in the aromatic ring further made the compounds more potent in acetamide compounds resulting in an interesting analogue 32. However, the introduction of fluorine (analogue 34) on the already potent non-fluorine thiocarbamate 21 did not have any influence on the activity.

  12. Monitoring of Geoengineering Effects and their Natural and Anthropogenic Analogues

    NASA Astrophysics Data System (ADS)

    Duren, R. M.; Robock, A.; Stephens, G. L.; MacMynowski, D. G.

    2011-12-01

    A number of climate intervention concepts, referred to as "geoengineering," are being considered as an alternative approach to managing climate change. However, before we go down the path of deliberate climate intervention including precursor field-experiments, it is essential that we take the necessary steps to validate our understanding that underpins any of the proposed intervention concepts in order to understand all likely consequences and put in place the necessary strategies for monitoring the expected and unintended consequences of such intervention. The Keck Institute for Space Studies (KISS) is undertaking a project to identify specific priorities for improved scientific understanding and focused efforts to address selected priorities. The KISS project does not advocate the deployment of geoengineering or monitoring systems for potential field experiments but is rather a precautionary study with the following goals: 1) enumeration of where major gaps in our understanding exist in solar radiation management (SRM) approaches, 2) identification of the research that would be required to improve understanding of such impacts including modeling and observation of natural and anthropogenic analogues to geoengineering, and 3) a preliminary assessment of where gaps exist in observations of relevance to SRMs and what is needed to fill such gaps. This study focuses primarily on SRM rather than other proposed geoengineering techniques such as carbon dioxide removal from the atmosphere because there exist a number of analogues to the SRMs that currently operate on Earth that provide a unique opportunity to assess our understanding of the response of the climate system to associated changes in solar radiation. Additionally, the processes related to these analogues are also fundamental to understanding climate change itself being of central relevance to how climate is forced by aerosol and respond through clouds, among other influences (e.g., such research has potential

  13. Properties of granular analogue model materials: A community wide survey

    NASA Astrophysics Data System (ADS)

    Klinkmüller, Matthias; Schreurs, Guido; Rosenau, Matthias; Kemnitz, Helga

    2016-04-01

    We report the material properties of 26 granular analogue materials used in 14 analogue modelling laboratories. We determined physical characteristics such as bulk density, grain size distribution, and grain shape, and performed ring shear tests to determine friction angles and cohesion, and uniaxial compression tests to evaluate the compaction behaviour. Mean grain size of the materials varied between (c. 100 and 400 micrometer). Analysis of grain shape factors show that the four different classes of granular materials (14 quartz sands, 5 dyed quartz sands, 4 heavy mineral sands and 3 size fractions of glass beads) can be broadly divided into two groups consisting of 12 angular and 14 rounded materials. Grain shape has an influence on friction angles, with most angular materials having higher internal friction angles (between c. 35° and 40°) than rounded materials, whereas well-rounded glass beads have the lowest internal friction angles (between c. 25° and 30°). We interpret this as an effect of intergranular sliding versus rolling . Most angular materials have also higher basal friction angles (tested for a specific foil) than more rounded materials, suggesting that angular grains scratch and wear the foil., Most materials have a cohesion in the order of 10-100 Pa except for well-rounded glass beads, which show a trend towards a quasi-cohesionless (C <10 Pa) Coulomb-type material. The uniaxial confined compression tests reveal that rounded grains generally show less compaction than angular grains. We interpret this to be related to the initial packing density reached during sieving which is higher for rounded grains than for angular grains. Ring-shear test data show that angular grains undergo a longer strain-hardening phase than more rounded materials. This might explain why analogue models consisting of angular grains accommodate deformation in a more distributed manner prior to strain localisation than models consisting of rounded grains. Also, models

  14. Transitional lava flows as potential analogues for lunar impact melts

    NASA Astrophysics Data System (ADS)

    Neish, Catherine; Hughes, Scott; Hamilton, Christopher; Kobs Nawotniak, Shannon; Garry, William Brent; Skok, John Roma; Elphic, Richard; Carter, Lynn; Bandfield, Joshua; Osinski, Gordon; Lim, Darlene; Heldmann, Jennifer

    2015-11-01

    Lunar impact melt deposits are among the roughest surface materials on the Moon at the decimeter scale, even though they appear smooth at the meter scale. These characteristics distinguish them from well-studied terrestrial analogues, such as Hawaiian pāhoehoe and ´a´ā lava flows. The morphology of impact melt deposits can be related to their emplacement conditions, so understanding the origin of these unique surface properties will inform us as to the circumstances under which they were formed. Although there is no perfect archetype for lunar impact melts on Earth, certain terrestrial environments lend themselves as functional analogues. Specifically, a variety of transitional lava flow types develop if the surface of a pāhoehoe-like flow is disrupted, producing ‘slabby’ or ‘rubbly’ flows that are extremely rough at the decimeter scale. We investigated the surface roughness of transitional lava flows at Craters of the Moon (COTM) National Monument, comparing radar imagery and high-resolution topographic profiles to similar data sets acquired by the Lunar Reconnaissance Orbiter for impact melt deposits on the Moon. Results suggest that the lava flows at COTM have similar radar properties to lunar impact melt deposits, but the terrestrial flows are considerably rougher at the meter scale. It may be that lunar impact melts represent a unique lava type not observed on Earth, whose surface texture is influenced by their high emplacement temperatures and/or cooling in a vacuum. Information about the surface properties of lunar impact melt deposits will be critical for future landed missions that wish to sample these materials.

  15. Polyamine analogues bind human serum albumin.

    PubMed

    Beauchemin, R; N'soukpoé-Kossi, C N; Thomas, T J; Thomas, T; Carpentier, R; Tajmir-Riahi, H A

    2007-10-01

    Polyamine analogues show antitumor activity in experimental models, and their ability to alter activity of cytotoxic chemotherapeutic agents in breast cancer is well documented. Association of polyamines with nucleic acids and protein is included in their mechanism of action. The aim of this study was to examine the interaction of human serum albumin (HSA) with several polyamine analogues, such as 1,11-diamino-4,8-diazaundecane (333), 3,7,11,15-tetrazaheptadecane.4HCl (BE-333), and 3,7,11,15,19-pentazahenicosane.5HCl (BE-3333), in aqueous solution at physiological conditions using a constant protein concentration and various polyamine contents (microM to mM). FTIR, UV-visible, and CD spectroscopic methods were used to determine the polyamine binding mode and the effects of polyamine complexation on protein stability and secondary structure. Structural analysis showed that polyamines bind nonspecifically (H-bonding) via polypeptide polar groups with binding constants of K333 = 9.30 x 10(3) M(-1), KBE-333 = 5.63 x 10(2) M(-1), and KBE-3333 = 3.66 x 10(2) M(-1). The protein secondary structure showed major alterations with a reduction of alpha-helix from 55% (free protein) to 43-50% and an increase of beta-sheet from 17% (free protein) to 29-36% in the 333, BE-333, and BE-3333 complexes, indicating partial protein unfolding upon polyamine interaction. HSA structure was less perturbed by polyamine analogues compared to those of the biogenic polyamines.

  16. New synthetic approaches towards analogues of bedaquiline.

    PubMed

    Priebbenow, Daniel L; Barbaro, Lisa; Baell, Jonathan B

    2016-10-12

    Multi-drug resistant tuberculosis (MDR-TB) is of growing global concern and threatens to undermine increasing efforts to control the worldwide spread of tuberculosis (TB). Bedaquiline has recently emerged as a new drug developed to specifically treat MDR-TB. Despite being highly effective as a result of its unique mode of action, bedaquiline has been associated with significant toxicities and as such, safety concerns are limiting its clinical use. In order to access pharmaceutical agents that exhibit an improved safety profile for the treatment of MDR-TB, new synthetic pathways to facilitate the preparation of bedaquiline and analogues thereof have been discovered.

  17. The Lehmer Matrix and Its Recursive Analogue

    DTIC Science & Technology

    2010-01-01

    for failing to comply with a collection of information if it does not display a currently valid OMB control number . 1. REPORT DATE 2010 2. REPORT...TYPE 3. DATES COVERED 00-00-2010 to 00-00-2010 4. TITLE AND SUBTITLE The Lehmer matrix and its recursive analogue 5a. CONTRACT NUMBER 5b...GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) 5d. PROJECT NUMBER 5e. TASK NUMBER 5f. WORK UNIT NUMBER 7. PERFORMING ORGANIZATION NAME(S) AND

  18. U.S. Nuclear Regulatory Commission natural analogue research program

    SciTech Connect

    Kovach, L.A.; Ott, W.R.

    1995-09-01

    This article describes the natural analogue research program of the U.S. Nuclear Regulatory Commission (US NRC). It contains information on the regulatory context and organizational structure of the high-level radioactive waste research program plan. It also includes information on the conditions and processes constraining selection of natural analogues, describes initiatives of the US NRC, and describes the role of analogues in the licensing process.

  19. CO2 Removal using a Synthetic Analogue of Carbonic Anhydrase

    SciTech Connect

    Cordatos, Harry

    2010-09-14

    Project attempts to develop a synthetic analogue for carbonic anhydrase and incorporate it in a membrane for separation of CO2 from coal power plant flue gas. Conference poster presents result of first 9 months of project progress including concept, basic system architecture and membrane properties target, results of molecular modeling for analogue - CO2 interaction, and next steps of testing analogue resistance to flue gas contaminants.

  20. Synthesis of a cyanopeptide-analogue with trypsin activating properties.

    PubMed

    Radau, G; Rauh, D

    2000-04-17

    An efficient synthesis of a peptidic analogue of cyanobacterial metabolites with proposed serine protease inhibitory activity has been developed. Surprisingly, one trypsin activating compound was obtained.

  1. Multiple spectroscopic and magnetic techniques show that chloroquine induces formation of the μ-oxo dimer of ferriprotoporphyrin IX.

    PubMed

    Kuter, David; Benjamin, Stefan J; Egan, Timothy J

    2014-04-01

    Interaction of the antimalarial chloroquine (CQ) with ferriprotoporphyrin IX, Fe(III)PPIX, was investigated in aqueous solution (pH7.4) and as a precipitate from aqueous medium at pH5.0. In solution, spectrophotometric titrations indicated strong association (logKobs 13.3±0.2) and a Job plot gave a stoichiometry of 1:2 CQ:Fe(III)PPIX. UV-visible absorbance and magnetic circular dichroism spectra of the complex were compared to various Fe(III)PPIX species. Close similarity to the spectra of the μ-oxo dimer, μ-[Fe(III)PPIX]2O, was revealed. The induction of this species by CQ was confirmed by magnetic susceptibility measurements using the Evans NMR method. The observed low-magnetic moment (2.25±0.02 μB) could only be attributed to antiferromagnetically coupled Fe(III) centers. The value was comparable to that of μ-[Fe(III)PPIX]2O (2.0±0.1 μB). In the solid-state, mass spectrometry confirmed the presence of CQ in the complex. Dissolution of this solid in aqueous solution (pH7.4) resulted in a solution with a UV-visible spectrum consistent with the same 1:2 stoichiometry observed in the Job plot. Magnetic susceptibility measurements made on the solid using an Evans balance produced a magnetic moment (2.3±0.1 μB) consistent with that in solution. Diffusion coefficients of CQ and its complex with Fe(III)PPIX were measured in aqueous solution (3.3±0.3 and 0.6±0.2×10(-10) m(2)·s(-1), respectively). The latter was used in conjunction with an empirical relationship between diffusion coefficient and molar volume to estimate the degree of aggregation. The findings suggest the formation of a 2:4 CQ:Fe(III)PPIX complex in aqueous solution at pH7.4.

  2. In Vitro Increase in Chloroquine Accumulation Induced by Dihydroethano- and Ethenoanthracene Derivatives in Plasmodium falciparum-Parasitized Erythrocytes

    PubMed Central

    Pradines, Bruno; Alibert, Sandrine; Houdoin, Carole; Santelli-Rouvier, Christiane; Mosnier, Joel; Fusai, Thierry; Rogier, Christophe; Barbe, Jacques; Parzy, Daniel

    2002-01-01

    The effects of a series of dihydroethano- and ethenoanthracene derivatives on chloroquine (CQ) accumulation in CQ-susceptible strain 3D7 and CQ-resistant clone W2 were assessed. The levels of CQ accumulation increased little or none in CQ-susceptible strain 3D7 and generally increased markedly in CQ-resistant strain W2. At 10 μM, 28 compounds yielded cellular accumulation ratios (CARs) greater than that observed with CQ alone in W2. At 10 μM, in strain W2, 21 of 31 compounds had CQ CARs two or more times higher than that of CQ alone, 15 of 31 compounds had CQ CARs three or more times higher than that of CQ alone, 13 of 31 compounds had CQ CARs four or more times higher than that of CQ alone, and 9 of 31 compounds had CQ CARs five or more times higher than that of CQ alone. At 1 μM, 17 of 31 compounds had CQ CARs two or more times higher than that of CQ alone, 12 of 31 compounds had CQ CARs three or more times higher than that of CQ alone, 6 of 31 compounds had CQ CARs four or more times higher than that of CQ alone, and 3 of 31 compounds had CQ CARs five or more times higher than that of CQ alone. At 1 μM, 17 of 31 compounds were more potent inducers of CQ accumulation than verapamil and 12 of 31 compounds were more potent inducers of CQ accumulation than promethazine. The nature of the basic group seems to be associated with increases in the levels of CQ accumulation. At 1 and 10 μM, 10 of 14 and 13 of 14 compounds with amino group (amines and diamines), respectively, had CARs ≥3, while at 1 and 10 μM, only 1 of the 13 derivatives with amido groups had CARs ≥3. Among 12 of the 31 compounds which were more active inducers of CQ accumulation than promethazine at 1 μM, 10 had amino groups and 1 had an amido group. PMID:12069956

  3. Long-term predictions using natural analogues

    SciTech Connect

    Ewing, R.C.

    1995-09-01

    One of the unique and scientifically most challenging aspects of nuclear waste isolation is the extrapolation of short-term laboratory data (hours to years) to the long time periods (10{sup 3}-10{sup 5} years) required by regulatory agencies for performance assessment. The direct validation of these extrapolations is not possible, but methods must be developed to demonstrate compliance with government regulations and to satisfy the lay public that there is a demonstrable and reasonable basis for accepting the long-term extrapolations. Natural systems (e.g., {open_quotes}natural analogues{close_quotes}) provide perhaps the only means of partial {open_quotes}validation,{close_quotes} as well as data that may be used directly in the models that are used in the extrapolation. Natural systems provide data on very large spatial (nm to km) and temporal (10{sup 3}-10{sup 8} years) scales and in highly complex terranes in which unknown synergisms may affect radionuclide migration. This paper reviews the application (and most importantly, the limitations) of data from natural analogue systems to the {open_quotes}validation{close_quotes} of performance assessments.

  4. Self-Powered Analogue Smart Skin.

    PubMed

    Shi, Mayue; Zhang, Jinxin; Chen, Haotian; Han, Mengdi; Shankaregowda, Smitha A; Su, Zongming; Meng, Bo; Cheng, Xiaoliang; Zhang, Haixia

    2016-04-26

    The progress of smart skin technology presents unprecedented opportunities for artificial intelligence. Resolution enhancement and energy conservation are critical to improve the perception and standby time of robots. Here, we present a self-powered analogue smart skin for detecting contact location and velocity of the object, based on a single-electrode contact electrification effect and planar electrostatic induction. Using an analogue localizing method, the resolution of this two-dimensional smart skin can be achieved at 1.9 mm with only four terminals, which notably decreases the terminal number of smart skins. The sensitivity of this smart skin is remarkable, which can even perceive the perturbation of a honey bee. Meanwhile, benefiting from the triboelectric mechanism, extra power supply is unnecessary for this smart skin. Therefore, it solves the problems of batteries and connecting wires for smart skins. With microstructured poly(dimethylsiloxane) films and silver nanowire electrodes, it can be covered on the skin with transparency, flexibility, and high sensitivity.

  5. Arene-Ru(II)-Chloroquine Complexes Interact With DNA, Induce Apoptosis on Human Lymphoid Cell Lines and Display Low Toxicity to Normal Mammalian Cells

    PubMed Central

    Martínez, Alberto; Rajapakse, Chandima S.K.; Varela-Ramírez, Armando; Lema, Carolina; Aguilera, Renato J.; Sánchez-Delgado, Roberto A.

    2010-01-01

    The complexes [Ru(η6-p-cymene)(CQ)Cl2] (1), [Ru(η6-benzene)(CQ)Cl2] (2), [Ru(η6-p-cymene)(CQ)(H2O)2][BF4]2 (3), [Ru(η6- p-cymene)(en)(CQ)][PF6]2 (4), [Ru(η6-p-cymene)(η6-CQDP)][BF4]2 (5) (CQ = chloroquine base; CQDP = chloroquine diphosphate; en = ethylenediamine) interact with DNA to a comparable extent to that of CQ and in analogous intercalative manner with no evidence for any direct contribution of the metal, as shown by spectrophotometric and fluorimetric titrations, thermal denaturation measurements, circular dichroism spectroscopy and electrophoresis mobility shift assays. Complexes 1–5 induced cytotoxicity in Jurkat and SUP-T1 cancer cells primarily via apoptosis. Despite the similarities in the DNA binding behavior of complexes 1–5 with those of CQ the antitumor properties of the metal drugs do not correlate with those of CQ, indicating that DNA is not the principal target in the mechanism of cytotoxicity of these compounds. Importantly, the Ru-CQ complexes are generally less toxic toward normal mouse splenocytes and human foreskin fibroblast cells than the standard antimalarial drug CQDP and therefore this type of compound shows promise for drug development. PMID:20605217

  6. Chloroquine-induced nitric oxide as a potential treatment of erectile dysfunction associated with the metabolic syndrome: the science and the fiction.

    PubMed

    Ahmed, Mohamed H

    2007-05-01

    Erectile dysfunction is an important cause of decreased quality of life in men. It is estimated that approximately 30 million men in the US and 100 million worldwide may have erectile dysfunction. Data from epidemiological studies indicate a higher prevalence of impotence in obese men. Obesity may be a risk factor for sexual dysfunction in both sexes; data for the metabolic syndrome are very preliminary and need to be confirmed in larger epidemiological studies. The high prevalence of erectile dysfunction in patients with cardiovascular risk factors suggests that abnormalities of the vasodilator system of penile arteries play an important role in the pathophysiology of erectile dysfunction. Nitric oxide released during non-adrenergic, non-cholinergic neurotransmission and from the endothelium is probably the principal neurotransmitter mediating penile erection. It has been shown that chloroquine administration was associated with an increase in nitric oxide synthesis. Chloroquine was also postulated to enhance insulin sensitivity, which suggests potential benefit in treating the metabolic syndrome-related erectile dysfunction.

  7. Enhanced non-peptidergic intraepidermal fiber density and an expanded subset of chloroquine-responsive trigeminal neurons in a mouse model of dry skin itch

    PubMed Central

    Valtcheva, Manouela V.; Samineni, Vijay K.; Golden, Judith P.; Gereau, Robert W.; Davidson, Steve

    2015-01-01

    Chronic pruritic conditions are often associated with dry skin and loss of epidermal barrier integrity. In this study, repeated application of acetone and ether, followed by water (AEW) to the cheek skin of mice produced persistent scratching behavior with no increase in pain-related forelimb wiping, indicating the generation of itch without pain. Cheek skin immunohistochemistry showed a 64.5% increase in total epidermal innervation in AEW-treated mice compared to water-treated controls. This increase was independent of scratching, because mice prevented from scratching by Elizabethan collars showed similar hyperinnervation. To determine the effects of dry skin treatment on specific subsets of peripheral fibers, we examined Ret-positive, CGRP-positive, and GFRα3-positive intraepidermal fiber density. AEW treatment increased Ret-positive fibers, but not CGRP-positive or GFRα3-positive fibers, suggesting that a specific subset of non-peptidergic fibers could contribute to dry skin itch. To test whether trigeminal ganglion neurons innervating the cheek exhibited altered excitability after AEW treatment, primary cultures of retrogradely labeled neurons were examined using whole-cell patch clamp electrophysiology. AEW treatment produced no differences in measures of excitability compared to water-treated controls. In contrast, a significantly higher proportion of trigeminal ganglion neurons were responsive to the non-histaminergic pruritogen chloroquine after AEW treatment. We conclude that non-peptidergic, Ret-positive fibers and chloroquine-sensitive neurons may contribute to dry skin pruritus. PMID:25640289

  8. Establishment and application of a novel isothermal amplification assay for rapid detection of chloroquine resistance (K76T) in Plasmodium falciparum

    PubMed Central

    Chahar, Madhvi; Mishra, Neelima; Anvikar, Anup; Dixit, Rajnikant; Valecha, Neena

    2017-01-01

    Chloroquine (CQ) resistance in Plasmodium falciparum is determined by the mutations in the chloroquine resistance transporter (Pfcrt) gene. The point mutation at codon 76 (K76T), which has been observed in more than 91% of P. falciparum isolates in India, is the major determinant of CQ resistance. To overcome the limitations and challenges of traditional methods, in this investigation we developed an easy to use loop mediated isothermal amplification (LAMP) protocol for rapid detection of the K76T mutation associated with CQ resistance in P. falciparum with naked eye visualization. In- house designed primers were synthesized and optimized to specifically distinguish the CQ resistant mutants of P. falciparum. The LAMP reaction was optimal at 61 °C for 60 min and calcein dye was added prior to amplification to enable visual detection. We demonstrate the detection limit of <2 ng/μl respectively, supporting the high sensitivity of this calcein based LAMP method. To the best of our knowledge this is the first report on the establishment of an easy, reliable and cost effective LAMP assay for rapid and specific detection of highly CQ resistance in P. falciparum malaria. PMID:28134241

  9. Synthesis and photophysical characterisation of a fluorescent nucleoside analogue that signals the presence of an abasic site in RNA.

    PubMed

    Tanpure, Arun A; Srivatsan, Seergazhi G

    2012-11-05

    The synthesis and site-specific incorporation of an environment-sensitive fluorescent nucleoside analogue (2), based on a 5-(benzofuran-2-yl)pyrimidine core, into DNA oligonucleotides (ONs), and its photophysical properties within these ONs are described. Interestingly and unlike 2-aminopurine (a widely used nucleoside analogue probe), when incorporated into an ON and hybridised with a complementary ON, the emissive nucleoside 2 displays significantly higher emission intensity than the free nucleoside. Furthermore, photophysical characterisation shows that the fluorescence properties of the nucleoside analogue within ONs are significantly influenced by flanking bases, especially by guanosine. By utilising the responsiveness of the nucleoside to changes in base environment, a DNA ON reporter labelled with the emissive nucleoside 2 was constructed; this signalled the presence of an abasic site in a model depurinated sarcin/ricin RNA motif of a eukaryotic 28S rRNA.

  10. A nonlinear dynamic analogue model of substorms

    NASA Astrophysics Data System (ADS)

    Klimas, A. J.; Baker, D. N.; Roberts, D. A.; Fairfield, D. H.; Büchner, J.

    Linear prediction filter studies have shown that the magnetospheric response to energy transfer from the solar wind contains both directly driven and unloading components. These studies have also shown that the magnetospheric response is significantly nonlinear and, thus, the linear prediction filtering technique and other correlative techniques which assume a linear magnetospheric response cannot give a complete deacription of that response. Here, the solar wind-magnetosphere interaction is discussed within the framework of deterministic nonlinear dynamics. An earlier dripping faucet mechanical analogue to the magnetosphere is first reviewed and then the plasma physical counterpart to the mechanical model is constructed. A Faraday loop in the magnetotail is considered and the relationship of electric potentials on the loop to changes in the magnetic flux threading the loop is developed. This approach leads to a model of geomagnetic activity which is similar to the earlier mechanical model but described in terms of the geometry and plasma contents of the magnetotail. This Faraday loop response model contains analogues to both the directly driven and the storage-release magnetospheric responses and it includes, in a fundamental way, the inherent nonlinearity of the solar wind-magnetosphere system. It can be chancterized as a nonlinear, damped harmonic oscillator that is driven by the loading-unloading substorm cycle. The model is able to explain many of the features of the linear prediction filter results. In particular, at low geomagnetic activity levels the model exbibits the "regular dripping" response which provides an explanation for the unloading component at 1 hour lag in the linear prediction filters. Further, the model suggests that the disappearance of the unloading component in the linear prediction filters at high geomagnetic activity levels is due to a chaotic transition beyond which the loading-unloading mechanism becomes aperiodic. The model predicts

  11. Selenium analogues of raloxifene as promising antiproliferative agents in treatment of breast cancer.

    PubMed

    Arsenyan, Pavel; Paegle, Edgars; Domracheva, Ilona; Gulbe, Anita; Kanepe-Lapsa, Iveta; Shestakova, Irina

    2014-11-24

    Synthetic protocols for the preparation of selenium analogues of raloxifene were elaborated. General aim of the current research is to improve the positive impact of selenium atom introduction in drug design. Antiproliferative activity on CCL-8 (mouse sarcoma), MDA-MB-435s (human melanoma), MES-SA (human uterus sarcoma), MCF-7 (human breast adenocarcinoma), HT-1080 (human fibrosarcoma), MG-22A (mouse hepatoma) tumor cell lines, and normal cell line NIH 3T3 (mouse fibroblasts) was studied. Influence of aminoethoxy "tail" and benzoyl group position on SAR was discussed. Results of in vivo studies on BALB/c female mice with 4T1 cell induced breast cancer model showed that selenium analogue of raloxifene is able to suppress estrogen-depending tumor growth.

  12. Tren-based analogues of bacillibactin: structure and stability.

    PubMed

    Dertz, Emily A; Xu, Jide; Raymond, Kenneth N

    2006-07-10

    Synthetic analogues were designed to highlight the effect of the glycine moiety of bacillibactin on the overall stability of the ferric complex as compared to synthetic analogues of enterobactin. Insertion of a variety of amino acids to catecholamide analogues based on a Tren (tris(2-aminoethyl)amine) backbone increased the overall acidity of the ligands, causing an enhancement of the stability of the resulting ferric complex as compared to TRENCAM. Solution thermodynamic behavior of these siderophores and their synthetic analogues was investigated through potentiometric and spectrophotometric titrations. X-ray crystallography, circular dichroism, and molecular modeling were used to determine the chirality and geometry of the ferric complexes of bacillibactin and its analogues. In contrast to the Tren scaffold, addition of a glycine to the catechol chelating arms causes an inversion of the trilactone backbone, resulting in opposite chiralities of the two siderophores and a destabilization of the ferric complex of bacillibactin compared to ferric enterobactin.

  13. Analogue Divider by Averaging a Triangular Wave

    NASA Astrophysics Data System (ADS)

    Selvam, Krishnagiri Chinnathambi

    2017-03-01

    A new analogue divider circuit by averaging a triangular wave using operational amplifiers is explained in this paper. The triangle wave averaging analog divider using operational amplifiers is explained here. The reference triangular waveform is shifted from zero voltage level up towards positive power supply voltage level. Its positive portion is obtained by a positive rectifier and its average value is obtained by a low pass filter. The same triangular waveform is shifted from zero voltage level to down towards negative power supply voltage level. Its negative portion is obtained by a negative rectifier and its average value is obtained by another low pass filter. Both the averaged voltages are combined in a summing amplifier and the summed voltage is given to an op-amp as negative input. This op-amp is configured to work in a negative closed environment. The op-amp output is the divider output.

  14. Naturalness in an emergent analogue spacetime.

    PubMed

    Liberati, Stefano; Visser, Matt; Weinfurtner, Silke

    2006-04-21

    Effective field theories (EFTs) have been widely used as a framework in order to place constraints on the Planck suppressed Lorentz violations predicted by various models of quantum gravity. There are, however, technical problems in the EFT framework when it comes to ensuring that small Lorentz violations remain small--this is the essence of the "naturalness" problem. Herein we present an "emergent" spacetime model, based on the "analogue gravity" program, by investigating a specific condensed-matter system. Specifically, we consider the class of two-component BECs subject to laser-induced transitions between the components, and we show that this model is an example for Lorentz invariance violation due to ultraviolet physics. Furthermore, our model explicitly avoids the naturalness problem, and makes specific suggestions regarding how to construct a physically reasonable quantum gravity phenomenology.

  15. Derivatisable Cyanobactin Analogues: A Semisynthetic Approach

    PubMed Central

    Oueis, Emilia; Adamson, Catherine; Mann, Greg; Ludewig, Hannes; Redpath, Philip; Migaud, Marie

    2015-01-01

    Abstract Many natural cyclic peptides have potent and potentially useful biological activities. Their use as therapeutic starting points is often limited by the quantities available, the lack of known biological targets and the practical limits on diversification to fine‐tune their properties. We report the use of enzymes from the cyanobactin family to heterocyclise and macrocyclise chemically synthesised substrates so as to allow larger‐scale syntheses and better control over derivatisation. We have made cyclic peptides containing orthogonal reactive groups, azide or dehydroalanine, that allow chemical diversification, including the use of fluorescent labels that can help in target identification. We show that the enzymes are compatible and efficient with such unnatural substrates. The combination of chemical synthesis and enzymatic transformation could help renew interest in investigating natural cyclic peptides with biological activity, as well as their unnatural analogues, as therapeutics. PMID:26507241

  16. A simple analogue of lung mechanics.

    PubMed

    Sherman, T F

    1993-12-01

    A model of the chest and lungs can be easily constructed from a bottle of water, a balloon, a syringe, a rubber stopper, glass and rubber tubing, and clamps. The model is a more exact analogue of the body than the classic apparatus of Hering in two respects: 1) the pleurae and intrapleural fluid are represented by water rather than air, and 2) the subatmospheric "intrapleural" pressure is created by the elasticity of the "lung" (balloon) rather than by a vacuum pump. With this model, students can readily see how the lung is inflated and deflated by movements of the "diaphragm and chest" (syringe plunger) and how intrapleural pressures change as this is accomplished.

  17. Terrestrial Analogues for Lunar Impact Melt Flows

    NASA Technical Reports Server (NTRS)

    Neish, C. D.; Hamilton, C. W.; Hughes, S. S.; Nawotniak, S. Kobs; Garry, W. B.; Skok, J. R.; Elphic, R. C.; Schaefer, E.; Carter, L. M.; Bandfield, J. L.; Osinski, G. R.; Lim, D.; Heldmann, J. L.

    2016-01-01

    Lunar impact melt deposits have unique physical properties. They have among the highest observed radar returns at S-Band (12.6 cm wavelength), implying that they are rough at the decimeter scale. However, they are also observed in high-resolution optical imagery to be quite smooth at the meter scale. These characteristics distinguish them from well-studied terrestrial analogues, such as Hawaiian pahoehoe and ?a ?a lava flows. The morphology of impact melt deposits can be related to their emplacement conditions, so understanding the origin of these unique surface properties will help to inform us as to the circumstances under which they were formed. In this work, we seek to find a terrestrial analogue for well-preserved lunar impact melt flows by examining fresh lava flows on Earth. We compare the radar return and high-resolution topographic variations of impact melt flows to terrestrial lava flows with a range of surface textures. The lava flows examined in this work range from smooth Hawaiian pahoehoe to transitional basaltic flows at Craters of the Moon (COTM) National Monument and Preserve in Idaho to rubbly and spiny pahoehoe-like flows at the recent eruption at Holuhraun in Iceland. The physical properties of lunar impact melt flows appear to differ from those of all the terrestrial lava flows studied in this work. This may be due to (a) differences in post-emplacement modification processes or (b) fundamental differences in the surface texture of the melt flows due to the melts' unique emplacement and/or cooling environment. Information about the surface properties of lunar impact melt deposits will be critical for future landed missions that wish to sample these materials.

  18. Natural analogues of nuclear waste glass corrosion.

    SciTech Connect

    Abrajano, T.A. Jr.; Ebert, W.L.; Luo, J.S.

    1999-01-06

    This report reviews and summarizes studies performed to characterize the products and processes involved in the corrosion of natural glasses. Studies are also reviewed and evaluated on how well the corrosion of natural glasses in natural environments serves as an analogue for the corrosion of high-level radioactive waste glasses in an engineered geologic disposal system. A wide range of natural and experimental corrosion studies has been performed on three major groups of natural glasses: tektite, obsidian, and basalt. Studies of the corrosion of natural glass attempt to characterize both the nature of alteration products and the reaction kinetics. Information available on natural glass was then compared to corresponding information on the corrosion of nuclear waste glasses, specifically to resolve two key questions: (1) whether one or more natural glasses behave similarly to nuclear waste glasses in laboratory tests, and (2) how these similarities can be used to support projections of the long-term corrosion of nuclear waste glasses. The corrosion behavior of basaltic glasses was most similar to that of nuclear waste glasses, but the corrosion of tektite and obsidian glasses involves certain processes that also occur during the corrosion of nuclear waste glasses. The reactions and processes that control basalt glass dissolution are similar to those that are important in nuclear waste glass dissolution. The key reaction of the overall corrosion mechanism is network hydrolysis, which eventually breaks down the glass network structure that remains after the initial ion-exchange and diffusion processes. This review also highlights some unresolved issues related to the application of an analogue approach to predicting long-term behavior of nuclear waste glass corrosion, such as discrepancies between experimental and field-based estimates of kinetic parameters for basaltic glasses.

  19. Terrestrial analogues for lunar impact melt flows

    NASA Astrophysics Data System (ADS)

    Neish, C. D.; Hamilton, C. W.; Hughes, S. S.; Nawotniak, S. Kobs; Garry, W. B.; Skok, J. R.; Elphic, R. C.; Schaefer, E.; Carter, L. M.; Bandfield, J. L.; Osinski, G. R.; Lim, D.; Heldmann, J. L.

    2017-01-01

    Lunar impact melt deposits have unique physical properties. They have among the highest observed radar returns at S-Band (12.6 cm wavelength), implying that they are rough at the decimeter scale. However, they are also observed in high-resolution optical imagery to be quite smooth at the meter scale. These characteristics distinguish them from well-studied terrestrial analogues, such as Hawaiian pāhoehoe and ´a´ā lava flows. The morphology of impact melt deposits can be related to their emplacement conditions, so understanding the origin of these unique surface properties will help to inform us as to the circumstances under which they were formed. In this work, we seek to find a terrestrial analogue for well-preserved lunar impact melt flows by examining fresh lava flows on Earth. We compare the radar return and high-resolution topographic variations of impact melt flows to terrestrial lava flows with a range of surface textures. The lava flows examined in this work range from smooth Hawaiian pāhoehoe to transitional basaltic flows at Craters of the Moon (COTM) National Monument and Preserve in Idaho to rubbly and spiny pāhoehoe-like flows at the recent eruption at Holuhraun in Iceland. The physical properties of lunar impact melt flows appear to differ from those of all the terrestrial lava flows studied in this work. This may be due to (a) differences in post-emplacement modification processes or (b) fundamental differences in the surface texture of the melt flows due to the melts' unique emplacement and/or cooling environment. Information about the surface properties of lunar impact melt deposits will be critical for future landed missions that wish to sample these materials.

  20. Analogues of uracil nucleosides with intrinsic fluorescence (NIF-analogues): synthesis and photophysical properties.

    PubMed

    Segal, Meirav; Fischer, Bilha

    2012-02-28

    Uridine cannot be utilized as fluorescent probe due to its extremely low quantum yield. For improving the uracil fluorescence characteristics we extended the natural chromophore at the C5 position by coupling substituted aromatic rings directly or via an alkenyl or alkynyl linker to create fluorophores. Extension of the uracil base was achieved by treating 5-I-uridine with the appropriate boronic acid under the Suzuki coupling conditions. Analogues containing an alkynyl linker were obtained from 5-I-uridine and the suitable boronic acid in a Sonogashira coupling reaction. The uracil fluorescent analogues proposed here were designed to satisfy the following requirements: a minimal chemical modification at a position not involved in base-pairing, resulting in relatively long absorption and emission wavelengths and high quantum yield. 5-((4-Methoxy-phenyl)-trans-vinyl)-2'-deoxy-uridine, 6b, was found to be a promising fluorescent probe. Probe 6b exhibits a quantum yield that is 3000-fold larger than that of the natural chromophore (Φ 0.12), maximum emission (478 nm) which is 170 nm red shifted as compared to uridine, and a Stokes shift of 143 nm. In addition, since probe 6b adopts the anti conformation and S sugar puckering favored by B-DNA, it makes a promising nucleoside analogue to be incorporated in an oligonucleotide probe for detection of genetic material.

  1. Anti-malarial prescriptions in three health care facilities after the emergence of chloroquine resistance in Niakhar, Senegal (1992–2004)

    PubMed Central

    Munier, Aline; Diallo, Aldiouma; Cot, Michel; Ndiaye, Ousmane; Arduin, Pascal; Chippaux, Jean-Philippe

    2009-01-01

    Background In the rural zone of Niakhar in Senegal, the first therapeutic failures for chloroquine (CQ) were observed in 1992. In 2003, the national policy regarding first-line treatment of uncomplicated malaria was modified, replacing CQ by a transitory bi-therapy amodiaquine/sulphadoxine-pyrimethamine (AQ/SP), before the implementation of artemisinin-based combination therapy (ACT) in 2006. The aims of the study were to assess the evolution of anti-malarial prescriptions in three health care facilities between 1992 and 2004, in parallel with increasing CQ resistance in the region. Methods The study was conducted in the area of Niakhar, a demographic surveillance site located in a sahelo-sudanese region of Senegal, with mesoendemic and seasonal malaria transmission. Health records of two public health centres and a private catholic dispensary were collected retrospectively to cover the period 1992–2004. Results Records included 110,093 consultations and 292,965 prescribed treatments. Twenty-five percent of treatments were anti-malarials, prescribed to 49% of patients. They were delivered all year long, but especially during the rainy season, and 20% of patients with no clinical malaria diagnosis received anti-malarials. Chloroquine and quinine represented respectively 55.7% and 34.6% of prescribed anti-malarials. Overall, chloroquine prescriptions rose from 1992 to 2000, in parallel with clinical malaria; then the CQ prescription rate decreased from 2000 and was concomitant with the rise of SP and the persistence of quinine use. AQ and SP were mainly used as bi-therapy after 2003, at the time of national treatment policy change. Conclusion The results show the overall level of anti-malarial prescription in the study area for a considerable number of patients over a large period of time. Even though resistance to CQ rapidly increased from 1992 to 2001, no change in CQ prescription was observed until the early 2000s, possibly due to the absence of an obvious

  2. Cytotoxicity of Ru(II) piano-stool complexes with chloroquine and chelating ligands against breast and lung tumor cells: Interactions with DNA and BSA.

    PubMed

    Colina-Vegas, Legna; Villarreal, Wilmer; Navarro, Maribel; de Oliveira, Clayton Rodrigues; Graminha, Angélica E; Maia, Pedro Ivo da S; Deflon, Victor M; Ferreira, Antonio G; Cominetti, Marcia Regina; Batista, Alzir A

    2015-12-01

    The synthesis and spectroscopic characterization of nine π-arene piano-stool ruthenium (II) complexes with aromatic dinitrogen chelating ligands or containing chloroquine (CQ), are described in this study: [Ru(η(6)-C10H14)(phen)Cl]PF6 (1), [Ru(η(6)-C10H14)(dphphen)Cl]PF6 (2), [Ru(η(6)-C10H14)(bipy)Cl]PF6 (3), [Ru(η(6)-C10H14)(dmebipy)Cl]PF6 (4) and [Ru(η(6)-C10H14)(bdutbipy)Cl]PF6 (5), [Ru(η(6)-C10H14)(phen)CQ](PF6)2 (6), [Ru(η(6)-C10H14)(dphphen)CQ](PF6)2 (7), [Ru(η(6)-C10H14)(bipy)CQ](PF6)2 (8), [Ru(η(6)-C10H14)(dmebipy)CQ](PF6)2 (9): [1,10-phenanthroline (phen), 4,7-diphenyl-1,10-phenanthroline (dphphen), 2,2'-bipyridine (bipy), 5,5'-dimethyl-2,2'-bipyridine (dmebipy), and 4,4'-di-t-butyl-2,2'-bipyridine (dbutbipy)]. The solid state structures of five ruthenium complexes (1-5) were determined by X-ray crystallography. Electrochemical experiments were performed by cyclic voltammetry to estimate the redox potential of the Ru(II)/Ru(III) couple in each case. Their interactions with DNA and BSA, and activity against four cell lines (L929, A549, MDA-MB-231 and MCF-7) were evaluated. Compounds 2, 6 through 9, interact with DNA which was comparable to the one observed for free chloroquine. The results of fluorescence titration revealed that these complexes strongly quenched the intrinsic fluorescence of BSA following a static quenching procedure. Binding constants (Kb) and the number of binding sites (n~1) were calculated using modified Stern-Volmer equations. The thermodynamic parameters ΔG at different temperatures were calculated and subsequently the values of ΔH and ΔS were also calculated, which revealed that hydrophobic and electrostatic interactions play a major role in the BSA-complex association. The MTT assay results indicated that complexes 2, 5 and 7 showed cytostatic effects at appreciably lower concentrations than those needed for cisplatin, chloroquine and doxorubicin.

  3. Design of multi-epitope, analogue-based cancer vaccines.

    PubMed

    Fikes, John D; Sette, Alessandro

    2003-09-01

    The current objective of our cancer programme is to develop an effective vaccine based on rationally designed T cell epitope analogues, for use in the adjuvant setting for non-small cell lung cancer (NSCLC) and colon cancer. Analogue epitopes, enhanced for either human leukocyte antigen (HLA) binding or T cell receptor (TCR) signalling, have been shown to be more effective at breaking immunological tolerance than cognate wild-type epitopes. Although encouraging early-phase clinical data has been obtained by others using a limited number of HLA-A2-restricted epitope analogues, the clinical benefits and immune correlates for vaccines comprised of multiple epitope analogues restricted by multiple HLA supertypes remains to be investigated. Clinical studies are currently being conducted on EP-2101, a prototype vaccine that delivers multiple HLA-A2-restricted analogue epitopes. In parallel, fixed anchor and heteroclitic analogues restricted by three other commonly expressed HLA supertypes are being identified. These analogues will be incorporated into future vaccines including optimised minigenes (epigenes) and tested in preclinical and clinical studies addressing various different cancer indications.

  4. Behavior of a fluorescent analogue of calmodulin in living 3T3 cells

    PubMed Central

    1985-01-01

    We have prepared and partially characterized a lissamine-rhodamine B fluorescent analogue of calmodulin, LRB-CM. The analogue had a dye/protein ratio of approximately 1.0 and contained no free dye or contaminating labeled proteins. LRB-CM was indistinguishable from native calmodulin upon SDS PAGE and in assays of phosphodiesterase and myosin light chain kinase. The emission spectrum of LRB-CM was insensitive to changes in pH, ionic strength, and temperature over the physiological range, but the apparent quantum yield was influenced somewhat by divalent cation concentration. LRB-CM injected into living Swiss 3T3 fibroblasts became associated with nitrobenzoxadiazole- phallacidin staining stress fibers in some interphase cells. LRB-CM and acetamidofluorescein-labeled actin co-injected into the same cell both became associated with fibers in some cells, but in most cases association of the two analogues with fibers was mutually exclusive. This suggests that calmodulin may differ from actin in the timing of incorporation into stress fibers or that we have distinguished distinct populations of stress fibers. We were able to detect no direct interaction of LRB-CM with actin by fluorescence photobleaching recovery (FRAP) of aqueous solutions. Interaction of LRB-CM with myosin light chain kinase also was not detected by FRAP. This suggests that the mean lifetime of the calmodulin-myosin light chain kinase complex is too short to affect the diffusion coefficient of calmodulin. We examined various fluorescent derivatives of proteins and dextrans as suitable control molecules for quantitative fluorescent analogue cytochemistry in living cells. Fluorescein isothiocyanate-dextrans were found to be preferable to all the proteins tested, since their mobilities in cytoplasm were inversely dependent on molecular size and there was no evidence of binding to intracellular components. In contrast, FRAP of LRB-CM in the cytoplasm of living 3T3 cells suggested that the analogue

  5. The antimalarial activity of Ru-chloroquine complexes against resistant Plasmodium falciparum is related to lipophilicity, basicity, and heme aggregation inhibition ability near water/n-octanol interfaces.

    PubMed

    Martínez, Alberto; Rajapakse, Chandima S K; Jalloh, Dalanda; Dautriche, Cula; Sánchez-Delgado, Roberto A

    2009-08-01

    We have measured water/n-octanol partition coefficients, pK(a) values, heme binding constants, and heme aggregation inhibition activity of a series of ruthenium-pi-arene-chloroquine (CQ) complexes recently reported to be active against CQ-resistant strains of Plasmodium falciparum. Measurements of heme aggregation inhibition activity of the metal complexes near water/n-octanol interfaces qualitatively predict their superior antiplasmodial action against resistant parasites, in relation to CQ; we conclude that this modified method may be a better predictor of antimalarial potency than standard tests in aqueous acidic buffer. Some interesting tendencies emerge from our data, indicating that the antiplasmodial activity is related to a balance of effects associated with the lipophilicity, basicity, and structural details of the compounds studied.

  6. 25OHD analogues and vacuum blood collection tubes dramatically affect the accuracy of automated immunoassays

    PubMed Central

    Yu, Songlin; Cheng, Xinqi; Fang, Huiling; Zhang, Ruiping; Han, Jianhua; Qin, Xuzhen; Cheng, Qian; Su, Wei; Hou, Li’an; Xia, Liangyu; Qiu, Ling

    2015-01-01

    Variations in vitamin D quantification methods are large, and influences of vitamin D analogues and blood collection methods have not been systematically examined. We evaluated the effects of vitamin D analogues 25OHD2 and 3-epi 25OHD3 and blood collection methods on vitamin D measurement, using five immunoassay systems and liquid chromatography-tandem mass spectrometry (LC-MS/MS). Serum samples (332) were selected from routine vitamin D assay requests, including samples with or without 25OHD2 or 3-epi 25OHD3, and analysed using various immunoassay systems. In samples with no 25OHD2 or 3-epi 25OHD3, all immunoassays correlated well with LC-MS/MS. However, the Siemens system produced a large positive mean bias of 12.5 ng/mL and a poor Kappa value when using tubes with clot activator and gel separator. When 25OHD2 or 3-epi 25OHD3 was present, correlations and clinical agreement decreased for all immunoassays. Serum 25OHD in VACUETTE tubes with gel and clot activator, as measured by the Siemens system, produced significantly higher values than did samples collected in VACUETTE tubes with no additives. Bias decreased and clinical agreement improved significantly when using tubes with no additives. In conclusion, most automated immunoassays showed acceptable correlation and agreement with LC-MS/MS; however, 25OHD analogues and blood collection tubes dramatically affected accuracy. PMID:26420221

  7. Synthesis and biological evaluation of enantiomerically pure cyclopropyl analogues of combretastatin A4.

    PubMed

    Ty, Nancy; Pontikis, Renée; Chabot, Guy G; Devillers, Emmanuelle; Quentin, Lionel; Bourg, Stéphane; Florent, Jean-Claude

    2013-03-01

    To evaluate the influence of stereochemistry on biological activities of cis-cyclopropyl combretastatin A4 (CA4) analogues, we have prepared several cyclopropyl compounds in their pure enantiomeric forms. The key reactions in our synthesis are the cyclopropanation of a (Z)-alkenylboron compound bearing a chiral auxiliary, and the cross-coupling of both enantiomeric cyclopropyl trifluoroborate salts with aryl and olefinic halides. Three pairs of cis-cyclopropyl CA4 analogues were evaluated for their potential antivascular activities. The diarylcyclopropyl compounds with SR-configuration (-)-1b, (-)-2b and the cyclopropylvinyl enantiomer (+)-3a with RR-configuration were the most potent tubulin polymerization inhibitors. A correlation was noted between anti-tubulin activity and rounding up activity of endothelial cells. The cytotoxic activity on B16 melanoma cells was in the submicromolar range for most compounds, but unlike the anti-tubulin activity, there was no difference in cytotoxic activity between racemic and enantiomerically pure forms for the three series of compounds. Molecular docking studies within the colchicine binding site of tubulin were in good agreement with the tubulin polymerization inhibitory data and confirmed the importance of the configuration of the synthesized cis-cyclopropyl CA4 analogues for potential antivascular activities.

  8. Strigolactone Analogues with a D‐Ring Modified at C‐2

    PubMed Central

    Mwakaboko, Alinanuswe S.

    2016-01-01

    Strigolactones (SLs) are important new plant hormones that receive much attention in current plant science. SLs are produced by many plants and are exuded by the root system. SLs are, amongst others, germination stimulants for seed of parasitic weeds. Naturally occurring SLs invariably contain three annelated rings, the ABC‐scaffold, connected to a butenolide (the D‐ring) via an enol ether unit. The synthesis of natural SLs requires many steps, therefore there is a continuous search for SL analogues with a simpler structure but with retention of bioactivity. In this study modified D‐ring variants are investigated, especially analogues having a methyl group at C‐2 instead of a hydrogen. For these analogues the ABC‐scaffolds of GR24 and Nijmegen‐1 were used. The coupling reaction proceeds profoundly better with chlorobutenolides than with the corresponding bromides. Bioassays reveal that the introduction an extra methyl at C‐2 does not influence the germination activity, which is relevant for gaining insight in the mode of action of SLs. PMID:27840586

  9. Promising Strategy To Improve Charge Separation in Organic Photovoltaics: Installing Permanent Dipoles in PCBM Analogues.

    PubMed

    de Gier, Hilde D; Jahani, Fatemeh; Broer, Ria; Hummelen, Jan C; Havenith, Remco W A

    2016-07-14

    A multidisciplinary approach involving organic synthesis and theoretical chemistry was applied to investigate a promising strategy to improve charge separation in organic photovoltaics: installing permanent dipoles in fullerene derivatives. First, a PCBM analogue with a permanent dipole in the side chain (PCBDN) and its reference analogue without a permanent dipole (PCBBz) were successfully synthesized and characterized. Second, a multiscale modeling approach was applied to investigate if a PCBDN environment around a central donor-acceptor complex indeed facilitates charge separation. Alignment of the embedding dipoles in response to charges present on the central donor-acceptor complex enhances charge separation. The good correspondence between experimentally and theoretically determined electronic and optical properties of PCBDN, PCBBz, and PCBM indicates that the theoretical analysis of the embedding effects of these molecules gives a reliable expectation for their influence on the charge separation process at a microscopic scale in a real device. This work suggests the following strategies to improve charge separation in organic photovoltaics: installing permanent dipoles in PCBM analogues and tuning the concentration of these molecules in an organic donor/acceptor blend.

  10. A chemoselective and continuous synthesis of m-sulfamoylbenzamide analogues

    PubMed Central

    Verlee, Arno; Heugebaert, Thomas; van der Meer, Tom; Kerchev, Pavel I; Van Breusegem, Frank

    2017-01-01

    For the synthesis of m-sulfamoylbenzamide analogues, small molecules which are known for their bioactivity, a chemoselective procedure has been developed starting from m-(chlorosulfonyl)benzoyl chloride. Although a chemoselective process in batch was already reported, a continuous-flow process reveals an increased selectivity at higher temperatures and without catalysts. In total, 15 analogues were synthesized, using similar conditions, with yields ranging between 65 and 99%. This is the first automated and chemoselective synthesis of m-sulfamoylbenzamide analogues. PMID:28326139

  11. Mars on Earth: soil analogues for future Mars missions

    NASA Astrophysics Data System (ADS)

    Marlow, Jeffrey J.; Martins, Zita; Sephton, Mark A.

    2008-04-01

    Preparations for missions to Mars are a major concern for scientists. Predicting how equipment and experiments will perform on the planet is difficult because tests are restricted to Earth. Mars soil analogues are being used to solve this problem. These terrestrial materials are chemically and physically similar to martian soils and, because they contain unusual minerals and trace amounts of organic matter, are scientifically interesting in their own right. However, no current analogue is appropriate for all necessary tests. Here we describe Mars soil analogues, identify limitations and suggest the need for new Mars simulants.

  12. Synthesis, antiarrhythmic activity, and toxicological evaluation of mexiletine analogues.

    PubMed

    Roselli, Mariagrazia; Carocci, Alessia; Budriesi, Roberta; Micucci, Matteo; Toma, Maddalena; Di Cesare Mannelli, Lorenzo; Lovece, Angelo; Catalano, Alessia; Cavalluzzi, Maria Maddalena; Bruno, Claudio; De Palma, Annalisa; Contino, Marialessandra; Perrone, Maria Grazia; Colabufo, Nicola Antonio; Chiarini, Alberto; Franchini, Carlo; Ghelardini, Carla; Habtemariam, Solomon; Lentini, Giovanni

    2016-10-04

    Four mexiletine analogues have been tested for their antiarrhythmic, inotropic, and chronotropic effects on isolated guinea pig heart tissues and to assess calcium antagonist activity, in comparison with the parent compound mexiletine. All analogues showed from moderate to high antiarrhythmic activity. In particular, three of them (1b,c,e) were more active and potent than the reference drug, while exhibiting only modest or no negative inotropic and chronotropic effects and vasorelaxant activity, thus showing high selectivity of action. All compounds showed no cytotoxicity and 1b,c,d did not impair motor coordination. All in, these new analogues exhibit an interesting cardiovascular profile and deserve further investigation.

  13. Quinine dimers are potent inhibitors of the Plasmodium falciparum chloroquine resistance transporter and are active against quinoline-resistant P. falciparum.

    PubMed

    Hrycyna, Christine A; Summers, Robert L; Lehane, Adele M; Pires, Marcos M; Namanja, Hilda; Bohn, Kelsey; Kuriakose, Jerrin; Ferdig, Michael; Henrich, Philipp P; Fidock, David A; Kirk, Kiaran; Chmielewski, Jean; Martin, Rowena E

    2014-03-21

    Chloroquine (CQ) resistance in the human malaria parasite Plasmodium falciparum is primarily conferred by mutations in the "chloroquine resistance transporter" (PfCRT). The resistance-conferring form of PfCRT (PfCRT(CQR)) mediates CQ resistance by effluxing the drug from the parasite's digestive vacuole, the acidic compartment in which CQ exerts its antiplasmodial effect. PfCRT(CQR) can also decrease the parasite's susceptibility to other quinoline drugs, including the current antimalarials quinine and amodiaquine. Here we describe interactions between PfCRT(CQR) and a series of dimeric quinine molecules using a Xenopus laevis oocyte system for the heterologous expression of PfCRT and using an assay that detects the drug-associated efflux of H(+) ions from the digestive vacuole in parasites that harbor different forms of PfCRT. The antiplasmodial activities of dimers 1 and 6 were also examined in vitro (against drug-sensitive and drug-resistant strains of P. falciparum) and in vivo (against drug-sensitive P. berghei). Our data reveal that the quinine dimers are the most potent inhibitors of PfCRT(CQR) reported to date. Furthermore, the lead compounds (1 and 6) were not effluxed by PfCRT(CQR) from the digestive vacuole but instead accumulated to very high levels within this organelle. Both 1 and 6 exhibited in vitro antiplasmodial activities that were inversely correlated with CQ. Moreover, the additional parasiticidal effect exerted by 1 and 6 in the drug-resistant parasites was attributable, at least in part, to their ability to inhibit PfCRT(CQR). This highlights the potential for devising new antimalarial therapies that exploit inherent weaknesses in a key resistance mechanism of P. falciparum.

  14. Analysis of Organic Molecules Extracted from Mars Analogues and Influence of Their Mineralogy Using N-Methyl-N-(tert-butyldimethylsilyl)Trifluoroacetamide Derivatization Coupled with Gas Chromatography Mass Spectrometry in Preparation for the Sample Analysis at Mars Derivatization Experiment on the Mars Science Laboratory Mission

    NASA Technical Reports Server (NTRS)

    Stalport, F.; Glavin, D. P.; Eigenbrode, J. L.; Bish, D.; Blake, D.; Coll, P.; Szopa, C.; Buch, A.; McAdam, A.; Dworkin, J. P.; Mahaffy, P. R.

    2012-01-01

    The search for complex organic molecules on Mars, including important biomolecules such as amino acids and carboxylic acids will require a chemical extraction and derivatization step to transform these organic compounds into species that are sufficiently volatile to be detected by gas chromatography mass spectrometry (GCMS). We have developed, a one-pot extraction and chemical derivatization protocol using N-methyl-N-(tert-butyldimethylsilyl)trifluoroacetamide (MTBSTFA) and dimethylformamide (DMF) for the Sample Analysis at Mars (SAM) experiment on the Mars Science Laboratory (MSL). The temperature and duration the derivatization reaction, pre-concentration of chemical derivatives, and gas chromatographic separation parameters have been optimized under SAM instrument design constraints. MTBSTFA/DMF extraction and derivatization at 300 C for several minutes of a variety of terrestrial Mars analogue materials facilitated the detection of amino acids and carboxylic acids in a surface soil sample collected from the Atacama Desert and a carbonate-rich stromatolite sample from Svalbard. However, the rapid reaction of MTBSTFA with water in several analogue materials that contained high abundances of hydrated minerals and the possible deactivation of derivatized compounds by iron oxides, as detected by XRD/XRF using the CheMin field unit Terra, proved to be highly problematic for the direct extraction of organics using MTBSTFA, The combination of pyrolysis and two different chemical derivatization methods employed by SAM should enable a wide range of organic compounds to be detected by GCMS if present on Mars,

  15. Mammary analogue secretory carcinoma mimicking salivary adenoma.

    PubMed

    Williams, Lindsay; Chiosea, Simion I

    2013-12-01

    Mammary analogue secretory carcinoma (MASC) is a recently described salivary gland tumor characterized by ETV6 translocation. It appears that prior studies have identified MASC by reviewing salivary gland carcinomas, such as acinic cell carcinoma and adenocarcinoma, not otherwise specified. To address the possibility of MASC mimicking benign salivary neoplasms we reviewed 12 salivary gland (cyst)adenomas diagnosed prior to the discovery of MASC. One encapsulated (cyst)adenoma of the parotid gland demonstrated features of MASC. The diagnosis was confirmed by fluorescence in situ hybridization with an ETV6 break-apart probe. An unusual complex pattern of ETV6 rearrangement with duplication of the telomeric/distal ETV6 probe was identified. This case illustrates that MASC may mimic salivary (cyst)adenomas. To more accurately assess true clinical and morphologic spectrum of MASC, future studies may have to include review of salivary (cyst)adenomas. The differential diagnosis of MASC may have to be expanded to include cases resembling salivary (cyst)adenomas.

  16. Fluorescent polyene ceramide analogues as membrane probes.

    PubMed

    Nieves, Ingrid; Artetxe, Ibai; Abad, José Luis; Alonso, Alicia; Busto, Jon V; Fajarí, Lluís; Montes, L Ruth; Sot, Jesús; Delgado, Antonio; Goñi, Félix M

    2015-03-03

    Three ceramide analogues have been synthesized, with sphingosine-like chains containing five conjugated double bonds. Pentaene I has an N-palmitoyl acyl chain, while the other two pentaenes contain also a doxyl radical, respectively, at C5 (Penta5dox) and at C16 (Penta16dox) positions of the N-acyl chain. Pentaene I maximum excitation and emission wavelengths in a phospholipid bilayer are 353 and 478 nm, respectively. Pentaene I does not segregate from the other lipids in the way natural ceramide does, but rather mixes with them in a selective way according to the lipid phases involved. Fluorescence confocal microscopy studies show that when lipid domains in different physical states coexist, Pentaene I emission is higher in gel than in fluid domains, and in liquid-ordered than in liquid-disordered areas. Electron paramagnetic resonance of the pentaene doxyl probes confirms that these molecules are sensitive to the physical state of the bilayer. Calorimetric and fluorescence quenching experiments suggest that the lipids under study orient themselves in lipid bilayers with their polar moieties located at the lipid-water interface. The doxyl radical in the N-acyl chain quenches the fluorescence of the pentaene group when in close proximity. Because of this property, Penta16dox can detect gel-fluid transitions in phospholipids. The availability of probes for lipids in the gel phase is important in view of novel evidence for the existence of gel microdomains in cell membranes.

  17. Actions of Thyroid Hormone Analogues on Chemokines

    PubMed Central

    Glinsky, Gennadi V.

    2016-01-01

    The extracellular domain of plasma membrane integrin αvβ3 contains a receptor for thyroid hormone (L-thyroxine, T4; 3,5,3′-triiodo-L-thyronine, T3); this receptor also binds tetraiodothyroacetic acid (tetrac), a derivative of T4. Tetrac inhibits the binding of T4 and T3 to the integrin. Fractalkine (CX3CL1) is a chemokine relevant to inflammatory processes in the CNS that are microglia-dependent but also important to normal brain development. Expression of the CX3CL1 gene is downregulated by tetrac, suggesting that T4 and T3 may stimulate fractalkine expression. Independently of its specific receptor (CX3CR1), fractalkine binds to αvβ3 at a site proximal to the thyroid hormone-tetrac receptor and changes the physical state of the integrin. Tetrac also affects expression of the genes for other CNS-relevant chemokines, including CCL20, CCL26, CXCL2, CXCL3, and CXCL10. The chemokine products of these genes are important to vascularity of the brain, particularly of the choroid plexus, to inflammatory processes in the CNS and, in certain cases, to neuroprotection. Thyroid hormones are known to contribute to regulation of each of these CNS functions. We propose that actions of thyroid hormone and hormone analogues on chemokine gene expression contribute to regulation of inflammatory processes in brain and of brain blood vessel formation and maintenance. PMID:27493972

  18. Sulphur Spring: Busy Intersection and Possible Martian Analogue

    NASA Technical Reports Server (NTRS)

    Nankivell, A.; Andre, N.; Thomas-Keprta, K.; Allen, C.; McKay, D.

    2000-01-01

    Life in extreme environments exhibiting conditions similar to early Earth and Mars, such as Sulphur Spring, may harbor microbiota serving as both relics from the past as well as present day Martian analogues.

  19. From BPA to its analogues: Is it a safe journey?

    PubMed

    Usman, Afia; Ahmad, Masood

    2016-09-01

    Bisphenol-A (BPA) is one of the most abundant synthetic chemicals in the world due to its uses in plastics. Its widespread exposure vis-a-vis low dose effects led to a reduction in its safety dose and imposition of ban on its use in infant feeding bottles. This restriction paved the way for the gradual market entry of its analogues. However, their structural similarity to BPA has put them under surveillance for endocrine disrupting potential. The application of these analogues is increasing and so are the studies reporting their toxicity. This review highlights the reasons which led to the ban of BPA and also reports the exposure and toxicological data available on its analogues. Hence, this compilation is expected to answer in a better way whether the replacement of BPA by these analogues is safer or more harmful?

  20. Cell-cycle analyses using thymidine analogues in fission yeast.

    PubMed

    Anda, Silje; Boye, Erik; Grallert, Beata

    2014-01-01

    Thymidine analogues are powerful tools when studying DNA synthesis including DNA replication, repair and recombination. However, these analogues have been reported to have severe effects on cell-cycle progression and growth, the very processes being investigated in most of these studies. Here, we have analyzed the effects of 5-ethynyl-2'-deoxyuridine (EdU) and 5-Chloro-2'-deoxyuridine (CldU) using fission yeast cells and optimized the labelling procedure. We find that both analogues affect the cell cycle, but that the effects can be mitigated by using the appropriate analogue, short pulses of labelling and low concentrations. In addition, we report sequential labelling of two consecutive S phases using EdU and 5-bromo-2'-deoxyuridine (BrdU). Furthermore, we show that detection of replicative DNA synthesis is much more sensitive than DNA-measurements by flow cytometry.

  1. Weather and event generators based on analogues of atmospheric circulation

    NASA Astrophysics Data System (ADS)

    Yiou, Pascal

    2015-04-01

    Analogues of atmospheric circulation have had numerous applications on weather prediction, climate reconstructions and detection/attribution analyses. A stochastic weather generator based on circulation analogues was recently proposed by Yiou (2014) to simulate sequences of European temperatures. One of the features of this weather generator is that it preserves the spatial and temporal structures of the climate variables to be simulated. This method is flexible enough to be combined efficiently with a storm detection algorithm in order to generate large catalogues of high impact extra-tropical storms that hit Europe. I will present the gist of the method of circulation analogues and some performances. Two promising applications for weather generators based on this method (ensemble climate prediction and extra-tropical storms) will be tested. References Yiou, P.: AnaWEGE: a weather generator based on analogues of atmospheric circulation, Geosci. Model Dev., 7, 531-543, doi:10.5194/gmd-7-531-2014, 2014.

  2. Effect of glutamate analogues on brain tumor cell lines.

    PubMed

    Campbell, G L; Bartel, R; Freidman, H S; Bigner, D D

    1985-10-01

    Glutamate analogues have been used in many different experimental approaches in neurobiology. A small number of these analogues have been classified as gliotoxic. We have examined the effect of seven glutamate analogues (five gliotoxic and two neurotoxic) on the growth and viability of four human glioma cell lines, one human medulloblastoma cell line, and one human sarcoma cell line. Aminoadipic acid and homocysteic acid predominantly affected the growth of two glioma cell lines in the presence of 4 mM glutamine. Phosphonobutyric acid predominantly affected the other two glioma cell lines and the medulloblastoma cell line in the presence of 4 mM glutamine. In medium containing no glutamine, all three analogues had marked effects on all the cell lines except the sarcoma cell line. These effects were dose dependent. We postulate that these results can in part be explained on the basis of metabolic compartmentalization.

  3. A Non-Verbal Analogue to the Verbal Transformation Effect

    ERIC Educational Resources Information Center

    Lass, Norman J.; And Others

    1973-01-01

    Investigates the effectiveness of non-speech auditory stimuli in eliciting transformations analogous to those reported for speech stimuli to determine if a non-verbal analogue to the verbal transformation effect exists. (DD)

  4. Amphiphilic Tobramycin Analogues as Antibacterial and Antifungal Agents

    PubMed Central

    Shrestha, Sanjib K.; Fosso, Marina Y.; Green, Keith D.

    2015-01-01

    In this study, we investigated the in vitro antifungal activities, cytotoxicities, and membrane-disruptive actions of amphiphilic tobramycin (TOB) analogues. The antifungal activities were established by determination of MIC values and in time-kill studies. Cytotoxicity was evaluated in mammalian cell lines. The fungal membrane-disruptive action of these analogues was studied by using the membrane-impermeable dye propidium iodide. TOB analogues bearing a linear alkyl chain at their 6″-position in a thioether linkage exhibited chain length-dependent antifungal activities. Analogues with C12 and C14 chains showed promising antifungal activities against tested fungal strains, with MIC values ranging from 1.95 to 62.5 mg/liter and 1.95 to 7.8 mg/liter, respectively. However, C4, C6, and C8 TOB analogues and TOB itself exhibited little to no antifungal activity. Fifty percent inhibitory concentrations (IC50s) for the most potent TOB analogues (C12 and C14) against A549 and Beas 2B cells were 4- to 64-fold and 32- to 64-fold higher, respectively, than their antifungal MIC values against various fungi. Unlike conventional aminoglycoside antibiotics, TOB analogues with alkyl chain lengths of C12 and C14 appear to inhibit fungi by inducing apoptosis and disrupting the fungal membrane as a novel mechanism of action. Amphiphilic TOB analogues showed broad-spectrum antifungal activities with minimal mammalian cell cytotoxicity. This study provides novel lead compounds for the development of antifungal drugs. PMID:26033722

  5. Adjuvant properties of a simplified C32 monomycolyl glycerol analogue.

    PubMed

    Bhowruth, Veemal; Minnikin, David E; Agger, Else Marie; Andersen, Peter; Bramwell, Vincent W; Perrie, Yvonne; Besra, Gurdyal S

    2009-04-01

    A simplified C(32) monomycolyl glycerol (MMG) analogue demonstrated enhanced immunostimulatory activity in a dioctadecyl ammonium bromide (DDA)/Ag85B-ESAT-6 formulation. Elevated levels of IFN-gamma and IL-6 were produced in spleen cells from mice immunised with a C(32) MMG analogue comparable activity to the potent Th1 adjuvant, trehalose 6,6'-di-behenate (TDB).

  6. Semisynthesis of salviandulin E analogues and their antitrypanosomal activity.

    PubMed

    Aoyagi, Yutaka; Fujiwara, Koji; Yamazaki, Akira; Sugawara, Naoko; Yano, Reiko; Fukaya, Haruhiko; Hitotsuyanagi, Yukio; Takeya, Koichi; Ishiyama, Aki; Iwatsuki, Masato; Otoguro, Kazuhiko; Yamada, Haruki; Ōmura, Satoshi

    2014-01-15

    A series of analogues of salviandulin E, a rearranged neoclerodane diterpene originally isolated from Salvia leucantha (Lamiaceae), were prepared and their in vitro activity against Trypanosoma brucei brucei was evaluated with currently used therapeutic drugs as positive controls. One of the 19 compounds prepared and assayed in the present study, butanoyl 3,4-dihydrosalviandulin E analogue was found to be a possible candidate for an antitrypanosomal drug with fairly strong antitrypanosomal activity and lower cytotoxicity.

  7. Catalytic antioxidants: regenerable tellurium analogues of vitamin E.

    PubMed

    Singh, Vijay P; Poon, Jia-fei; Engman, Lars

    2013-12-20

    In an effort to improve the chain-breaking capacity of the natural antioxidants, an octyltelluro group was introduced next to the phenolic moiety in β- and δ-tocopherol. The new vitamin E analogues quenched peroxyl radicals more efficiently than α-tocopherol and were readily regenerable by aqueous N-acetylcysteine in a simple membrane model composed of a stirring chlorobenzene/water two-phase system. The novel tocopherol analogues could also mimic the action of the glutathione peroxidase enzymes.

  8. Analogue and digital linear modulation techniques for mobile satellite

    NASA Technical Reports Server (NTRS)

    Whitmarsh, W. J.; Bateman, A.; Mcgeehan, J. P.

    1990-01-01

    The choice of modulation format for a mobile satellite service is complex. The subjective performance is summarized of candidate schemes and voice coder technologies. It is shown that good performance can be achieved with both analogue and digital voice systems, although the analogue system gives superior performance in fading. The results highlight the need for flexibility in the choice of signaling format. Linear transceiver technology capable of using many forms of narrowband modulation is described.

  9. The relevance of analogue studies for understanding obsessions and compulsions.

    PubMed

    Abramowitz, Jonathan S; Fabricant, Laura E; Taylor, Steven; Deacon, Brett J; McKay, Dean; Storch, Eric A

    2014-04-01

    Analogue samples are often used to study obsessive-compulsive (OC) symptoms and related phenomena. This approach is based on the hypothesis that results derived from such samples are relevant to understanding OC symptoms in individuals with a diagnosis of obsessive-compulsive disorder (OCD). Two decades ago, Gibbs (1996) reviewed the available literature and found initial support for this hypothesis. Since then there have been many important advances addressing this issue. The purpose of the present review was to synthesize various lines of research examining the assumptions of using analogue samples to draw inferences about people with OCD. We reviewed research on the prevalence of OC symptoms in non-clinical populations, the dimensional (vs. categorical) nature of these symptoms, phenomenology, etiology, and studies on developmental and maintenance factors in clinical and analogue samples. We also considered the relevance of analogue samples in OCD treatment research. The available evidence suggests research with analogue samples is highly relevant for understanding OC symptoms. Guidelines for the appropriate use of analogue designs and samples are suggested.

  10. Cladribine Analogues via O6-(Benzotriazolyl) Derivatives of Guanine Nucleosides

    PubMed Central

    Satishkumar, Sakilam; Vuram, Prasanna K.; Relangi, Siva Subrahmanyam; Gurram, Venkateshwarlu; Zhou, Hong; Kreitman, Robert J.; Montemayor, Michelle M. Martínez; Yang, Lijia; Kaliyaperumal, Muralidharan; Sharma, Somesh; Pottabathini, Narender; Lakshman, Mahesh K.

    2016-01-01

    Cladribine, 2-chloro-2′-deoxyadenosine, is a highly efficacious clinically used nucleoside for the treatment of hairy cell leukemia. It is also being evaluated against other lymphoid malignancies and has been a molecule of interest for well over half a century. In continuation of our interest on the amide bond-activation in purine nucleosides via the use of (benzotriazol-1yl-oxy)tris(dimethylamino)phosphonium hexafluorophosphate, we have evaluated the use of O6-(benzotriazol-1-yl)-2′-deoxyguanosine as a potential precursor to cladribine and its analogues. These compounds, after appropriate deprotection, were assessed for their biological activities and the data are presented herein. Against hairy cell leukemia (HCL), T-cell lymphoma (TCL), and chronic lymphocytic leukemia (CLL) cladribine was the most active against all. The bromo analogue of cladribine showed comparable activity to the ribose analogue of cladribine against HCL, but was more active against TCL and CLL. The bromo ribo analogue of cladribine possessed activity, but was least active among the C6-NH2-containing compounds. Substitution with alkyl groups at the exocyclic amino group appears detrimental to activity, and only the C6 piperidinyl cladribine analogue demonstrated any activity. Against adenocarcinoma MDA-MB-231 cells, only cladribine and its ribose analogue were most active. PMID:26556315

  11. Analogue gravitational phenomena in Bose-Einstein condensates

    NASA Astrophysics Data System (ADS)

    Finazzi, Stefano

    2012-08-01

    Analogue gravity is based on the simple observation that perturbations propagating in several physical systems can be described by a quantum field theory in a curved spacetime. While phenomena like Hawking radiation are hardly detectable in astrophysical black holes, these effects may be experimentally tested in analogue systems. In this Thesis, focusing on Bose-Einstein condensates, we present our recent results about analogue models of gravity from three main perspectives: as laboratory tests of quantum field theory in curved spacetime, for the techniques that they provide to address various issues in general relativity, and as toy models of quantum gravity. The robustness of Hawking-like particle creation is investigated in flows with a single black hole horizon. Furthermore, we find that condensates with two (white and black) horizons develop a dynamical instability known in general relativity as black hole laser effect. Using techniques borrowed from analogue gravity, we also show that warp drives, which are general relativistic spacetimes allowing faster-than-light travel, are unstable. Finally, the cosmological constant issue is investigated from an analogue gravity perspective and relativistic Bose-Einstein condensates are proposed as new analogue systems with novel interesting properties.

  12. Cladribine Analogues via O⁶-(Benzotriazolyl) Derivatives of Guanine Nucleosides.

    PubMed

    Satishkumar, Sakilam; Vuram, Prasanna K; Relangi, Siva Subrahmanyam; Gurram, Venkateshwarlu; Zhou, Hong; Kreitman, Robert J; Montemayor, Michelle M Martínez; Yang, Lijia; Kaliyaperumal, Muralidharan; Sharma, Somesh; Pottabathini, Narender; Lakshman, Mahesh K

    2015-10-09

    Cladribine, 2-chloro-2'-deoxyadenosine, is a highly efficacious, clinically used nucleoside for the treatment of hairy cell leukemia. It is also being evaluated against other lymphoid malignancies and has been a molecule of interest for well over half a century. In continuation of our interest in the amide bond-activation in purine nucleosides via the use of (benzotriazol-1yl-oxy)tris(dimethylamino)phosphonium hexafluorophosphate, we have evaluated the use of O⁶-(benzotriazol-1-yl)-2'-deoxyguanosine as a potential precursor to cladribine and its analogues. These compounds, after appropriate deprotection, were assessed for their biological activities, and the data are presented herein. Against hairy cell leukemia (HCL), T-cell lymphoma (TCL) and chronic lymphocytic leukemia (CLL), cladribine was the most active against all. The bromo analogue of cladribine showed comparable activity to the ribose analogue of cladribine against HCL, but was more active against TCL and CLL. The bromo ribose analogue of cladribine showed activity, but was the least active among the C6-NH₂-containing compounds. Substitution with alkyl groups at the exocyclic amino group appears detrimental to activity, and only the C6 piperidinyl cladribine analogue demonstrated any activity. Against adenocarcinoma MDA-MB-231 cells, cladribine and its ribose analogue were most active.

  13. Molecular Biodynamers: Dynamic Covalent Analogues of Biopolymers.

    PubMed

    Liu, Yun; Lehn, Jean-Marie; Hirsch, Anna K H

    2017-02-21

    Constitutional dynamic chemistry (CDC) features the use of reversible linkages at both molecular and supramolecular levels, including reversible covalent bonds (dynamic covalent chemistry, DCC) and noncovalent interactions (dynamic noncovalent chemistry, DNCC). Due to its inherent reversibility and stimuli-responsiveness, CDC has been widely utilized as a powerful tool for the screening of bioactive compounds, the exploitation of receptors or substrates driven by molecular recognition, and the fabrication of constitutionally dynamic materials. Implementation of CDC in biopolymer science leads to the generation of constitutionally dynamic analogues of biopolymers, biodynamers, at the molecular level (molecular biodynamers) through DCC or at the supramolecular level (supramolecular biodynamers) via DNCC. Therefore, biodynamers are prepared by reversible covalent polymerization or noncovalent polyassociation of biorelevant monomers. In particular, molecular biodynamers, biodynamers of the covalent type whose monomeric units are connected by reversible covalent bonds, are generated by reversible polymerization of bio-based monomers and can be seen as a combination of biopolymers with DCC. Owing to the reversible covalent bonds used in DCC, molecular biodynamers can undergo continuous and spontaneous constitutional modifications via incorporation/decorporation and exchange of biorelevant monomers in response to internal or external stimuli. As a result, they behave as adaptive materials with novel properties, such as self-healing, stimuli-responsiveness, and tunable mechanical and optical character. More specifically, molecular biodynamers combine the biorelevant characters (e.g., biocompatibility, biodegradability, biofunctionality) of bioactive monomers with the dynamic features of reversible covalent bonds (e.g., changeable, tunable, controllable, self-healing, and stimuli-responsive capacities), to realize synergistic properties in one system. In addition, molecular

  14. Molecular Biodynamers: Dynamic Covalent Analogues of Biopolymers

    PubMed Central

    2017-01-01

    Conspectus Constitutional dynamic chemistry (CDC) features the use of reversible linkages at both molecular and supramolecular levels, including reversible covalent bonds (dynamic covalent chemistry, DCC) and noncovalent interactions (dynamic noncovalent chemistry, DNCC). Due to its inherent reversibility and stimuli-responsiveness, CDC has been widely utilized as a powerful tool for the screening of bioactive compounds, the exploitation of receptors or substrates driven by molecular recognition, and the fabrication of constitutionally dynamic materials. Implementation of CDC in biopolymer science leads to the generation of constitutionally dynamic analogues of biopolymers, biodynamers, at the molecular level (molecular biodynamers) through DCC or at the supramolecular level (supramolecular biodynamers) via DNCC. Therefore, biodynamers are prepared by reversible covalent polymerization or noncovalent polyassociation of biorelevant monomers. In particular, molecular biodynamers, biodynamers of the covalent type whose monomeric units are connected by reversible covalent bonds, are generated by reversible polymerization of bio-based monomers and can be seen as a combination of biopolymers with DCC. Owing to the reversible covalent bonds used in DCC, molecular biodynamers can undergo continuous and spontaneous constitutional modifications via incorporation/decorporation and exchange of biorelevant monomers in response to internal or external stimuli. As a result, they behave as adaptive materials with novel properties, such as self-healing, stimuli-responsiveness, and tunable mechanical and optical character. More specifically, molecular biodynamers combine the biorelevant characters (e.g., biocompatibility, biodegradability, biofunctionality) of bioactive monomers with the dynamic features of reversible covalent bonds (e.g., changeable, tunable, controllable, self-healing, and stimuli-responsive capacities), to realize synergistic properties in one system. In addition

  15. Analogue models of subduction megathrust earthquakes: improving rheology and monitoring technique

    NASA Astrophysics Data System (ADS)

    Brizzi, Silvia; Corbi, Fabio; Funiciello, Francesca; Moroni, Monica

    2015-04-01

    Most of the world's great earthquakes (Mw > 8.5, usually known as mega-earthquakes) occur at shallow depths along the subduction thrust fault (STF), i.e., the frictional interface between the subducting and overriding plates. Spatiotemporal occurrences of mega-earthquakes and their governing physics remain ambiguous, as tragically demonstrated by the underestimation of recent megathrust events (i.e., 2011 Tohoku). To help unravel seismic cycle at STF, analogue modelling has become a key-tool. First properly scaled analogue models with realistic geometries (i.e., wedge-shaped) suitable for studying interplate seismicity have been realized using granular elasto-plastic [e.g., Rosenau et al., 2009] and viscoelastic materials [i.e., Corbi et al., 2013]. In particular, viscoelastic laboratory experiments realized with type A gelatin 2.5 wt% simulate, in a simplified yet robust way, the basic physics governing subduction seismic cycle and related rupture process. Despite the strength of this approach, analogue earthquakes are not perfectly comparable to their natural prototype. In this work, we try to improve subduction seismic cycle analogue models by modifying the rheological properties of the analogue material and adopting a new image analysis technique (i.e., PEP - ParticlE and Prediction velocity). We test the influence of lithosphere elasticity by using type A gelatin with greater concentration (i.e., 6 wt%). Results show that gelatin elasticity plays important role in controlling seismogenic behaviour of STF, tuning the mean and the maximum magnitude of analogue earthquakes. In particular, by increasing gelatin elasticity, we observe decreasing mean magnitude, while the maximum magnitude remains the same. Experimental results therefore suggest that lithosphere elasticity could be one of the parameters that tunes seismogenic behaviour of STF. To increase gelatin elasticity also implies improving similarities with their natural prototype in terms of coseismic

  16. Habitability & Astrobiology Research in Mars Terrestrial Analogues

    NASA Astrophysics Data System (ADS)

    Foing, Bernard

    2014-05-01

    We performed a series of field research campaigns (ILEWG EuroMoonMars) in the extreme Utah desert relevant to Mars environments, and in order to help in the interpretation of Mars missions measurements from orbit (MEX, MRO) or from the surface (MER, MSL), or Moon geochemistry (SMART-1, LRO). We shall give an update on the sample analysis in the context of habitability and astrobiology. Methods & Results: In the frame of ILEWG EuroMoonMars campaigns (2009 to 2013) we deployed at Mars Desert Research station, near Hanksville Utah, a suite of instruments and techniques [A, 1, 2, 9-11] including sample collection, context imaging from remote to local and microscale, drilling, spectrometers and life sensors. We analyzed how geological and geochemical evolution affected local parameters (mineralogy, organics content, environment variations) and the habitability and signature of organics and biota. Among the important findings are the diversity in the composition of soil samples even when collected in close proximity, the low abundances of detectable PAHs and amino acids and the presence of biota of all three domains of life with significant heterogeneity. An extraordinary variety of putative extremophiles was observed [3,4,9]. A dominant factor seems to be soil porosity and lower clay-sized particle content [6-8]. A protocol was developed for sterile sampling, contamination issues, and the diagnostics of biodiversity via PCR and DGGE analysis in soils and rocks samples [10, 11]. We compare the 2009 campaign results [1-9] to new measurements from 2010-2013 campaigns [10-12] relevant to: comparison between remote sensing and in-situ measurements; the study of minerals; the detection of organics and signs of life. Keywords: field analogue research, astrobiology, habitability, life detection, Earth-Moon-Mars, organics References [A] Foing, Stoker & Ehrenfreund (Editors, 2011) "Astrobiology field Research in Moon/Mars Analogue Environments", Special Issue of International

  17. Antitumor Agents 284. New Desmosdumotin B Analogues with Bicyclic B-ring as Cytotoxic and Antitubulin Agents

    PubMed Central

    Nakagawa-Goto, Kyoko; Wu, Pei-Chi; Lai, Chin-Yu; Hamel, Ernest; Zhu, Hao; Zhang, Liying; Kozaka, Takashi; Ohkoshi, Emika; Goto, Masuo; Bastow, Kenneth F.; Lee, Kuo-Hsiung

    2011-01-01

    We previously reported that the biological activity of analogues of desmosdumotin B (1) was dramatically changed depending on the B-ring system. A naphthalene B-ring analogue 3 exerted potent in vitro activity against a diverse panel of human tumor cell lines with GI50 values of 0.8–2.1 μM. In contrast, 1-analogues with a phenyl B-ring showed unique selective activity against P-glycoprotein (P-gp) overexpressing multidrug resistance cell line. We have now prepared and evaluated 1-analogues with bicyclic or tricyclic aromatic B-ring systems as in vitro inhibitors of human cancer cell line proliferation. Among all synthesized derivatives, 21 with a benzo[b]thiophenyl B-ring was highly active, with GI50 values of 0.06–0.16 μM, and this activity was not influenced by overexpression of P-gp. Furthermore, 21 inhibited tubulin assembly in vitro with an IC 50 value of 2.0 μM and colchicine binding by 78% as well as cellular microtubule polymerization and spindle formation. PMID:21284385

  18. Nitroglycerin enhances the propagation of cortical spreading depression: comparative studies with sumatriptan and novel kynurenic acid analogues

    PubMed Central

    Knapp, Levente; Szita, Bence; Kocsis, Kitti; Vécsei, László; Toldi, József

    2017-01-01

    Background The complex pathophysiology of migraine is not yet clearly understood; therefore, experimental models are essential for the investigation of the processes related to migraine headache, which include cortical spreading depression (CSD) and NO donor-induced neurovascular changes. Data on the assessment of drug efficacy in these models are often limited, which prompted us to investigate a novel combined migraine model in which an effective pharmacon could be more easily identified. Materials and methods In vivo electrophysiological experiments were performed to investigate the effect of nitroglycerin (NTG) on CSD induced by KCl application. In addition, sumatriptan and newly synthesized neuroactive substances (analogues of the neuromodulator kynurenic acid [KYNA]) were also tested. Results The basic parameters of CSDs were unchanged following NTG administration; however, propagation failure was decreased compared to the controls. Sumatriptan decreased the number of CSDs, whereas propagation failure was as minimal as in the NTG group. On the other hand, both of the KYNA analogues restored the ratio of propagation to the control level. Discussion The ratio of propagation appeared to be the indicator of the effect of NTG. This is the first study providing direct evidence that NTG influences CSD; furthermore, we observed different effects of sumatriptan and KYNA analogues. Sumatriptan changed the generation of CSDs, whereas the analogues acted on the propagation of the waves. Our experimental design overlaps with a large spectrum of processes present in migraine pathophysiology, and it can be a useful experimental model for drug screening. PMID:28053504

  19. Reversal of methylcholanthrene-induced changes in mouse prostates in vitro by retinoic acid and its analogues.

    PubMed Central

    Lasnitzki, I.

    1976-01-01

    The influence of vitamin A-related compounds on hyperplasia and metaplasia induced by methylcholanthrene was studied in mouse prostate glands in organ culture. Methylcholanthrene was found to cause extensive hyperplasia and squamous metaplasia of the prostatic epithelium which persisted after withdrawal of the carcinogen. The retinoids included retinoic acid and 6 of its structural analogues synthesized in an attempt to enhance the anticarcinogenic action and reduce the toxicity of the parent compound. These where the cyclopentenyl analogus 7699, A2-retinoic acid, 13-cis-alpha-retinoic acid and 3 aromatic analogues. Administration of the compounds following the carcinogen reduced the extent and incidence of hyperplasia significantly and with the exception of one compound reversed the squamous metaplasia. Two of the aromatic analogues, one with a terminal ethylamide group (1430), and the other with a terminal ethylester group (9369), proved to be the most potent inhibitors, followed by compound 7699 and (9369), proved to be the most potent inhibitors, followed by compound 7699 and retinoic acid. A2-retinoic acid and 13-cis-alpha-retinoic acid showed the lowest activity. The inhibition of hyperplasia appeared to be mediated via a reduction of DNA synthesis. It seemed unrelated to either the biological growth-promoting activity of the compounds or their surface-active properties. It is tentatively suggested that vitamin A and its analogues may act as hormones. Images Fig. 2 Fig. 3 Fig. 4 Fig. 5 Fig. 6 Fig. 7 Fig. 8 PMID:987794

  20. Design of potent substrate-analogue inhibitors of canine renin

    NASA Technical Reports Server (NTRS)

    Hui, K. Y.; Siragy, H. M.; Haber, E.

    1992-01-01

    Through a systematic study of structure-activity relationships, we designed potent renin inhibitors for use in dog models. In assays against dog plasma renin at neutral pH, we found that, as in previous studies of rat renin inhibitors, the structure at the P2 position appears to be important for potency. The substitution of Val for His at this position increases potency by one order of magnitude. At the P3 position, potency appears to depend on a hydrophobic side chain that does not necessarily have to be aromatic. Our results also support the approach of optimizing potency in a renin inhibitor by introducing a moiety that promotes aqueous solubility (an amino group) at the C-terminus of the substrate analogue. In the design of potent dog plasma renin inhibitors, the influence of the transition-state residue 4(S)-amino-3(S)-hydroxy-5-cyclohexylpentanoic acid (ACHPA)-commonly used as a substitute for the scissile-bond dipeptide to boost potency-is not obvious, and appears to be sequence dependent. The canine renin inhibitor Ac-paF-Pro-Phe-Val-statine-Leu-Phe-paF-NH2 (compound 15; IC50 of 1.7 nM against dog plasma renin at pH 7.4; statine, 4(S)-amino-3(S)-hydroxy-6-methylheptanoic acid; paF, para-aminophenylalanine) had a potent hypotensive effect when infused intravenously into conscious, sodium-depleted, normotensive dogs. Also, compound 15 concurrently inhibited plasma renin activity and had a profound diuretic effect.

  1. Terrestrial research in Mars analogue environments

    NASA Astrophysics Data System (ADS)

    Osipov, G.

    Fatty acids (FA) content was measured by GC-MS SIM technique in Sulfide ores of present day (Mid-Atlantic Ridge and others) and ancient (Ural Paleocene, Russia) black smokers; Early Proterozoic kerites of Volyn; Siberian, Canadian and Antarctic permafrosts and also in rocks of East-European platform Achaean crystalline basement. Analysis was shown presence those and only those fatty acids which are specific to microorganisms. FA with 12 up 19 of carbon atoms are thought to be a bacterial biomass sign. 3-Hydroxy fatty acids also found in samples and are strong specific markers of gram-negative bacteria. Cultivation yield living bacteria in some cases. The East-European platform Achaean crystalline basement rocks opened by Vorotilov Deep Well (VDW) drilled through Puchezh-Katunski impact structure were studied within depths 2575 - 2805 m. 34 microbial lipid markers were detected by GC-MS and 22 species were identified. Bacteria of g. Bacillus reached 6,8 % in subsurface communities. However, members of gg. Clostridium (37,1 - 33,2 %) and Rhodococcus (27,6 - 33,7 %) were absolute dominants within studied depth interval. Some lipid patterns of kerite samples could be assessed to definite genera or, in special cases, to species of contemporary microorganisms. For instance, 2-hydroxylauric acid is specific to Pseudomonas putida group or Acinetobacter spp., and hydroxymyristic together with hydroxypalmitic are specific to P.cepacea and cyanobacteria. 3-hydroxystearic acid was known as component of Acetobacter diazothrophycus and Gloebacter violaceous cyanobacterium. 10-hydroxystearic acid associated with Nocardia spp., which oxidizes oleic acid in organic substrates. 10-methylhexadecanoic (10Me16) acid together with 10Me14, 10Me15 and 10Me17 analogues are markers of actinomycetes. Significant part of Black Smokers organic matter is probably biogenic. Fatty acid features strongly assigns it to bacterial, microeucariotic and planta cells. Par example 3-hydroxy acids are

  2. Therapeutic Assessment of Chloroquine-Primaquine Combined Regimen in Adult Cohort of Plasmodium vivax Malaria from Primary Care Centres in Southwestern India

    PubMed Central

    Saravu, Kavitha; Kumar, Rishikesh; Ashok, Herikudru; Kundapura, Premananda; Kamath, Veena; Kamath, Asha; Mukhopadhyay, Chiranjay

    2016-01-01

    Background Several reports of chloroquine treatment failure and resistance in Plasmodium vivax malaria from Southeast Asian countries have been published. Present study was undertaken to assess the efficacy of chloroquine-primaquine (CQ-PQ) combined regimen for the treatment of P. vivax malaria patients who were catered by the selected primary health centres (PHCs) of Udupi taluk, Udupi district, Karnataka, India. Method Five PHCs were selected within Udupi taluk based on probability proportional to size. In-vivo therapeutic efficacy assessment of CQ (1500 mg over three days) plus PQ (210 mg over 14 days) regimen was carried out in accordance with the World Health Organization’s protocol of 28 days follow-up among microscopically diagnosed monoinfection P. vivax cohort. Results In total, 161 participants were recruited in the study of which, 155 (96.3%) participants completed till day 28 follow-up, fully complied with the treatment regimen and showed adequate clinical and parasitological response. Loss to follow up was noted with 5 (3.1%) participants and non-compliance with treatment regimen occurred with one participant (0.6%). Glucose-6-phosphate dehydrogenase deficiency (G6PDd, <30% of normal mean activity) was noted among 5 (3.1%) participants and one of them did develop PQ induced dark-brown urination which subsided after PQ discontinuation. G6PDd patients were treated with PQ 45 mg/week for eight weeks while PQ was discontinued in one case with G6PD 1.4 U/g Hb due to complaint of reddish-brown coloured urine by 48 hours of PQ initiation. Nested polymerase chain reaction test revealed 45 (28%) cases as mixed (vivax and falciparum) malaria. Conclusions The CQ-PQ combined regimen remains outstandingly effective to treat uncomplicated P. vivax malaria in Udupi taluk and thus it should continue as first line regimen. For all P. vivax cases, G6PD screening before PQ administration must be mandatory and made available in all PHCs. PMID:27315280

  3. Conformational preferences of 1-amino-2-phenylcyclohexanecarboxylic acid, a phenylalanine cyclohexane analogue

    PubMed Central

    Alemán, Carlos; Jiménez, Ana I.; Cativiela, Carlos; Nussinov, Ruth; Casanovas, Jordi

    2009-01-01

    The intrinsic conformational preferences of the restricted phenylalanine analogue generated by including the α and β carbon atoms into a cyclohexane ring (1-amino-2-phenylcyclohexanecarboxylic acid, c6Phe) have been determined using quantum mechanical calculations. Specifically, the conformational profile of the N-acetyl-N’-methylamide derivative of the c6Phe stereoisomers exhibiting either a cis or a trans relative orientation between the amino and phenyl substituents has been analyzed in different environments (gas phase, chloroform and aqueous solutions). Calculations were performed using B3LYP, MP2 and HF methods combined with the 6-31+G(d,p) and 6-311++G(d,p) basis sets, and a self-consistent reaction-field (SCRF) method was applied to analyze the influence of the solvent. The amino acids investigated can be viewed as constrained phenylalanine analogues with a rigidly oriented aromatic side chain that may interact with the peptide backbone not only sterically but also electronically through the aromatic π orbitals. Their conformational propensities have been found to be strongly influenced by the specific orientation of the aromatic substituent in each stereoisomer and the conformation adopted by the cyclohexane ring, as well as by the environment. PMID:19772338

  4. Review of Insulin and its Analogues in Diabetes Mellitus

    PubMed Central

    Mane, Krishnappa; Chaluvaraju, KC; Niranjan, MS; Zaranappa, TR; Manjuthej, TR

    2012-01-01

    Diabetes is a metabolic disorder where in human body does not produce or properly uses insulin, a hormone that is required to convert sugar, starches and other food into energy. Diabetes finally leads to more complications and to prevent these complications insulin and its analogues are used. After more than half a century of treating diabetics with animal insulin’s, recombinant DNA technologies and advanced protein chemistry made human insulin preparations available in the early 1980s. As the next step, over the last decade, insulin analogues were constructed by changing the structure of the native protein with the goal of improving the therapeutic properties of it, because the pharmacokinetic characteristics of rapid, intermediate and long-acting preparations of human insulin make it almost impossible to achieve sustained normoglycemia. The first clinically available insulin analogue, lispro, confirmed the hopes by showing that improved glycaemic control can be achieved without an increase in hypoglycaemic events. Two new insulin analogues, insulin glargine and insulin aspart, have recently been approved for clinical use in the United States and several other analogues are being intensively tested. PMID:24826038

  5. Fluorescent analogues of methotrexate: characterization and interaction with dihydrofolate reductase.

    PubMed

    Kumar, A A; Kempton, R J; Anstead, G M; Freisheim, J H

    1983-01-18

    The dansylated derivatives of lysine and ornithine analogues of methotrexate exhibit fluorescence properties characteristic of the dansyl moiety with an excitation at 328 nm and an emission maximum at 580 nm in aqueous media. As in the case of dansyl amino acids, the fluorescence emission is dependent upon the polarity of the medium. In solvents of low dielectric constant there is an enhancement of the dansyl fluorescence intensity as well as a shift to shorter wavelengths. The dansylated analogues show a reduction in the quantum yields as compared to N epsilon-dansyl-L-lysine and 5-(N,N-dimethylamino)-1-naphthalenesulfonic acid. The absorption spectra of the two dansyl analogues are similar to the spectra of the parent basic amino acid precursors but with reduced molar extinction values. The two fluorescent analogues of methotrexate were found to be potent inhibitors of purified dihydrofolate reductases from Lactobacillus casei and from chicken liver. The binding of these fluorescent analogues to either dihydrofolate reductase resulted in 10-15-nm blue shift of the ligand emission maxima and a 2-5-fold enhancement of the emission. These fluorescent properties of the bound ligands indicate a possible interaction of the dansyl moiety with a region on the enzyme molecule which is more hydrophobic relative to the surrounding solvent.

  6. Theoretical study on absorption and emission spectra of adenine analogues.

    PubMed

    Liu, Hongxia; Song, Qixia; Yang, Yan; Li, Yan; Wang, Haijun

    2014-04-01

    Fluorescent nucleoside analogues have attracted much attention in studying the structure and dynamics of nucleic acids in recent years. In the present work, we use theoretical calculations to investigate the structural and optical properties of four adenine analogues (termed as A1, A2, A3, and A4), and also consider the effects of aqueous solution and base pairing. The results show that the fluorescent adenine analogues can pair with thymine to form stable H-bonded WC base pairs. The excited geometries of both adenine analogues and WC base pairs are similar to the ground geometries. The absorption and emission maxima of adenine analogues are greatly red shifted compared with nature adenine, the oscillator strengths of A1 and A2 are stronger than A3 and A4 in both absorption and emission spectra. The calculated low-energy peaks in the absorption spectra are in good agreement with the experimental data. In general, the aqueous solution and base pairing can slightly red-shift both the absorption and emission maxima, and can increase the oscillator strengths of absorption spectra, but significantly decrease the oscillator strengths of A3 in emission spectra.

  7. Bioluminescent properties of obelin and aequorin with novel coelenterazine analogues.

    PubMed

    Gealageas, Ronan; Malikova, Natalia P; Picaud, Sandrine; Borgdorff, Aren J; Burakova, Ludmila P; Brûlet, Philippe; Vysotski, Eugene S; Dodd, Robert H

    2014-04-01

    The main analytical use of Ca(2+)-regulated photoproteins from luminous coelenterates is for real-time non-invasive visualization of intracellular calcium concentration ([Ca(2+)]i) dynamics in cells and whole organisms. A limitation of this approach for in vivo deep tissue imaging is the fact that blue light emitted by the photoprotein is highly absorbed by tissue. Seven novel coelenterazine analogues were synthesized and their effects on the bioluminescent properties of recombinant obelin from Obelia longissima and aequorin from Aequorea victoria were evaluated. Only analogues having electron-donating groups (m-OCH3 and m-OH) on the C6 phenol moiety or an extended resonance system at the C8 position (1-naphthyl and α-styryl analogues) showed a significant red shift of light emission. Of these, only the α-styryl analogue displayed a sufficiently high light intensity to allow eventual tissue penetration. The possible suitability of this compound for in vivo assays was corroborated by studies with aequorin which allowed the monitoring of [Ca(2+)]i dynamics in cultured CHO cells and in hippocampal brain slices. Thus, the α-styryl coelenterazine analogue might be potentially useful for non-invasive, in vivo bioluminescence imaging in deep tissues of small animals.

  8. Effect of extrusion temperature and moisture content of corn flour on crystallinity and hardness of rice analogues

    NASA Astrophysics Data System (ADS)

    Budi, Faleh Setia; Hariyadi, Purwiyatno; Budijanto, Slamet; Syah, Dahrul

    2015-12-01

    Rice analogues are food products made of broken rice and/or any other carbohydrate sources to have similar texture and shape as rice. They are usually made by hot extrusion processing. The hot extrusion process may change the crystallinity of starch and influence the characteristic of rice analogues. Therefore, this research aimed to study the effect of moisture content of incoming dough and temperature of extrusion process on the crystallinity and hardness of resulting rice analogues. The dough's were prepared by mixing of corn starch-flour with ratio 10/90 (w/w) and moisture content of 35%, 40% and 45% (w/w) and extrusion process were done at temperature of 70, 80, 90°C by using of twin screw extruder BEX-DS-2256 Berto. The analyses were done to determine the type of crystal, degree of crystallinity, and hardness of the resulting rice analogues. Our result showed that the enhancement of extrusion temperature from 70 - 90°C increased degree of crystallinity from 5.86 - 15.00% to 10.70 - 18.87% and hardness from 1.71 - 4.36 kg to 2.05 - 5.70 kg. The raising of dough moisture content from 35 - 45% decreased degree of crystallinity from 15.00 - 18.87% to 5.86 - 10.70% and hardness from 4.36 - 5.70 kg to 1.71 - 2.05 kg. The increase of degree of crystallinity correlated positively with the increase of hardness of rice analogues (r = 0.746, p = 0.05).

  9. Glucose as substrate and signal in priming: Results from experiments with non-metabolizable glucose analogues

    NASA Astrophysics Data System (ADS)

    Mason-Jones, Kyle; Kuzyakov, Yakov

    2016-04-01

    Priming of soil organic matter remains the subject of intense research, but a mechanistic explanation of the phenomenon remains to be demonstrated. This is largely due to the multiple effects of easily available carbon on the soil microbial community, and the challenge of separating these influences from one another. Several glucose analogues can be taken up by microbial glucose transporters and have similar regulatory effects on metabolism. These substances are, however, not easily catabolized by the common glycolytic pathway, limiting their energy value. Therefore, they can be used to distinguish between the action of glucose as a metabolic signal, and its influence as an energy source. We incubated an agricultural Haplic Luvisol under controlled conditions for 24 days after addition of: 1) glucose, 2) 3-O-methyl-glucose, 3) α-methylglucoside or 4) 2-deoxyglucose, at three concentration levels, along with a control treatment of water addition. CO2 efflux from soil was monitored by trapping evolved CO2 in NaOH and back-titration with HCl. On the first day after amendment, CO2 efflux from soil increased strongly for glucose and much less for the analogues, relative to the control. Only glucose caused a peak in efflux within the first two days. Peak mineralization of 2-deoxyglucose and α-methylglucoside was delayed until the third day, while CO2 from 3-O-methyl-glucose increased gradually, with a peak delayed by approximately a week. For glucose, the immediate increase in respiration was strongly dependent on the amount of glucose added, but this was not the case for the analogues, indicating that the catabolic potential for these substances was saturated. This is consistent with only a small part of the microbial community being capable of utilizing these carbon sources. In a subsequent experiment, 14C-labelled glucose or 14C-labelled 3-O-methyl-glucose were added to the same soil, enabling quantification of the priming effect. For 3-O-methyl-glucose, priming was

  10. New rubrolide analogues as inhibitors of photosynthesis light reactions.

    PubMed

    Varejão, Jodieh O S; Barbosa, Luiz C A; Ramos, Gabriela Álvarez; Varejão, Eduardo V V; King-Díaz, Beatriz; Lotina-Hennsen, Blas

    2015-04-01

    Natural products called rubrolides have been investigated as a model for the development of new herbicides that act on the photosynthesis apparatus. This study comprises a comprehensive analysis of the photosynthesis inhibitory ability of 27 new structurally diverse rubrolide analogues. In general, the results revealed that the compounds exhibited efficient inhibition of the photosynthetic process, but in some cases low water solubility may be a limiting factor. To elucidate their mode of action, the effects of the compounds on PSII and PSI, as well as their partial reaction on chloroplasts and the chlorophyll a fluorescence transients were measured. Our results showed that some of the most active rubrolide analogues act as a Hill reaction inhibitors at the QB level by interacting with the D1 protein at the reducing side of PSII. All of the active analogues follow Tice's rule of 5, which indicates that these compounds present physicochemical properties suitable for herbicides.

  11. Analogue peptides for the immunotherapy of human acute myeloid leukemia.

    PubMed

    Hofmann, Susanne; Mead, Andrew; Malinovskis, Aleksandrs; Hardwick, Nicola R; Guinn, Barbara-Ann

    2015-11-01

    The use of peptide vaccines, enhanced by adjuvants, has shown some efficacy in clinical trials. However, responses are often short-lived and rarely induce notable memory responses. The reason is that self-antigens have already been presented to the immune system as the tumor develops, leading to tolerance or some degree of host tumor cell destruction. To try to break tolerance against self-antigens, one of the methods employed has been to modify peptides at the anchor residues to enhance their ability to bind major histocompatibility complex molecules, extending their exposure to the T-cell receptor. These modified or analogue peptides have been investigated as stimulators of the immune system in patients with different cancers with variable but sometimes notable success. In this review we describe the background and recent developments in the use of analogue peptides for the immunotherapy of acute myeloid leukemia describing knowledge useful for the application of analogue peptide treatments for other malignancies.

  12. Synthesis and antioxidant activity of a procyanidin B3 analogue.

    PubMed

    Mizuno, Mirei; Nakanishi, Ikuo; Matsubayashi, Satoko; Imai, Kohei; Arai, Takuya; Matsumoto, Ken-Ichiro; Fukuhara, Kiyoshi

    2017-02-15

    Proanthocyanidin, an oligomer of catechin, is a natural antioxidant and a potent inhibitor of lectin-like oxidized LDL receptor-1, which is involved in the pathogenesis of arteriosclerosis. We synthesized proanthocyanidin analogue 1, in which the geometry of one catechin molecule in procyanidin B3, a dimer of (+)-catechin, is constrained to be planar. The antioxidant activities of the compounds were evaluated in terms of their capacities to scavenge galvinoxyl radicals, and results demonstrate that while procyanidin was 3.8 times more potent than (+)-catechin, the radical scavenging activity of proanthocyanidin analogue 1 was further increased to 1.9 times that of procyanidin B3. This newly designed proanthocyanidin analogue 1 may be a promising lead compound for the treatment of arteriosclerosis and related cerebrovascular diseases.

  13. Analogue modelling of syntectonic leucosomes in migmatitic schists

    NASA Astrophysics Data System (ADS)

    Druguet, Elena; Carreras, Jordi

    2006-10-01

    Migmatites from the Cap de Creus tectonometamorphic belt display a wide variety of structures, from those formed when the leucosomes were melt-bearing, to those developed during solid-state deformation. The observed field structures have been modelled by means of analogue experiments. The materials used in the models are layered plasticine as a schist analogue, and chocolate as analogue of the crystallizing leucosome. A model for the development of syntectonic migmatites is proposed in which initial melt-bearing patches, preferentially formed within fertile pelitic layers, progressively evolve towards lens-shaped veins. Furthermore, heterogeneous deformation of anisotropic metasediments facilitates formation of extensional sites for further melt accumulation and transport. Melt crystallization implies a rapid increase in effective viscosity of leucosomes producing a reversal in competence contrast with respect to the enclosing schists. During the whole process, deformation localizes around crystallizing veins, giving rise to different and contrasting structures for melt-bearing and for solid-state stages.

  14. Design of novel CSA analogues as potential safeners and fungicides.

    PubMed

    Zheng, Yang; Liu, Bin; Gou, Zhaopin; Li, Yao; Zhang, Xiao; Wang, Yanqing; Yu, Shujing; Li, Yonghong; Sun, Dequn

    2015-02-15

    Study of safeners has been seldom reported in literature. In this work, a series of novel acylsulfamoylbenzamide analogues was designed and synthesized with newly developed safener cyprosulfamide (CSA) as the leading compound. The activity assay against the herbicide thiencarbazone-methyl (TCM) on maize revealed that fifteen compounds showed better protective effect than CSA on the fresh weight of aerial parts, twelve compounds exhibited better activity on the dry weight of aerial parts. Remarkably, two compounds (6Ih, 7II) had protective effect on the four aspects of TCM treated maize. Further antifungal assay showed their excellent activity against Physollospora piricola. The structure-activity relationships of CSA analogues as safeners and fungicides were discussed and it might be valuable for further molecular modification of new CSA analogues.

  15. Conception, synthesis, and biological evaluation of original discodermolide analogues.

    PubMed

    de Lemos, Elsa; Agouridas, Evangelos; Sorin, Geoffroy; Guerreiro, Antonio; Commerçon, Alain; Pancrazi, Ange; Betzer, Jean-François; Lannou, Marie-Isabelle; Ardisson, Janick

    2011-08-29

    Due to its intriguing biological activity profile and potential chemotherapeutic application discodermolide (DDM) proved to be an attractive target. Therefore, notable efforts have been carried out directed toward its total synthesis and toward the production and evaluation of synthetic analogues. Recently, we achieved the total synthesis of DDM. At the present, guided by the knowledge gained during our DDM total synthesis and by the requirement of keeping the bioactive "U" shape conformation, we report the convergent preparation of five original analogues. Three types of changes were realized through modification of the terminal (Z)-diene moiety, of the methyl group at the C14-position, and the lactone region. All analogues were active in the nanomolar range and two of them turned out to be equipotent to DDM.

  16. Migrastatin analogues target fascin to block tumour metastasis.

    PubMed

    Chen, Lin; Yang, Shengyu; Jakoncic, Jean; Zhang, J Jillian; Huang, Xin-Yun

    2010-04-15

    Tumour metastasis is the primary cause of death of cancer patients. Development of new therapeutics preventing tumour metastasis is urgently needed. Migrastatin is a natural product secreted by Streptomyces, and synthesized migrastatin analogues such as macroketone are potent inhibitors of metastatic tumour cell migration, invasion and metastasis. Here we show that these migrastatin analogues target the actin-bundling protein fascin to inhibit its activity. X-ray crystal structural studies reveal that migrastatin analogues bind to one of the actin-binding sites on fascin. Our data demonstrate that actin cytoskeletal proteins such as fascin can be explored as new molecular targets for cancer treatment, in a similar manner to the microtubule protein tubulin.

  17. Largazole Analogues Embodying Radical Changes in the Depsipeptide Ring: Development of a More Selective and Highly Potent Analogue.

    PubMed

    Almaliti, Jehad; Al-Hamashi, Ayad A; Negmeldin, Ahmed T; Hanigan, Christin L; Perera, Lalith; Pflum, Mary Kay H; Casero, Robert A; Tillekeratne, L M Viranga

    2016-12-08

    A number of analogues of the marine-derived histone deacetylase inhibitor largazole incorporating major structural changes in the depsipeptide ring were synthesized. Replacing the thiazole-thiazoline fragment of largazole with a bipyridine group gave analogue 7 with potent cell growth inhibitory activity and an activity profile similar to that of largazole, suggesting that conformational change accompanying switching hybridization from sp(3) to sp(2) at C-7 is well tolerated. Analogue 7 was more class I selective compared to largazole, with at least 464-fold selectivity for class I HDAC proteins over class II HDAC6 compared to a 22-fold selectivity observed with largazole. To our knowledge 7 represents the first example of a potent and highly cytotoxic largazole analogue not containing a thiazoline ring. The elimination of a chiral center derived from the unnatural amino acid R-α-methylcysteine makes the molecule more amenable to chemical synthesis, and coupled with its increased class I selectivity, 7 could serve as a new lead compound for developing selective largazole analogues.

  18. Synthesis of daidzin analogues as potential agents for alcohol abuse.

    PubMed

    Gao, Guang-Yao; Li, Dian-Jun; Keung, Wing Ming

    2003-09-01

    Daidzin, the active principle of an herbal remedy for 'alcohol addiction', has been shown to reduce alcohol consumption in all laboratory animals tested to date. Correlation studies using structural analogues of daidzin suggests that it acts by raising the monoamine oxidase (MAO)/mitochondrial aldehyde dehydrogenase (ALDH-2) activity ratio (J. Med. Chem. 2000, 43, 4169). Structure-activity relationship (SAR) studies on the 7-O-substituted analogues of daidzin have revealed structural features important for ALDH-2 and MAO inhibition (J. Med. Chem. 2001, 44, 3320). We here evaluated effects of substitutions at 2, 5, 6, 8, 3' and 4' positions of daidzin on its potencies for ALDH-2 and MAO inhibition. Results show that analogues with 4'-substituents that are small, polar and with hydrogen bonding capacities are most potent ALDH-2 inhibitors, whereas those that are non-polar and with electron withdrawing capacities are potent MAO inhibitors. Analogues with a 5-OH group are less potent ALDH-2 inhibitors but are more potent MAO inhibitors. All the 2-, 6-, 8- and 3'-substituted analogues tested so far do not inhibit ALDH-2 and/or have decreased potencies for MAO inhibition. This, together with the results obtained from previous studies, suggests that a potent antidipsotropic analogue would be a 4',7-disubstituted isoflavone. The 4'-substituent should be small, polar, and with hydrogen bonding capacities such as, -OH and -NH(2); whereas the 7-substituent should be a straight-chain alkyl with a terminal polar function such as -(CH(2))(n)-OH with 2< or =n < or =6, -(CH(2))(n)-COOH with 5< or =n < or =10, or -(CH(2))(n)-NH(2) with n > or =4.

  19. The Object-analogue approach for probabilistic forecasting

    NASA Astrophysics Data System (ADS)

    Frediani, M. E.; Hopson, T. M.; Anagnostou, E. N.; Hacker, J.

    2015-12-01

    The object-analogue is a new method to estimate forecast uncertainty and to derive probabilistic predictions of gridded forecast fields over larger regions rather than point locations. The method has been developed for improving the forecast of 10-meter wind speed over the northeast US, and it can be extended to other forecast variables, vertical levels, and other regions. The object-analogue approach combines the analog post-processing technique (Hopson 2005; Hamill 2006; Delle Monache 2011) with the Method for Object-based Diagnostic Evaluation (MODE) for forecast verification (Davis et al 2006a, b). Originally, MODE is used to verify mainly precipitation forecasts using features of a forecast region represented by an object. The analog technique is used to reduce the NWP systematic and random errors of a gridded forecast field. In this study we use MODE-derived objects to characterize the wind fields forecasts into attributes such as object area, centroid location, and intensity percentiles, and apply the analogue concept to these objects. The object-analogue method uses a database of objects derived from reforecasts and their respective reanalysis. Given a real-time forecast field, it searches the database and selects the top-ranked objects with the most similar set of attributes using the MODE fuzzy logic algorithm for object matching. The attribute probabilities obtained with the set of selected object-analogues are used to derive a multi-layer probabilistic prediction. The attribute probabilities are combined into three uncertainty layers that address the main concerns of most applications: location, area, and magnitude. The multi-layer uncertainty can be weighted and combined or used independently in such that it provides a more accurate prediction, adjusted according to the application interest. In this study we present preliminary results of the object-analogue method. Using a database with one hundred storms we perform a leave-one-out cross-validation to

  20. STED microscopy detects and quantifies liquid phase separation in lipid membranes using a new far-red emitting fluorescent phosphoglycerolipid analogue.

    PubMed

    Honigmann, Alf; Mueller, Veronika; Hell, Stefan W; Eggeling, Christian

    2013-01-01

    We have developed a bright, photostable, and far-red emitting fluorescent phosphoglycerolipid analogue to probe diffusion characteristics of lipids in membranes. The lipid analogue consists of a saturated (C18) phosphoethanolamine and a hydrophilic far-red emitting fluorescent dye (KK114) that is tethered to the head group by a long polyethylenglycol linker. In contrast to reported far-red emitting fluorescent lipid analogues, this one partitions predominantly into liquid ordered domains of phase-separated ternary bilayers. We performed fluorescence correlation spectroscopy with a super-resolution STED microscope (STED-FCS) to measure the lateral diffusion of the new lipid analogue in the liquid ordered (Lo) and disordered (Ld) phase. On a mica support, we observed micrometer large phases and found that the lipid analogue diffuses freely on all tested spatial scales (40-250 nm) in both the Ld and Lo phase with diffusion coefficients of 1.8 microm2 s(-1) and 0.7 microm2 s(-1) respectively. This indicates that the tight molecular packing of the Lo phase mainly slows down the diffusion rather than causing anomalous sub-diffusion. The same ternary mixture deposited on acid-cleaned glass forms Lo nanodomains of < 40 nm to 300 nm in diameter as only revealed by STED microscopy, which demonstrates the severe influence of interactions with the substrate on the sizes of domains in membranes. When averaging over different positions, STEd-FCS measurements on such glass supported membranes displayed anomalous sub-diffusion. This anomaly can be attributed to a transient partitioning of the lipid analogue into the nano-domains, where diffusion is slowed down. Our results suggest that STED-FCS in combination with a Lo-partitioning fluorescent lipid analogue can directly probe the presence of Lo nano-domains, which in the future should allow the study of potential lipid rafts in live-cell membranes.

  1. Prospects of intermittent preventive treatment of adults against malaria in areas of seasonal and unstable malaria transmission, and a possible role for chloroquine.

    PubMed

    Giha, Hayder A

    2010-04-01

    Chloroquine (CQ) is outmoded as an antimalarial drug in most of the malarial world because of the high resistance rate of parasites. The parasite resistance to CQ is attributed to pfcrt/pfmdr1 gene mutations. Recent studies showed that parasites with mutations of pfcrt/pfmdr1 genes are less virulent, and that those with dhfr/dhps mutations are more susceptible to host immune clearance; the former and latter mutations are linked. In the era of artemisinin-based combination therapy, the frequency of pfcrt/pfmdr1 wild variants is expected to rise. In areas of unstable malaria transmission, the unpredictable severe epidemics of malaria and epidemics of severe malaria could result in high mortality rate among the semi-immune population. With this in mind, the use of CQ for intermittent preventive treatment of adults (IPTa) is suggested as a feasible control measure to reduce malaria mortality in adults and older children without reducing uncomplicated malaria morbidity. The above is discussed in a multidisciplinary approach validating the deployment of molecular techniques in malaria control and showing a possible role for CQ as a rescue drug after being abandoned.

  2. Feasibility of amlodipine besylate, chloroquine phosphate, dapsone, phenytoin, pyridoxine hydrochloride, sulfadiazine, sulfasalazine, tetracycline hydrochloride, trimethoprim and zonisamide in SyrSpend(®) SF PH4 oral suspensions.

    PubMed

    Ferreira, Anderson O; Polonini, Hudson C; Silva, Sharlene L; Patrício, Fernando B; Brandão, Marcos Antônio F; Raposo, Nádia R B

    2016-01-25

    The objective of this study was to evaluate the feasibility of 10 commonly used active pharmaceutical ingredients (APIs) compounded in oral suspensions using an internationally used suspending vehicle (SyrSpend(®) SF PH4 liquid): (i) amlodipine, (as besylate) 1.0mg/mL; (ii) chloroquine phosphate,15.0 mg/mL; (iii) dapsone, 2.0 mg/mL; (iv) phenytoin, 15.0 mg/mL; (v) pyridoxine hydrochloride, 50.0 mg/mL; (vi) sulfadiazine, 100.0 mg/mL; (vii) sulfasalazine, 100.0 mg/mL; (viii) tetracycline hydrochloride, 25.0 mg/mL; (ix) trimethoprim, 10.0 mg/mL; and (x) zonisamide, 10.0 mg/mL. All suspensions were stored both at controlled refrigeration (2-8 °C) and controlled room temperature (20-25 °C). Feasibility was assessed by measuring the percent recovery at varying time points throughout a 90-day period. API quantification was performed by high-performance liquid chromatography (HPLC-UV), via a stability-indicating method. Given the percentage of recovery of the APIs within the suspensions, the expiration date of the final products (API+vehicle) was at least 90 days for all suspensions with regard to both the controlled temperatures. This suggests that the vehicle is stable for compounding APIs from different pharmacological classes.

  3. Signaling of chloroquine-induced stress in the yeast Saccharomyces cerevisiae requires the Hog1 and Slt2 mitogen-activated protein kinase pathways.

    PubMed

    Baranwal, Shivani; Azad, Gajendra Kumar; Singh, Vikash; Tomar, Raghuvir S

    2014-09-01

    Chloroquine (CQ) has been under clinical use for several decades, and yet little is known about CQ sensing and signaling mechanisms or about their impact on various biological pathways. We employed the budding yeast Saccharomyces cerevisiae as a model organism to study the pathways targeted by CQ. Our screening with yeast mutants revealed that it targets histone proteins and histone deacetylases (HDACs). Here, we also describe the novel role of mitogen-activated protein kinases Hog1 and Slt2, which aid in survival in the presence of CQ. Cells deficient in Hog1 or Slt2 are found to be CQ hypersensitive, and both proteins were phosphorylated in response to CQ exposure. CQ-activated Hog1p is translocated to the nucleus and facilitates the expression of GPD1 (glycerol-3-phosphate dehydrogenase), which is required for the synthesis of glycerol (one of the major osmolytes). Moreover, cells treated with CQ exhibited an increase in intracellular reactive oxygen species (ROS) levels and the effects were rescued by addition of reduced glutathione to the medium. The deletion of SOD1, the superoxide dismutase in yeast, resulted in hypersensitivity to CQ. We have also observed P38 as well as P42/44 phosphorylation in HEK293T human cells upon exposure to CQ, indicating that the kinds of responses generated in yeast and human cells are similar. In summary, our findings define the multiple biological pathways targeted by CQ that might be useful for understanding the toxicity modulated by this pharmacologically important molecule.

  4. On slow light as a black hole analogue

    NASA Astrophysics Data System (ADS)

    Unruh, W. G.; Schützhold, R.

    2003-07-01

    Although slow light (electromagnetically induced transparency) would seem an ideal medium in which to institute a “dumb hole” (black hole analogue), it suffers from a number of problems. We show that the high phase velocity in the slow light regime ensures that the system cannot be used as an analogue displaying Hawking radiation. Even though an appropriately designed slow-light setup may simulate classical features of black holes—such as horizon, mode mixing, “Bogoliubov” coefficients, etc.—it does not reproduce the related quantum effects.

  5. Naturally occurring crystalline phases: analogues for radioactive waste forms

    SciTech Connect

    Haaker, R.F.; Ewing, R.C.

    1981-01-01

    Naturally occurring mineral analogues to crystalline phases that are constituents of crystalline radioactive waste forms provide a basis for comparison by which the long-term stability of these phases may be estimated. The crystal structures and the crystal chemistry of the following natural analogues are presented: baddeleyite, hematite, nepheline; pollucite, scheelite;sodalite, spinel, apatite, monazite, uraninite, hollandite-priderite, perovskite, and zirconolite. For each phase in geochemistry, occurrence, alteration and radiation effects are described. A selected bibliography for each phase is included.

  6. Non-natural acetogenin analogues as potent Trypanosoma brucei inhibitors

    PubMed Central

    Florence, Gordon J.; Fraser, Andrew L.; Gould, Eoin R.; King, Elizabeth F.; Menzies, Stefanie K.; Morris, Joanne C.; Tulloch, Lindsay B.; Smith, Terry K.

    2015-01-01

    A series of novel bis-tetrahydropyran 1,4-triazole analogues based on the acetogenin framework display low micromolar trypanocidal activities towards both bloodstream and insect forms of Trypanosoma brucei, the causative agent of African sleeping sickness. A divergent synthetic strategy was adopted for the synthesis of the key tetrahydropyran intermediates to enable rapid access to diastereochemical variation either side of the 1,4-triazole core. The resulting diastereomeric analogues displayed varying degrees of trypanocidal activity and selectivity in structure activity relationship studies. PMID:25145275

  7. Retro-1 Analogues Differentially Affect Oligonucleotide Delivery and Toxin Trafficking.

    PubMed

    Yang, Bing; Ming, Xin; Abdelkafi, Hajer; Pons, Valerie; Michau, Aurelien; Gillet, Daniel; Cintrat, Jean-Christophe; Barbier, Julien; Juliano, Rudy

    2016-11-21

    Retro-1 is a small molecule that displays two important biological activities: First, it blocks the actions of certain toxins by altering their intracellular trafficking. Second, it enhances the activity of oligonucleotides by releasing them from entrapment in endosomes. This raises the question of whether the two actions involve the same cellular target. Herein we report the effects of several Retro-1 analogues on both toxins and oligonucleotides. We found analogues that affect toxins but not oligonucleotides and vice-versa, while Retro-1 is the only compound that affects both. This indicates that the molecular target(s) involved in the two processes are distinct.

  8. Synthesis and evaluation of heterocyclic analogues of bromoxynil.

    PubMed

    Cutulle, Matthew A; Armel, Gregory R; Brosnan, James T; Best, Michael D; Kopsell, Dean A; Bruce, Barry D; Bostic, Heidi E; Layton, Donovan S

    2014-01-15

    One attractive strategy to discover more active and/or crop-selective herbicides is to make structural changes to currently registered compounds. This strategy is especially appealing for those compounds with limited herbicide resistance and whose chemistry is accompanied with transgenic tools to enable herbicide tolerance in crop plants. Bromoxynil is a photosystem II (PSII) inhibitor registered for control of broadleaf weeds in several agronomic and specialty crops. Recently at the University of Tennessee-Knoxville several analogues of bromoxynil were synthesized including a previously synthesized pyridine (2,6-dibromo-5-hydroxypyridine-2-carbonitrile sodium salt), a novel pyrimidine (4,6-dibromo-5-hydroxypyrimidine-2-carbonitrile sodium salt), and a novel pyridine N-oxide (2,6-dibromo-1-oxidopyridin-1-ium-4-carbonitrile). These new analogues of bromoxynil were also evaluated for their herbicidal activity on soybean (Glycine max), cotton (Gossypium hirsutum), redroot pigweed (Amaranthus retroflexus), velvetleaf (Abutilon theophrasti), large crabgrass (Digitaria sanguinalis), and pitted morningglory ( Ipomoea lacunose ) when applied at 0.28 kg ha(-1). A second study was conducted on a glyphosate-resistant weed (Amaranthus palmeri) with the compounds being applied at 0.56 kg ha(-1). Although all compounds were believed to inhibit PSII by binding in the quinone binding pocket of D1, the pyridine and pyridine-N-oxide analogues were clearly more potent than bromoxynil on Amaranthus retroflexus. However, application of the pyrimidine herbicide resulted in the least injury to all species tested. These variations in efficacy were investigated using molecular docking simulations, which indicate that the pyridine analogue may form a stronger hydrogen bond in the pocket of the D1 protein than the original bromoxynil. A pyridine analogue was able to control the glyphosate-resistant Amaranthus palmeri with >80% efficacy. The pyridine analogues of bromoxynil showed potential

  9. Relationship between antimold activity and molecular structure of cinnamaldehyde analogues.

    PubMed

    Zhang, Yuanyuan; Li, Shujun; Kong, Xianchao

    2013-03-01

    A quantitative structure-activity relationship (QSAR) modeling of the antimold activity of cinnamaldehyde analogues against of Aspergillus niger and Paecilomyces variotii was presented. The molecular descriptors of cinnamaldehyde analogues were calculated by the CODESSA program, and these descriptors were selected by best multi-linear regression method (BMLR). Satisfactory multilinear regression models of Aspergillus niger and Paecilomyces variotii were obtained with R(2)=0.9099 and 0.9444, respectively. The models were also satisfactorily validated using internal validation and leave one out validation. The QSAR models provide the guidance for further synthetic work.

  10. Synthesis and antihistamine evaluations of novel loratadine analogues.

    PubMed

    Wang, Yue; Wang, Juan; Lin, Yan; Si-Ma, Li-Feng; Wang, Dong-hua; Chen, Li-Gong; Liu, Deng-Ke

    2011-08-01

    A series of loratadine analogues containing hydroxyl group and chiral center were synthesized. The effect of the synthesized compounds on the histamine-induced contractions of guinea-pig ileum muscles was studied. In addition, the in vivo asthma-relieving effect of the analogues in the histamine induced asthmatic reaction in guinea-pigs was determined. Most of the compounds exhibited definite H(1) antihistamine activity. The S-enantiomers, compounds 2, 4 and 8, are more potent than the R-enantiomers, compounds 1, 3 and 7. Compound 6 was the most active one among the eight synthesized compounds.

  11. Fluorescent diethylcarbamazine analogues: sites of accumulation in Brugia malayi.

    PubMed

    Junnila, Amy; Bohle, D Scott; Prichard, Roger; Perepichka, Inna; Spina, Carla

    2007-01-01

    New fluorescein and rhodamine B-labeled antifilarial drug DEC analogues for use in drug localization studies with confocal microscopy have been prepared by a high-yield three-step synthesis. The resulting beta-amine-substituted DEC analogue has a single ethyl substituent which is beta-aminated to accommodate the fluorophore of either fluorescein isothiocyananate or rhodamine B. Confocal microscopy is used to show that the drug accumulates in the adult filarial worms in the pharynx, esophagus, and near the nerve ring of all adults, as well as in the uteri and vulva and the testes of the females and males.

  12. Lava Flow Interactions with Topographic Obstacles: Morphologic Analysis, Analogue Modeling, and Molten Basalt Experiments

    NASA Astrophysics Data System (ADS)

    Dietterich, H. R.; Cashman, K. V.; Rust, A.; Lev, E.; Dietrich, J. T.

    2014-12-01

    Underlying topography controls lava flow emplacement by influencing flow paths, lengths, and advance rates. The morphology of the pre-eruptive surface provides input into lava flow models and the design of artificial diversion barriers, although the dynamics of interactions between topographic obstacles and lava flows are not well known. We investigate these factors by combining morphologic analysis of Hawaiian lava flows with scaling derived from analogue and molten basalt experiments. A comparison of pre- and post-eruptive topographic data shows that flows thicken on the upslope side of topographic barriers, a feature that has been employed to calculate flow velocities from simple energy conversion. Observations also document effects of flow branching and confinement on flow advance rate, with confined flows in Hawai'i traveling further and faster than those that branch. To explain these observations we perform laboratory experiments using Newtonian and Bingham analogue fluids, as well as molten basalt. Conditions of flow splitting and subsequent advance are defined using experiments with both V-shaped and cylindrical obstacles that divide an unconfined flow. Oblique linear obstacles are used to explore flow confinement and diversion. We find that the degree of thickening, which determines the height of an obstacle capable of holding back the flow, is controlled by both initial flow velocity and obstacle geometry. Key is the ability of the flow to pass around the obstacle, such that larger and wider obstacles cause greater thickening than smaller and narrower obstacles. Flow advance rate is largely unaffected by branching in the Newtonian analogue experiments, but decreases after splitting in the molten basalt experiments because of surface cooling. Interestingly, flows into oblique obstacles are diverted but travel faster. Together these data provide the basis for a theoretical description of the interaction dynamics of viscous (and cooling) lava flows with

  13. Adsorption on molecularly imprinted polymers of structural analogues of a template. Single-component adsorption isotherm data

    SciTech Connect

    Kim, Hyunjung; Guiochon, Georges A

    2005-10-01

    structural analogues that have the same stereochemistry as the template is highest for the imprinted molecule (Fmoc-L-Trp). The separation of the template from the substrates with the same stereochemistry is influenced by the number of the functional groups on the substrates that can interact with the highest affinity sites on the MIP. The separation of the enantiomers of the analogues of the substrates was also achieved on the MIP, and these enantiomeric separations are influenced by the hydrophobicity of the substrates.

  14. Identification and in vivo and in vitro characterization of long acting and melanocortin 4 receptor (MC4-R) selective α-melanocyte-stimulating hormone (α-MSH) analogues.

    PubMed

    Conde-Frieboes, Kilian; Thøgersen, Henning; Lau, Jesper F; Sensfuss, Ulrich; Hansen, Thomas K; Christensen, Leif; Spetzler, Jane; Olsen, Helle B; Nilsson, Cecilia; Raun, Kirsten; Dahl, Kirsten; Hansen, Birgit S; Wulff, Birgitte S

    2012-03-08

    We report in vitro and in vivo data of new α-melanocyte-stimulating hormone (α-MSH) analogues which are N-terminal modified with a long chain fatty acid derivative. While keeping the pharmacophoric motif (d-Phe-Arg-Trp) fixed, we tried to improve selectivity and physicochemical parameters like solubility and stability of these analogues by replacing amino acids further away from the motif. Receptor specific changes in binding affinity to the melanocortin receptors were observed between the acetyl derivatives and the fatty acid analogues. Furthermore, amino acids at the N-terminal of α-MSH (Ser-Tyr-Ser) not considered to be part of the pharmacophore were found to have an influence on the MC4/MC1 receptor selectivity. While the acetyl analogues have an in vivo effect for around 7 h, the long chain fatty acid analogues have an effect up to 48 h in an acute feeding study in male Sprague-Dawley rats after a single subcutaneous administration.

  15. Missions to Mars: Characterisation of Mars analogue rocks for the International Space Analogue Rockstore (ISAR)

    NASA Astrophysics Data System (ADS)

    Bost, Nicolas; Westall, Frances; Ramboz, Claire; Foucher, Frédéric; Pullan, Derek; Meunier, Alain; Petit, Sabine; Fleischer, Iris; Klingelhöfer, Göstar; Vago, Jorge L.

    2013-07-01

    Instruments for surface missions to extraterrestrial bodies should be cross-calibrated using a common suite of relevant materials. Such work is necessary to improve instrument performance and aids in the interpretation of in-situ measurements. At the CNRS campus in Orléans, the Observatoire des Sciences de l'Univers en région Centre (OSUC) has created a collection of well-characterised rocks and minerals for testing and calibrating instruments to be flown in space missions. The characteristics of the analogue materials are documented in an accompanying online database. In view of the recent and upcoming rover missions to Mars (NASA's 2011 Mars Science Laboratory (MSL) and ESA/Roscosmos' 2018 ExoMars), we are concentrating initially on materials of direct relevance to the red planet. The initial collection consists of 15 well-studied rock and mineral samples, including a variety of basalts (ultramafic, weathered, silicified, primitive), sediments (volcanic sands, chert, and a banded iron formation -BIF-), and the phyllosilicate nontronite (a clay). All the samples were characterised petrographically, petrologically, and geochemically using the types of analyses likely to be performed during in-situ missions, in particular ExoMars: hand specimen description; optical microscopy; mineralogical analysis by XRD, Raman and IR spectrometry; iron phase analysis by Mössbauer spectroscopy (MBS), elemental analysis by Energy-Dispersive X-ray spectroscopy (EDX), microprobe, Inductively Coupled Plasma Atomic Emission Spectrometry (ICP-AES) and Mass Spectrometry (ICP-MS); and reduced carbon analysis by Raman spectrometry.

  16. [Oxazaphosphorinane drugs. New analogues, metabolic studies, and therapeutic approaches].

    PubMed

    Misiura, Konrad

    2004-01-01

    Recent studies on oxazaphosphorinane drugs, with the main focus on those carried out in Poland, are briefly reviewed. Research leading to the introduction of the new antitumor drug (S)-(-)-bromofosfamide are presented. The utility of phosphorus nuclear magnetic resonance in studies of ifosfamide metabolism and an application of analogues of the final, active metabolite of this drug in gene therapy are shown.

  17. An Analysis of an Autoclitic Analogue in Pigeons

    ERIC Educational Resources Information Center

    Kuroda, Toshikazu; Lattal, Kennon A.; García-Penagos, Andrés

    2014-01-01

    Using a conditional discrimination procedure, pigeons were exposed to a nonverbal analogue of qualifying autoclitics such as "definitely" and "maybe." It has been suggested that these autoclitics are similar to tacts except that they are under the control of private discriminative stimuli. Instead of the conventional assumption…

  18. A Macroscopic Analogue of the Nuclear Pairing Potential

    ERIC Educational Resources Information Center

    Dunlap, Richard A.

    2013-01-01

    A macroscopic system involving permanent magnets is used as an analogue to nucleons in a nucleus to illustrate the significance of the pairing interaction. This illustrates that the view of the total nuclear energy based only on the nucleon occupancy of the energy levels can yield erroneous results and it is only when the pairing interaction is…

  19. Facile Synthesis of Natural Alkoxynaphthalene Analogues from Plant Alkoxybenzenes.

    PubMed

    Tsyganov, Dmitry V; Krayushkin, Mikhail M; Konyushkin, Leonid D; Strelenko, Yuri A; Semenova, Marina N; Semenov, Victor V

    2016-04-22

    Analogues of the bioactive natural alkoxynaphthalene pycnanthulignene D were synthesized by an efficient method. The starting plant allylalkoxybenzenes (1) are easily available from the plant essential oils of sassafras, dill, and parsley. The target 1-arylalkoxynaphthalenes (5) exhibited antiproliferative activity in a phenotypic sea urchin embryo assay.

  20. A Laboratory Analogue for the Study of Peer Sexual Harassment

    ERIC Educational Resources Information Center

    Mitchell, Damon; Hirschman, Richard; Angelone, D. J.; Lilly, Roy S.

    2004-01-01

    The purpose of this study was to develop a laboratory analogue for the study of peer sexual harassment, and to examine person and situational factors associated with male on female peer sexual harassment. One hundred twenty-two male participants were given the opportunity to tell jokes to a female confederate from a joke list that included…

  1. Interaction of tRNA with antitumor polyamine analogues.

    PubMed

    N'soukpoé-Kossi, C N; Ahmed Ouameur, A; Thomas, T; Thomas, T J; Tajmir-Riahi, H A

    2009-08-01

    We studied the interaction between tRNA and three polyamine analogues (1,11-diamino-4,8-diazaundecane.4HCl (333), 3,7,11,15-tetrazaheptadecane.4HCl (BE-333), and 3,7,11,15,19-pentazahenicosane.5HCl (BE-3333)) using FTIR, UV-visible, and CD spectroscopic methods. Spectroscopic evidence showed that polyamine analogues bound tRNA via guanine N7, adenine, uracil O2, and the backbone phosphate (PO2-) groups, while the most reactive sites for biogenic polyamines were guanine N7/O6, adenine N7, uracil O2, and sugar 2'-OH groups as well as the backbone phosphate group. The binding constants of polyamine analogue-tRNA recognition were lower than those of the biogenic polyamine-tRNA complexes, with K333 = 2.8 (+/-0.5) x 10(4), K(BE-333) = 3.7 (+/-0.7) x 10(4), K(BE-3333) = 4.0 (+/-0.9) x 10(4), K(spm) = 8.7 (+/-0.9) x 10(5), K(spd) = 6.1 (+/-0.7) x 10(5), and K(put) = 1.0 (+/-0.3) x 10(5) mol/L. tRNA remained in the A-family conformation; however, it aggregated at high polyamine analogue concentrations.

  2. Cellular Cations Control Conformational Switching of Inositol Pyrophosphate Analogues.

    PubMed

    Hager, Anastasia; Wu, Mingxuan; Wang, Huanchen; Brown, Nathaniel W; Shears, Stephen B; Veiga, Nicolás; Fiedler, Dorothea

    2016-08-22

    The inositol pyrophosphate messengers (PP-InsPs) are emerging as an important class of cellular regulators. These molecules have been linked to numerous biological processes, including insulin secretion and cancer cell migration, but how they trigger such a wide range of cellular responses has remained unanswered in many cases. Here, we show that the PP-InsPs exhibit complex speciation behaviour and propose that a unique conformational switching mechanism could contribute to their multifunctional effects. We synthesised non-hydrolysable bisphosphonate analogues and crystallised the analogues in complex with mammalian PPIP5K2 kinase. Subsequently, the bisphosphonate analogues were used to investigate the protonation sequence, metal-coordination properties, and conformation in solution. Remarkably, the presence of potassium and magnesium ions enabled the analogues to adopt two different conformations near physiological pH. Understanding how the intrinsic chemical properties of the PP-InsPs can contribute to their complex signalling outputs will be essential to elucidate their regulatory functions.

  3. Fluorescence Studies Of A Cholesterol-Analogue Probe

    NASA Astrophysics Data System (ADS)

    Drew, Jacinta; Szabo, Arthur G.; Morand, Peter

    1988-06-01

    A novel cholesterol-analogue probe1,2 with a diene-(2-naphthyl) fluorophore in the sidechain (Figure 1), hereafter referred to as DN-Chol, has had its steady-state and time-resolved fluorescence properties characterized in solvents and in various viscosity mineral oils.

  4. A new analogue of fatty alcohol from Tamarix hampeana L.

    PubMed

    Aykac, Ahmet; Akgül, Yurdanur

    2010-01-01

    New analogues of a long-chain secondary alcohol (1) and laserine (2) were isolated from the flowers of Tamarix hampeana L. The isolated compounds were identified using 1D and 2D NMR, LCMS/APCI, and chemical methods. Laserine was isolated for the first time from T. hampeana L.

  5. Cyclization of nucleotide analogues as an obstacle to polymerization

    NASA Technical Reports Server (NTRS)

    Hill, A. R. Jr; Nord, L. D.; Orgel, L. E.; Robins, R. K.

    1988-01-01

    Cyclization of activated nucleotide analogues by intramolecular phosphodiester-bond formation is likely to compete very effectively with template-directed condensation except in the cases of ribo- and arabinonucleotides. This could have excluded derivatives of most sugars from growing polyribonucleotide chains and thus reduced chain-termination in prebiotic polynucleotide synthesis.

  6. Synthesis of (+)-crocacin D and simplified bioactive analogues.

    PubMed

    Pasqua, Adele E; Ferrari, Frank D; Crawford, James J; Whittingham, William G; Marquez, Rodolfo

    2015-03-01

    The total synthesis of (+)-crocacin D has been achieved in 15 steps (9 isolated intermediates) and 14% overall yield from commercially available starting materials and using (+)-crocacin C as a key intermediate. A number of simplified analogues and their biological activities are also reported.

  7. Trehalose Analogues: Latest Insights in Properties and Biocatalytic Production

    PubMed Central

    Walmagh, Maarten; Zhao, Renfei; Desmet, Tom

    2015-01-01

    Trehalose (α-d-glucopyranosyl α-d-glucopyranoside) is a non-reducing sugar with unique stabilizing properties due to its symmetrical, low energy structure consisting of two 1,1-anomerically bound glucose moieties. Many applications of this beneficial sugar have been reported in the novel food (nutricals), medical, pharmaceutical and cosmetic industries. Trehalose analogues, like lactotrehalose (α-d-glucopyranosyl α-d-galactopyranoside) or galactotrehalose (α-d-galactopyranosyl α-d-galactopyranoside), offer similar benefits as trehalose, but show additional features such as prebiotic or low-calorie sweetener due to their resistance against hydrolysis during digestion. Unfortunately, large-scale chemical production processes for trehalose analogues are not readily available at the moment due to the lack of efficient synthesis methods. Most of the procedures reported in literature suffer from low yields, elevated costs and are far from environmentally friendly. “Greener” alternatives found in the biocatalysis field, including galactosidases, trehalose phosphorylases and TreT-type trehalose synthases are suggested as primary candidates for trehalose analogue production instead. Significant progress has been made in the last decade to turn these into highly efficient biocatalysts and to broaden the variety of useful donor and acceptor sugars. In this review, we aim to provide an overview of the latest insights and future perspectives in trehalose analogue chemistry, applications and production pathways with emphasis on biocatalysis. PMID:26084050

  8. q-bosons and the q-analogue quantized field

    NASA Technical Reports Server (NTRS)

    Nelson, Charles A.

    1995-01-01

    The q-analogue coherent states are used to identify physical signatures for the presence of a 1-analogue quantized radiation field in the q-CS classical limits where the absolute value of z is large. In this quantum-optics-like limit, the fractional uncertainties of most physical quantities (momentum, position, amplitude, phase) which characterize the quantum field are O(1). They only vanish as O(1/absolute value of z) when q = 1. However, for the number operator, N, and the N-Hamiltonian for a free q-boson gas, H(sub N) = h(omega)(N + 1/2), the fractional uncertainties do still approach zero. A signature for q-boson counting statistics is that (Delta N)(exp 2)/ (N) approaches 0 as the absolute value of z approaches infinity. Except for its O(1) fractional uncertainty, the q-generalization of the Hermitian phase operator of Pegg and Barnett, phi(sub q), still exhibits normal classical behavior. The standard number-phase uncertainty-relation, Delta(N) Delta phi(sub q) = 1/2, and the approximate commutation relation, (N, phi(sub q)) = i, still hold for the single-mode q-analogue quantized field. So, N and phi(sub q) are almost canonically conjugate operators in the q-CS classical limit. The q-analogue CS's minimize this uncertainty relation for moderate (absolute value of z)(exp 2).

  9. Thymidine analogues to assess microperfusion in human tumors

    SciTech Connect

    Janssen, Hilde L.; Ljungkvist, Anna S.; Rijken, Paul F.; Sprong, Debbie; Bussink, Jan; Kogel, Albert J. van der; Haustermans, Karin M.; Begg, Adrian C. . E-mail: a.begg@nki.nl

    2005-07-15

    Purpose: To validate the use of the thymidine analogues as local perfusion markers in human tumors (no labeling indicates no perfusion) by comparison with the well-characterized perfusion marker Hoechst 33342. Methods and Materials: Human tumor xenografts from gliomas and head-and-neck cancers were injected with iododeoxyuridine (IdUrd) or bromodeoxyuridine (BrdUrd) and the fluorescent dye Hoechst 33342. In frozen sections, each blood vessel was scored for the presence of IdUrd/BrdUrd labeling and Hoechst in surrounding cells. The percentage of analogue-negative vessels was compared with the fraction of Hoechst-negative vessels. Collocalization of the two markers was also scored. Results: We found considerable intertumor variation in the fraction of perfused vessels, measured by analogue labeling, both in the human tumor xenografts and in a series of tumor biopsies from head-and-neck cancer patients. There was a significant correlation between the Hoechst-negative and IdUrd/BrdUrd-negative vessels in the xenografts (r 85, p = 0.0004), despite some mismatches on a per-vessel basis. Conclusions: Thymidine analogues can be successfully used to rank tumors according to their fraction of perfused vessels. Whether this fraction correlates with the extent of acute hypoxia needs further confirmation.

  10. Vitamin D analogues: Potential use in cancer treatment.

    PubMed

    Duffy, Michael J; Murray, Alyson; Synnott, Naoise C; O'Donovan, Norma; Crown, John

    2017-04-01

    The vitamin D receptor (VDR) is a member of the thyroid-steroid family of nuclear transcription factors. Following binding of the active form of vitamin D, i.e., 1,25(OH)2D3 (also known as calcitriol) and interaction with co-activators and co-repressors, VDR regulates the expression of several different genes. Although relatively little work has been carried out on VDR in human cancers, several epidemiological studies suggest that low circulating levels of vitamin D are associated with both an increased risk of developing specific cancer types and poor outcome in patients with specific diagnosed cancers. These associations apply especially in colorectal and breast cancer. Consistent with these findings, calcitriol as well as several of its synthetic analogues have been shown to inhibit tumor cell growth in vitro and in diverse animal model systems. Indeed, some of these vitamin D analogues with low calcemic inducing activity (e.g., EB1089, inecalcitol, paricalcitol) have progressed to clinical trials in patients with cancer. Preliminary results from these trials suggest that these vitamin D analogues have minimal toxicity, but clear evidence of efficacy remains to be shown. Although evidence of efficacy for mono-treatment with vitamin D analogues is currently lacking, several studies have reported that supplementation with calcitriol or the presence of high endogenous circulating levels of vitamin D enhances response to standard therapies.

  11. Synthesis of chlorins, bacteriochlorins and their tetraaza analogues

    NASA Astrophysics Data System (ADS)

    Dudkin, S. V.; Makarova, E. A.; Lukyanets, E. A.

    2016-07-01

    The currently known methods for the synthesis of hydrogenated derivatives of synthetic porphyrins — chlorins, bacteriochlorins, isobacteriochlorins and their tetraaza analogues — are considered. Reactions involving quasi-isolated double bonds including reduction, oxidative addition and cycloaddition are presented. Examples of direct synthesis of these macroheterocycles are given. The bibliography includes 168 references.

  12. Non-robust numerical simulations of analogue extension experiments

    NASA Astrophysics Data System (ADS)

    Naliboff, John; Buiter, Susanne

    2016-04-01

    Numerical and analogue models of lithospheric deformation provide significant insight into the tectonic processes that lead to specific structural and geophysical observations. As these two types of models contain distinct assumptions and tradeoffs, investigations drawing conclusions from both can reveal robust links between first-order processes and observations. Recent studies have focused on detailed comparisons between numerical and analogue experiments in both compressional and extensional tectonics, sometimes involving multiple lithospheric deformation codes and analogue setups. While such comparisons often show good agreement on first-order deformation styles, results frequently diverge on second-order structures, such as shear zone dip angles or spacing, and in certain cases even on first-order structures. Here, we present finite-element experiments that are designed to directly reproduce analogue "sandbox" extension experiments at the cm-scale. We use material properties and boundary conditions that are directly taken from analogue experiments and use a Drucker-Prager failure model to simulate shear zone formation in sand. We find that our numerical experiments are highly sensitive to numerous numerical parameters. For example, changes to the numerical resolution, velocity convergence parameters and elemental viscosity averaging commonly produce significant changes in first- and second-order structures accommodating deformation. The sensitivity of the numerical simulations to small parameter changes likely reflects a number of factors, including, but not limited to, high angles of internal friction assigned to sand, complex, unknown interactions between the brittle sand (used as an upper crust equivalent) and viscous silicone (lower crust), highly non-linear strain weakening processes and poor constraints on the cohesion of sand. Our numerical-analogue comparison is hampered by (a) an incomplete knowledge of the fine details of sand failure and sand

  13. Flow of a blood analogue fluid in a compliant abdominal aortic aneurysm model: experimental modelling.

    PubMed

    Deplano, Valérie; Knapp, Yannick; Bailly, Lucie; Bertrand, Eric

    2014-04-11

    The aim of this work is to develop a unique in vitro set-up in order to analyse the influence of the shear thinning fluid-properties on the flow dynamics within the bulge of an abdominal aortic aneurysm (AAA). From an experimental point of view, the goals are to elaborate an analogue shear thinning fluid mimicking the macroscopic blood behaviour, to characterise its rheology at low shear rates and to propose an experimental device able to manage such an analogue fluid without altering its feature while reproducing physiological flow rate and pressure, through compliant AAA. Once these experimental prerequisites achieved, the results obtained in the present work show that the flow dynamics is highly dependent on the fluid rheology. The main results point out that the propagation of the vortex ring, generated in the AAA bulge, is slower for shear thinning fluids inducing a smaller travelled distance by the vortex ring so that it never impacts the anterior wall in the distal region, in opposition to Newtonian fluids. Moreover, scalar shear rate values are globally lower for shear thinning fluids inducing higher maximum stress values than those for the Newtonian fluids. Consequently, this work highlights that a Newtonian fluid model is finally inadequate to obtain a reliable prediction of the flow dynamics within AAA.

  14. Topographic modelling of caldera analogues using Structure from Motion - Multiview stereo-photogrammetry

    NASA Astrophysics Data System (ADS)

    Ulusoy, İnan; Aydın, Eda; Evren Çubukçu, H.

    2016-04-01

    Analogue caldera models have long been used in volcanology to investigate structural evolution of volcanoes during tumescence and collapse periods. Influence of tectonic forces on volcanic features are also in the scope of those experiments. As well as interior modelling of the caldera experiments, topographic modelling is essential for digital monitoring and quantification purposes. Topographic modelling of those sandbox models is possible using laser scanning techniques. Particle tracking using still images is another way to demonstrate and quantify the structure and movement during the experiment. The quantum leap in the digital photography and computation tools and ease of access to both, provides the use of a new modelling technique in various scales and applications in Geology. Although the roots are older, Structure from Motion - Multiview stereo-photogrammetry (SfM-MVS) is a relatively new technique for surface modelling via several high resolution photographs. We have used SfM-MVS to digitally model the elevation of the tumescence and collapse cycles in analogue caldera experiments. Several sandbox experiments have been modelled using SfM-MVS technique stage by stage during tumescence and collapse periods. It has been possible to evaluate the structural evolution of the collapse models. Additionally, using particle tracking via still images acquired during the experiments, we have modelled the superficial evolution of the caldera structure. SfM-MVS is an effective low budget method for modelling in decimetric scale down to millimetre/micrometre precision.

  15. Analogue Sites for Mars Missions - A report from two workshops

    NASA Astrophysics Data System (ADS)

    Hipkin, V.; Voytek, M. A.; Glamoclija, M.

    2014-12-01

    Fieldwork, at terrestrial sites that are analogous in some way to Mars, has a key role in defining questions addressed by Mars missions. For MSL, the question is whether its landing site was habitable, and for Mars 2020, the question is how do we search for and what are signs of life in ancient habitable environments. Implementing these investigations by means of a rover mission on a distant planetary surface has challenges due to a limited set of tools and period of operations. Using this context of planetary missions is important in shaping how analog research can be used to advance planetary science. Following a successful 2010 AGU fall meeting session entitled "Analogue Sites for Mars Missions", two community workshops were held at The Woodlands, TX March 2011 and the Carnegie Institute of Washington in July 2013. These activities represent an ongoing dialogue with the analogue and mission communities. The AGU session solicited presentations of current analogue research relevant to MSL, at which time the landing site selection process was still considering four final sites. The 2011 Woodlands workshop solicited details on representative science questions and analogue sites by means of an abstract template. The output from The Woodlands workshop was an initial metric to assess the utility of analogue sites against specific science questions, as well as recommendations for future activities. The 2013 Carnegie workshop, followed up on some of the recommendations from 2011. Both on-line interactive dialogue and in person discussions targeted broad topics, including 'the advantages and problems of using a great terrestrial analog for field testing', and 'knowing what we currently do about Mars, what would be the best place on the planet to collect the first suite of samples to be returned to Earth? What would be appropriate analog sites on Earth?'. The results and recommendations from both workshops are summarized to publicize and stimulate this ongoing discussion.

  16. Biological evaluation of a novel sorafenib analogue, t-CUPM.

    PubMed

    Wecksler, Aaron T; Hwang, Sung Hee; Liu, Jun-Yan; Wettersten, Hiromi I; Morisseau, Christophe; Wu, Jian; Weiss, Robert H; Hammock, Bruce D

    2015-01-01

    Sorafenib (Nexavar®) is currently the only FDA-approved small molecule targeted therapy for advanced hepatocellular carcinoma. The use of structural analogues and derivatives of sorafenib has enabled the elucidation of critical targets and mechanism(s) of cell death for human cancer lines. We previously performed a structure-activity relationship study on a series of sorafenib analogues designed to investigate the inhibition overlap between the major targets of sorafenib Raf-1 kinase and VEGFR-2, and an enzyme shown to be a potent off-target of sorafenib, soluble epoxide hydrolase. In the current work, we present the biological data on our lead sorafenib analogue, t-CUPM, demonstrating that this analogue retains cytotoxicity similar to sorafenib in various human cancer cell lines and strongly inhibits growth in the NCI-60 cell line panel. Co-treatment with the pan-caspase inhibitor, Z-VAD-FMK, failed to rescue the cell viability responses of both sorafenib and t-CUPM, and immunofluorescence microscopy shows similar mitochondrial depolarization and apoptosis-inducing factor release for both compounds. These data suggest that both compounds induce a similar mechanism of caspase-independent apoptosis in hepatoma cells. In addition, t-CUPM displays anti-proliferative effects comparable to sorafenib as seen by a halt in G0/G1 in cell cycle progression. The structural difference between sorafenib and t-CUPM significantly reduces inhibitory spectrum of kinases by this analogue, and pharmacokinetic characterization demonstrates a 20-fold better oral bioavailability of t-CUPM than sorafenib in mice. Thus, t-CUPM may have the potential to reduce the adverse events observed from the multikinase inhibitory properties and the large dosing regimens of sorafenib.

  17. Neurochemical binding profiles of novel indole and benzofuran MDMA analogues.

    PubMed

    Shimshoni, Jakob A; Winkler, Ilan; Golan, Ezekiel; Nutt, David

    2017-01-01

    3,4-Methylenedioxy-N-methylamphetamine (MDMA) has been shown to be effective in the treatment of post-traumatic stress disorder (PTSD) in numerous clinical trials. In the present study, we have characterized the neurochemical binding profiles of three MDMA-benzofuran analogues (1-(benzofuran-5-yl)-propan-2-amine, 5-APB; 1-(benzofuran-6-yl)-N-methylpropan-2-amine, 6-MAPB; 1-(benzofuran-5-yl)-N-methylpropan-2-amine, 5-MAPB) and one MDMA-indole analogue (1-(1H-indol-5-yl)-2-methylamino-propan-1-ol, 5-IT). These compounds were screened as potential second-generation anti-PTSD drugs, against a battery of human and non-human receptors, transporters, and enzymes, and their potencies as 5-HT2 receptor agonist and monoamine uptake inhibitors determined. All MDMA analogues displayed high binding affinities for 5-HT2a,b,c and NEα2 receptors, as well as significant 5-HT, DA, and NE uptake inhibition. 5-APB revealed significant agonist activity at the 5-HT2a,b,c receptors, while 6-MAPB, 5-MAPB, and 5-IT exhibited significant agonist activity at the 5-HT2c receptor. There was a lack of correlation between the results of functional uptake and the monoamine transporter binding assay. MDMA analogues emerged as potent and selective monoamine oxidase A inhibitors. Based on 6-MAPB favorable pharmacological profile, it was further subjected to IC50 determination for monoamine transporters. Overall, all MDMA analogues displayed higher monoamine receptor/transporter binding affinities and agonist activity at the 5-HT2a,c receptors as compared to MDMA.

  18. Cysteine analogues potentiate glucose-induced insulin release in vitro

    SciTech Connect

    Ammon, H.P.; Hehl, K.H.; Enz, G.; Setiadi-Ranti, A.; Verspohl, E.J.

    1986-12-01

    In rat pancreatic islets, cysteine analogues, including glutathione, acetylcysteine, cysteamine, D-penicillamine, L-cysteine ethyl ester, and cysteine-potentiated glucose (11.1 mM) induced insulin secretion in a concentration-dependent manner. Their maximal effects were similar and occurred at approximately 0.05, 0.05, 0.1, 0.5, 1.0, 1.0 mM, respectively. At substimulatory glucose levels (2.8 mM), insulin release was not affected by these compounds. In contrast, thiol compounds, structurally different from cysteine and its analogues, such as mesna, tiopronin, meso-2,3-dimercaptosuccinic acid (DMSA), dimercaprol (BAL), beta-thio-D-glucose, as well as those cysteine analogues that lack a free-thiol group, including L-cystine, cystamine, D-penicillamine disulfide, S-carbocysteine, and S-carbamoyl-L-cysteine, did not enhance insulin release at stimulatory glucose levels (11.1 mM); cystine (5 mM) was inhibitory. These in vitro data indicate that among the thiols tested here, only cysteine and its analogues potentiate glucose-induced insulin secretion, whereas thiols that are structurally not related to cysteine do not. This suggests that a cysteine moiety in the molecule is necessary for the insulinotropic effect. For their synergistic action to glucose, the availability of a sulfhydryl group is also a prerequisite. The maximal synergistic action is similar for all cysteine analogues tested, whereas the potency of action is different, suggesting similarity in the mechanism of action but differences in the affinity to the secretory system.

  19. Muraymycins, novel peptidoglycan biosynthesis inhibitors: synthesis and SAR of their analogues.

    PubMed

    Yamashita, Ayako; Norton, Emily; Petersen, Peter J; Rasmussen, Beth A; Singh, Guy; Yang, Youjin; Mansour, Tarek S; Ho, Douglas M

    2003-10-06

    A series of Muraymycin analogues was synthesized. These analogues showed excellent antimicrobial activity against gram-positive organisms. These analogues also showed excellent inhibitory activity against the target peptidoglycan biosynthesis enzyme MraY, the cell membrane associated transglycosylase responsible for the formation of Lipid II.

  20. Design, Synthesis, and Evaluation of Novel Ferroquine and Phenylequine Analogues as Potential Antiplasmodial Agents.

    PubMed

    Jacobs, Leon; de Kock, Carmen; de Villiers, Katherine A; Smith, Peter J; Smith, Vincent J; van Otterlo, Willem A L; Blackie, Margaret A L

    2015-12-01

    7-Chloroquinoline-based antimalarial drugs are effective in the inhibition of hemozoin formation in the food vacuole of the Plasmodium parasite, the causative agent of malaria. We synthesized five series of ferroquine (FQ) and phenylequine (PQ) derivatives, which display good in vitro efficacy toward both the chloroquine-sensitive (CQS) NF54 (IC50 : 4.2 nm) and chloroquine-resistant (CQR) Dd2 (IC50 : 33.7 nm) strains of P. falciparum. Several compounds were found to have good inhibitory activity against β-hematin formation in an NP-40 detergent assay, with IC50 values ranging between 10.4 and 19.2 μm.

  1. Anthrax Toxin Protective Antigen: Inhibition of Channel Function by Chloroquine and Related Compounds and Study of Binding Kinetics Using the Current Noise Analysis

    PubMed Central

    Orlik, Frank; Schiffler, Bettina; Benz, Roland

    2005-01-01

    Protective antigen (PA) of the tripartite anthrax toxin binds to a cell surface receptor and mediates the transport of two enzymatic components, edema factor and lethal factor, into the cytosol of host cells. Here recombinant PA63 from Bacillus anthracis was reconstituted into artificial lipid bilayer membranes and formed ion permeable channels. The heptameric PA63-channel contains a binding site for 4-aminoquinolones, which block ion transport through PA in vitro. This result allowed a detailed investigation of ligand binding and the stability constants for the binding of chloroquine, fluphenazine, and quinacrine to the binding site inside the PA63-channel were determined using titration experiments. Open PA63-channels exhibit 1/f noise in the frequency range between 1 and 100 Hz, whereas the spectral density of the ligand-induced current noise was of Lorentzian type. The analysis of the power density spectra allowed the evaluation of the on- and off-rate constants (\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\setlength{\\oddsidemargin}{-69pt} \\begin{document} \\begin{equation*}k_{1}\\end{equation*}\\end{document} and \\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\setlength{\\oddsidemargin}{-69pt} \\begin{document} \\begin{equation*}k_{-1}\\end{equation*}\\end{document}) of ligand binding. The on-rate constants of ligand binding were between 106 and 108 M−1 s−1 and were dependent on the ionic strength of the aqueous phase, sidedness of ligand addition, as well as the orientation and intensity of the applied electric field. The off-rates varied between ∼10 s−1 and 2600 s−1 and depended mainly on the structure of the ligand. PMID:15596516

  2. Iterative Approach to the Discovery of Novel Degarelix Analogues: Substitutions at Positions 3, 7 and 8. Part II

    PubMed Central

    Samant, Manoj P.; Gulyas, Jozsef; Hong, Doley J.; Croston, Glenn; Rivier, Catherine; Rivier, Jean

    2008-01-01

    Degarelix, (FE200486, Ac-d-2Nal1-d-4Cpa2-d-3Pal3-Ser4-4Aph(l-Hor)5-d-4Aph(Cbm)6-Leu7-Ilys8-Pro9-d-Ala10-NH2) is a potent and very long acting antagonist of gonadotropin-releasing hormone (GnRH) after subcutaneous administration in mammals including humans. Analogues of degarelix were synthesized, characterized and screened for the antagonism of GnRH-induced response in a reporter gene assay in HEK-293 cells expressing the human GnRH receptor. The duration of action was also determined in the castrated male rat assay in order to measure the extent (efficacy and duration of action) of inhibition of luteinizing hormone (LH) release. Structurally, this series of analogues has novel substitutions at positions 3, 7, 8 and Nα-methylation at positions 6, 7 and 8 in the structure of degarelix. These substitutions were designed to probe the spatial limitations of the receptors cavity and to map the steric and ionic boundaries. Some functional groups were introduced that were hypothesized to influence the phamacokinetic properties of the analogues like bioavailability, solubility, intra- or inter-molecular hydrogen bond forming capacity and ability to bind carrier proteins. Substitutions at positions 3 ([Nβ-(2-pyridyl-methyl)d-Dap3]degarelix, IC50 = 2.71 nM) (5), 7 ([Pra7]degarelix, IC50 = 2.11 nM) (16), 8 ([Nδ-(IGly)Orn8]degarelix, IC50 = 1.38 nM) (20), and N-methylation ([Nα-methyl-Leu7]degarelix, IC50 = 1.47 nM) (32) yielded analogues that were equipotent to degarelix (2) in vitro (IC50 = 1.64 nM) but shorter acting in vivo. Out of the 33 novel analogues tested for the duration of action in this series, two analogues ([Nε-cyclohexyl-Lys8]degarelix, IC50 = 1.50 nM) (23) and ([Nβ-(IβAla)Dap8]degarelix, IC50 = 1.98 nM) (26) had antagonist potencies and duration of action similar to that of azaline B {inhibited LH (>80%) release for >72 h after sc injection to castrated male rats at a standard dose of 50 µg/rat in 5% mannitol}. Under similar conditions analogues ([N

  3. Mars Analogue Field Research and Sample Analysis

    NASA Astrophysics Data System (ADS)

    Foing, Bernard H.

    2016-07-01

    We describe results from the data analysis from a series of field research campaigns (ILEWG EuroMoonMars campaigns 2009 to 2016) in the Utah desert and in other extreme environments (Iceland, Eifel, La Reunion) relevant to habitability and astrobiology in Mars environments, and in order to help in the interpretation of Mars missions measurements from orbit (MEX, MRO) or from the surface (MER, MSL). We discuss results relevant to the scientific study of the habitability factors influenced by the properties of dust, organics, water history and the diagnostics and characterisation of microbial life. We also discuss perspectives for the preparation of future lander and sample return missions. We deployed at Mars Desert Research station, Utah, a suite of instruments and techniques including sample collection, context imaging from remote to local and microscale, drilling, spectrometers and life sensors. We analyzed how geological and geochemical evolution affected local parameters (mineralogy, organics content, environment variations) and the habitability and signature of organics and biota. We find high diversity in the composition of soil samples even when collected in close proximity, the low abundances of detectable PAHs and amino acids and the presence of biota of all three domains of life with significant heterogeneity. An extraordinary variety of putative extremophiles was observed. A dominant factor seems to be soil porosity and lower clay-sized particle content. A protocol was developed for sterile sampling, contamination issues, and the diagnostics of biodiversity via PCR and DGGE analysis in soils and rocks samples. We compare campaign results from 2009-2013 campaigns in Utah and other sites to new measurements concerning: the comparison between remote sensing and in-situ measurements; the study of minerals; the detection of organics and signs of life.

  4. Synthesis and antioxidant activity of peptide-based ebselen analogues.

    PubMed

    Satheeshkumar, Kandhan; Mugesh, Govindasamy

    2011-04-18

    A series of di- and tripeptide-based ebselen analogues has been synthesized. The compounds were characterized by (1)H, (13)C, and (77)Se NMR spectroscopy and mass spectral techniques. The glutathione peroxidase (GPx)-like antioxidant activity has been studied by using H(2)O(2) , tert-butyl hydroperoxide (tBuOOH), and cumene hydroperoxide (Cum-OOH) as substrates, and glutathione (GSH) as a cosubstrate. Although all the peptide-based compounds have a selenazole ring similar to that of ebselen, the GPx activity of these compounds highly depends on the nature of the peptide moiety attached to the nitrogen atom of the selenazole ring. It was observed that the introduction of a phenylalanine (Phe) amino acid residue in the N-terminal reduces the activity in all three peroxide systems. On the other hand, the introduction of aliphatic amino acid residues such as valine (Val) significantly enhances the GPx activity of the ebselen analogues. The difference in the catalytic activity of dipeptide-based ebselen derivatives can be ascribed mainly to the change in the reactivity of these compounds toward GSH and peroxide. Although the presence of the Val-Ala-CO(2) Me moiety facilitates the formation of a catalytically active selenol species, the reaction of ebselen analogues that has a Phe-Ile-CO(2) Me residue with GSH does not generate the corresponding selenol. To understand the antioxidant activity of the peptide-based ebselen analogues in the absence of GSH, these compounds were studied for their ability to inhibit peroxynitrite (PN)-mediated nitration of bovine serum albumin (BSA) and oxidation of dihydrorhodamine 123. In contrast to the GPx activity, the PN-scavenging activity of the Phe-based peptide analogues was found to be comparable to that of the Val-based compounds. However, the introduction of an additional Phe residue to the ebselen analogue that had a Val-Ala dipeptide significantly reduced the potency of the parent compound in PN-mediated nitration.

  5. An analogue conceptual rainfall-runoff model for educational purposes

    NASA Astrophysics Data System (ADS)

    Herrnegger, Mathew; Riedl, Michael; Schulz, Karsten

    2016-04-01

    Conceptual rainfall-runoff models, in which runoff processes are modelled with a series of connected linear and non-linear reservoirs, remain widely applied tools in science and practice. Additionally, the concept is appreciated in teaching due to its somewhat simplicity in explaining and exploring hydrological processes of catchments. However, when a series of reservoirs are used, the model system becomes highly parametrized and complex and the traceability of the model results becomes more difficult to explain to an audience not accustomed to numerical modelling. Since normally the simulations are performed with a not visible digital code, the results are also not easily comprehensible. This contribution therefore presents a liquid analogue model, in which a conceptual rainfall-runoff model is reproduced by a physical model. This consists of different acrylic glass containers representing different storage components within a catchment, e.g. soil water or groundwater storage. The containers are equipped and connected with pipes, in which water movement represents different flow processes, e.g. surface runoff, percolation or base flow. Water from a storage container is pumped to the upper part of the model and represents effective rainfall input. The water then flows by gravity through the different pipes and storages. Valves are used for controlling the flows within the analogue model, comparable to the parameterization procedure in numerical models. Additionally, an inexpensive microcontroller-based board and sensors are used to measure storage water levels, with online visualization of the states as time series data, building a bridge between the analogue and digital world. The ability to physically witness the different flows and water levels in the storages makes the analogue model attractive to the audience. Hands-on experiments can be performed with students, in which different scenarios or catchment types can be simulated, not only with the analogue but

  6. Biofunctional constituent isolated from Citrullus colocynthis fruits and structure-activity relationships of its analogues show acaricidal and insecticidal efficacy.

    PubMed

    Jeon, Ju-Hyun; Lee, Hoi-Seon

    2014-08-27

    The acaricidal and insecticidal potential of the active constituent isolated from Citrullus colocynthis fruits and its structurally related analogues was evaluated by performing leaf disk, contact toxicity, and fumigant toxicity bioassays against Tetranychus urticae, Sitophilus oryzae, and Sitophilus zeamais adults. The active constituent of C. colocynthis fruits was isolated by chromatographic techniques and was identified as 4-methylquinoline on the basis of spectroscopic analyses. To investigate the structure-activity relationships, 4-methylquinoline and its structural analogues were tested against mites and two insect pests. On the basis of the LC50 values, 7,8-benzoquinoline was the most effective against T. urticae. Quinoline, 8-hydroxyquinoline, 2-methylquinoline, 4-methylquinoline, 6-methylquinoline, 8-methylquinoline, and 7,8-benzoquinoline showed high insecticidal activities against S. oryzae and S. zeamais regardless of the application method. These results indicate that introduction of a functional group into the quinoline skeleton and changing the position of the group have an important influence on the acaricidal and insecticidal activities. Furthermore, 4-methylquinoline isolated from C. colocynthis fruits, along with its structural analogues, could be effective natural pesticides for managing spider mites and stored grain weevils.

  7. Efficacy of chloroquine, amodiaquine and sulphadoxine-pyrimethamine for the treatment of uncomplicated falciparum malaria: revisiting molecular markers in an area of emerging AQ and SP resistance in Mali

    PubMed Central

    Tekete, Mamadou; Djimde, Abdoulaye A; Beavogui, Abdoul H; Maiga, Hamma; Sagara, Issaka; Fofana, Bakary; Ouologuem, Dinkorma; Dama, Souleymane; Kone, Aminatou; Dembele, Demba; Wele, Mamadou; Dicko, Alassane; Doumbo, Ogobara K

    2009-01-01

    Background To update the National Malaria Control Programme of Mali on the efficacy of chloroquine, amodiaquine and sulphadoxine-pyrimethamine in the treatment of uncomplicated falciparum malaria. Methods During the malaria transmission seasons of 2002 and 2003, 455 children – between six and 59 months of age, with uncomplicated malaria in Kolle, Mali, were randomly assigned to one of three treatment arms. In vivo outcomes were assessed using WHO standard protocols. Genotyping of msp1, msp2 and CA1 polymorphisms were used to distinguish reinfection from recrudescent parasites (molecular correction). Results Day 28 adequate clinical and parasitological responses (ACPR) were 14.1%, 62.3% and 88.9% in 2002 and 18.2%, 60% and 85.2% in 2003 for chloroquine, amodiaquine and sulphadoxine-pyrimethamine, respectively. After molecular correction, ACPRs (cACPR) were 63.2%, 88.5% and 98.0% in 2002 and 75.5%, 85.2% and 96.6% in 2003 for CQ, AQ and SP, respectively. Amodiaquine was the most effective on fever. Amodiaquine therapy selected molecular markers for chloroquine resistance, while in the sulphadoxine-pyrimethamine arm the level of dhfr triple mutant and dhfr/dhps quadruple mutant increased from 31.5% and 3.8% in 2002 to 42.9% and 8.9% in 2003, respectively. No infection with dhps 540E was found. Conclusion In this study, treatment with sulphadoxine-pyrimethamine emerged as the most efficacious on uncomplicated falciparum malaria followed by amodiaquine. The study demonstrated that sulphadoxine-pyrimethamine and amodiaquine were appropriate partner drugs that could be associated with artemisinin derivatives in an artemisinin-based combination therapy. PMID:19245687

  8. The impact of social support: an analogue investigation of the aftermath of trauma exposure.

    PubMed

    Pruitt, Larry D; Zoellner, Lori A

    2008-01-01

    Recent meta-analytic studies suggest that social support plays an important role in regulating the severity of post-traumatic adjustment; however, few studies have manipulated potential underlying mechanisms. This analogue study examined how various social reactions, following trauma exposure, influenced subsequent anxiety, affect, and intrusive thoughts. Ninety-three participants viewed a distressing videotape followed by a portrayal of positive, negative, or neutral social reactions. While negative reactions increased initial negative affect, neutral reactions increased later frequency and severity of intrusive thoughts. Based on this, it was suggested that "neutral" social reactions following trauma exposure may have the potential for being highly invalidating and in some circumstances may actually have more negative later effects than overtly negative ones.

  9. Photoelectron spectra and electronic structure of nitrogen analogues of boron β-diketonates

    NASA Astrophysics Data System (ADS)

    Tikhonov, Sergey A.; Vovna, Vitaliy I.; Borisenko, Aleksandr V.

    2016-07-01

    The electronic structure of the valence levels of seven nitrogen-containing boron complexes was investigated using methods of ultraviolet photoelectron spectroscopy and density functional theory. The ionization energies of π- and σ-levels were obtained from photoelectron spectra. The electronic structure of nitrogen-containing compounds was compared with the electronic structure of β-diketonates. It was shown the influence of various substituents on carbon and nitrogen atoms of six-membered ring on the electronic structure of complexes. The changes in the electronic structure after the substitution of atoms in condensed cycles have been identified. In order to compare the experimental vertical ionization energies IEi with Kohn-Sham orbital energies εi we used the analogue of Koopmans theorem and average amendment to the orbital energy of the electrons (δbari). For 26 electronic levels of seven studied complexes, the calculated values are in good accordance with experimental energy intervals between electron levels.

  10. Conformational equilibrium of phenylacetic acid and its halogenated analogues through theoretical studies, NMR and IR spectroscopy

    NASA Astrophysics Data System (ADS)

    Levandowski, Mariana N.; Rozada, Thiago C.; Melo, Ulisses Z.; Basso, Ernani A.; Fiorin, Barbara C.

    2017-03-01

    This paper presents a study on the conformational preferences of phenylacetic acid (PA) and its halogenated analogues (FPA, CPA, BPA). To clarify the effects that rule these molecules' behaviour, theoretical calculations were used, for both the isolated phase and solution, combined with nuclear magnetic resonance (NMR) and infrared (IR) spectroscopy. Most conformations of phenylacetic acid and its halogenated derivatives are stabilized through the hyperconjugative effect, which rules the conformational preference. NMR analyses showed that even with the variation in medium polarity, there was no significant change in the conformation population. Infrared spectroscopy showed similar results for all compounds under study. In most spectra, two bands were found through the carbonyl deconvolution, which is in accordance with the theoretical data. It was possible to prove that variation in the nature of the substituent in the ortho position had no significant influence on the conformational equilibrium.

  11. A boron-boron coupling reaction between two ethyl cation analogues.

    PubMed

    Litters, Sebastian; Kaifer, Elisabeth; Enders, Markus; Himmel, Hans-Jörg

    2013-12-01

    The design of larger architectures from smaller molecular building blocks by element-element coupling reactions is one of the key concerns of synthetic chemistry, so a number of strategies were developed for this bottom-up approach. A general scheme is the coupling of two elements with opposing polarity or that of two radicals. Here, we show that a B-B coupling reaction is possible between two boron analogues of the ethyl cation, resulting in the formation of an unprecedented dicationic tetraborane. The bonding properties in the rhomboid B₄ core of the product can be described as two B-B units connected by three-centre, two-electron bonds, sharing the short diagonal. Our discovery might lead the way to the long sought-after boron chain polymers with a structure similar to the silicon chains in β-SiB₃. Moreover, the reaction is a prime textbook example of the influence of multiple-centre bonding on reactivity.

  12. The synthesis of compatible solute analogues-solvent effects on selective glycosylation.

    PubMed

    Lourenço, Eva C; Ventura, M Rita

    2011-02-01

    Ethyl 6-O-acetyl-2,3,4-tribenzyl-1-d-thioglucoside and ethyl 6-O-acetyl-2,3,4-tribenzyl-1-d-thiogalactoside, as a mixture of anomers, were employed in the study of the influence of solvent in the stereoselectivity of the glycosylation reaction with small and reactive acceptors. High α-selectivities were obtained in the glycosylation reactions using NIS/TfOH as activator and ethyl ether as the solvent at -60°C. Other solvent mixtures such as dichloromethane, THF, THF/ethyl ether and toluene/dioxane were not nearly as selective. The corresponding thiogalactoside underwent similar glycosylations with the same solvents but with low anomer selectivity. These glycosides are key intermediates for the synthesis of new analogues of compatible solutes.

  13. Synthetic silvestrol analogues as potent and selective protein synthesis inhibitors.

    PubMed

    Liu, Tao; Nair, Somarajan J; Lescarbeau, André; Belani, Jitendra; Peluso, Stéphane; Conley, James; Tillotson, Bonnie; O'Hearn, Patrick; Smith, Sherri; Slocum, Kelly; West, Kip; Helble, Joseph; Douglas, Mark; Bahadoor, Adilah; Ali, Janid; McGovern, Karen; Fritz, Christian; Palombella, Vito J; Wylie, Andrew; Castro, Alfredo C; Tremblay, Martin R

    2012-10-25

    Misregulation of protein translation plays a critical role in human cancer pathogenesis at many levels. Silvestrol, a cyclopenta[b]benzofuran natural product, blocks translation at the initiation step by interfering with assembly of the eIF4F translation complex. Silvestrol has a complex chemical structure whose functional group requirements have not been systematically investigated. Moreover, silvestrol has limited development potential due to poor druglike properties. Herein, we sought to develop a practical synthesis of key intermediates of silvestrol and explore structure-activity relationships around the C6 position. The ability of silvestrol and analogues to selectively inhibit the translation of proteins with high requirement on the translation-initiation machinery (i.e., complex 5'-untranslated region UTR) relative to simple 5'UTR was determined by a cellular reporter assay. Simplified analogues of silvestrol such as compounds 74 and 76 were shown to have similar cytotoxic potency and better ADME characteristics relative to those of silvestrol.

  14. Noncommutative analogue Aharonov-Bohm effect and superresonance

    NASA Astrophysics Data System (ADS)

    Anacleto, M. A.; Brito, F. A.; Passos, E.

    2013-06-01

    We consider the idea of modeling a rotating acoustic black hole by an idealized draining bathtub vortex which is a planar circulating flow phenomenon with a sink at the origin. We find the acoustic metric for this phenomenon from a noncommutative Abelian Higgs model. As such the acoustic metric not only describes a rotating acoustic black hole but also inherits the noncommutative characteristic of the spacetime. We address the issues of superresonance and analogue Aharonov-Bohm (AB) effect in this background. We mainly show that the scattering of planar waves by a draining bathtub vortex leads to a modified AB effect and due to spacetime noncommutativity, the phase shift persists even in the limit where the parameters associated with the circulation and draining vanish. Finally, we also find that the analogue AB effect and superresonance are competing phenomena at a noncommutative spacetime.

  15. Neutral Diboron Analogues of Archetypal Aromatic Species by Spontaneous Cycloaddition.

    PubMed

    Arrowsmith, Merle; Böhnke, Julian; Braunschweig, Holger; Celik, Mehmet Ali; Claes, Christina; Ewing, William C; Krummenacher, Ivo; Lubitz, Katharina; Schneider, Christoph

    2016-09-05

    Among the numerous routes organic chemists have developed to synthesize benzene derivatives and heteroaromatic compounds, transition-metal-catalyzed cycloaddition reactions are the most elegant. In contrast, cycloaddition reactions of heavier alkene and alkyne analogues, though limited in scope, proceed uncatalyzed. In this work we present the first spontaneous cycloaddition reactions of lighter alkene and alkyne analogues. Selective addition of unactivated alkynes to boron-boron multiple bonds under ambient conditions yielded diborocarbon equivalents of simple aromatic hydrocarbons, including the first neutral 6 π-aromatic diborabenzene compound, a 2 π-aromatic triplet biradical 1,3-diborete, and a phosphine-stabilized 2 π-homoaromatic 1,3-dihydro-1,3-diborete. DFT calculations suggest that all three compounds are aromatic and show frontier molecular orbitals matching those of the related aromatic hydrocarbons, C6 H6 and C4 H4 (2+) , and homoaromatic C4 H5 (+) .

  16. Highly potent metallopeptide analogues of luteinizing hormone-releasing hormone

    SciTech Connect

    Bajusz, S.; Janaky, T.; Csernus, V.J.; Bokser, L.; Fekete, M.; Srkalovic, G.; Redding, T.W.; Schally, A.V. )

    1989-08-01

    Metal complexes related to the cytotoxic complexes cisplatin (cis-diamminedichloroplatinum(II)) and transbis(salicylaldoximato)copper(II) were incorporated into suitably modified luteinizing hormone-releasing hormone (LH-RH) analogues containing D-lysine at position 6. Some of the metallopeptides thus obtained proved to be highly active LH-RH agonists or antagonists. Most metallopeptide analogues of LH-RH showed high affinities for the membrane receptors of rat pituitary and human breast cancer cells. Some of these metallopeptides had cytotoxic activity against human breast cancer and prostate cancer and prostate cancer cell lines in vitro. Such cytostatic metallopeptides could be envisioned as targeted chemotherapeutic agents in cancers that contain receptors for LH-RH-like peptides.

  17. All-dielectric metasurface analogue of electromagnetically induced transparency.

    PubMed

    Yang, Yuanmu; Kravchenko, Ivan I; Briggs, Dayrl P; Valentine, Jason

    2014-12-16

    Metasurface analogues of electromagnetically induced transparency (EIT) have been a focus of the nanophotonics field in recent years, due to their ability to produce high-quality factor (Q-factor) resonances. Such resonances are expected to be useful for applications such as low-loss slow-light devices and highly sensitive optical sensors. However, ohmic losses limit the achievable Q-factors in conventional plasmonic EIT metasurfaces to values <~10, significantly hampering device performance. Here we experimentally demonstrate a classical analogue of EIT using all-dielectric silicon-based metasurfaces. Due to extremely low absorption loss and coherent interaction of neighbouring meta-atoms, a Q-factor of 483 is observed, leading to a refractive index sensor with a figure-of-merit of 103. Furthermore, we show that the dielectric metasurfaces can be engineered to confine the optical field in either the silicon resonator or the environment, allowing one to tailor light-matter interaction at the nanoscale.

  18. New homoisoflavonoid analogues protect cells by regulating autophagy.

    PubMed

    Gan, Li-She; Zeng, Lin-Wei; Li, Xiang-Rong; Zhou, Chang-Xin; Li, Jie

    2017-03-15

    As a special group of naturally occurring flavonoids, homoisoflavonoids have been discovered as active components of several traditional Chinese medicines for nourishing heart and mind. In this study, twenty homoisoflavonoid analogues, including different substitution groups on rings A and B, as well as heteroaromatic B ring, were synthesized and evaluated for their cardioprotective and neuroprotective activities. In a H2O2-induced H9c2 cardiomyocytes injury assay, nine homoisoflavonoid analogues showed promising activities in the same level as the positive control, diazoxide. Six cardioprotective compounds with representative structure diversities were then evaluated for their neuroprotective effects on MPP+ induced SH-SY5Y cell injury model. Furthermore, autophagy inducing monodansylcadaverine (MDC) fluorescence staining methods and molecular docking studies indicated the action mechanism of these compounds may involve autophagy regulating via class I PI3K signaling pathway.

  19. New selenium-75 labeled radiopharmaceuticals: selenonium analogues of dopamine

    SciTech Connect

    Sadek, S.A.; Basmadjian, G.P.; Hsu, P.M.; Rieger, J.A.

    1983-07-01

    Selenium-75 labeled selenonium analogues of dopamine, (2-(3,4-dimethoxyphenyl)ethyl)dimethylselenonium iodide and its dihydroxy analogue, were prepared by reducing (/sup 75/Se)selenious acid with sodium borohydride at pH 6.0 and reacting the NaSeH produced with 1-(3,4-dimethoxyphenyl)-2-(p-toluenesulfonyloxy)ethane. Tissue distribution studies in rats given the /sup 75/Se-labeled selenonium agents intravenously demonstrated high initial heart uptake. Prolonged adrenal retention and high adrenal to blood ratio of compound 4 were observed. The high uptake and adrenal to blood ratio suggest the potential use of compound 4 as a radiopharmaceutical for the adrenal gland.

  20. Geoscience in Support of a Mars Methane Analogue Mission

    NASA Astrophysics Data System (ADS)

    Boivin, Alexandre

    The Mars Methane Analogue Mission, funded by the Canadian Space Agency through its Analogue Missions program, simulates a Mars rover mission whose purpose is to detect, analyse, and determine the source of methane emissions on the planet's surface. As part of this project, both an electromagnetic induction sounder (EMIS) and a high-resolution triangulation-based 3D laser scanner were tested in the field to demonstrate the benefit of including these instruments on future rover missions. EMIS data was inverted in order to derive information on the conductivity and magnetic susceptibility of the near subsurface. 3D laser scanner data was processed with fracture detection as a goal in order to simplify the search for areas of potential methane seepage. Both instruments were found to be very valuable for future rover missions of this type.

  1. A rationally designed CD4 analogue inhibits experimental allergic encephalomyelitis

    NASA Astrophysics Data System (ADS)

    Jameson, Bradford A.; McDonnell, James M.; Marini, Joseph C.; Korngold, Robert

    1994-04-01

    EXPERIMENTAL allergic encephalomyelitis (EAE) is an acute inflammatory autoimmune disease of the central nervous system that can be elicited in rodents and is the major animal model for the study of multiple sclerosis (MS)1,2. The pathogenesis of both EAE and MS directly involves the CD4+ helper T-cell subset3-5. Anti-CD4 monoclonal antibodies inhibit the development of EAE in rodents6-9, and are currently being used in human clinical trials for MS. We report here that similar therapeutic effects can be achieved in mice using a small (rationally designed) synthetic analogue of the CD4 protein surface. It greatly inhibits both clinical incidence and severity of EAE with a single injection, but does so without depletion of the CD4+ subset and without the inherent immunogenicity of an antibody. Furthermore, this analogue is capable of exerting its effects on disease even after the onset of symptoms.

  2. Optical analogue of relativistic Dirac solitons in binary waveguide arrays

    SciTech Connect

    Tran, Truong X.; Longhi, Stefano; Biancalana, Fabio

    2014-01-15

    We study analytically and numerically an optical analogue of Dirac solitons in binary waveguide arrays in the presence of Kerr nonlinearity. Pseudo-relativistic soliton solutions of the coupled-mode equations describing dynamics in the array are analytically derived. We demonstrate that with the found soliton solutions, the coupled mode equations can be converted into the nonlinear relativistic 1D Dirac equation. This paves the way for using binary waveguide arrays as a classical simulator of quantum nonlinear effects arising from the Dirac equation, something that is thought to be impossible to achieve in conventional (i.e. linear) quantum field theory. -- Highlights: •An optical analogue of Dirac solitons in nonlinear binary waveguide arrays is suggested. •Analytical solutions to pseudo-relativistic solitons are presented. •A correspondence of optical coupled-mode equations with the nonlinear relativistic Dirac equation is established.

  3. Isobaric Analogue States Studied in Mirrored Fragmentation and Knockout Reactions

    SciTech Connect

    Bentley, M.A.; Pritychenko, B.; Paterson,I.; Brown,J.R.; Taylor,M.J.; Digen,C.Aa.; Adrich,P.; Bazin,D.; Cook.J.M.; Gade,A.; Glasmacher,T.; McDaniel,S.; Ratkiewicz,A.; Siwek,K.; D.Weisshaar,D.; Pritychenko,B.; Lenzi,S.M.

    2010-05-21

    A Gamma-ray spectroscopic study of excited states of isobaric multiplets has been performed in recent years, with a view to gaining a quantitative understanding of energy differences between excited states in terms of a range of Coulomb and other isospin breaking phenomena. Recently, the experimental programme has been augmented by a study of isobaric analogue states of mirror nuclei populated in mirrored fragmentation reactions. In this presentation, recent results on the T = 3/2 analogue states in the T{sub z} = {+-} 3/2 mirror pair {sup 53}Ni/{sup 53}Mn will be summarised. In this work, further strong evidence is found for the need to include an anomalous isospin-breaking two-body matrix element for angular-momentum couplings of J = 2, in addition the expected Coulomb contribution, in order to account for the experimental data.

  4. Animal analogues for the study of dental and oral diseases.

    PubMed

    Levy, B M

    1980-01-01

    The usual laboratory animals, such as rats and hamsters, may not fit the criteria for an analogue of human periodontal disease, although they may be useful in the study of dental caries. Rats, hamsters, mice, guinea pigs and rabbits have been the animals of choice in studies relating nutritional deficiencies and excesses to the dental and oral tissues. Gerbils, dogs, cats, horses, cows and fowl are useful in the study of mineralized tissues of teeth and bones. Recently, primate analogues have been developed for the study of periodontal diseaes and dental caries, the two most important dental diseases afflicting man. The use of a wide variety of laboratory animals in basic dental research makes it timely to review some of the guidelines for the selection of specific animals for particular diseases.

  5. Analogue Transformations in Physics and their Application to Acoustics

    PubMed Central

    García-Meca, C.; Carloni, S.; Barceló, C.; Jannes, G.; Sánchez-Dehesa, J.; Martínez, A.

    2013-01-01

    Transformation optics has shaped up a revolutionary electromagnetic design paradigm, enabling scientists to build astonishing devices such as invisibility cloaks. Unfortunately, the application of transformation techniques to other branches of physics is often constrained by the structure of the field equations. We develop here a complete transformation method using the idea of analogue spacetimes. The method is general and could be considered as a new paradigm for controlling waves in different branches of physics, from acoustics in quantum fluids to graphene electronics. As an application, we derive an “analogue transformation acoustics” formalism that naturally allows the use of transformations mixing space and time or involving moving fluids, both of which were impossible with the standard approach. To demonstrate the power of our method, we give explicit designs of a dynamic compressor, a spacetime cloak for acoustic waves and a carpet cloak for a moving aircraft. PMID:23774575

  6. Alligator rivers analogue project an OECD/NEA international project

    SciTech Connect

    Duerden, P.; Airey, P.; Pescatore, C.

    1994-12-31

    The Koongarra uranium deposit in the Alligator Rivers Region of the Northern Territory of Australia was studied as a natural analogue of the far field behaviour of high level waste repositories following groundwater ingress. A number of mathematical modelling approaches were developed for processes as diverse as groundwater transport, host rock weathering, radionuclide sorption, evolution of the uranium dispersion fan and the distribution of uranium series nuclides between mineral assemblages in weathered host rock. Some of these models are relevant to performance assessment at the level of individual processes and subsystem performance. Through the project, new insights into the application of the natural analogue approach to the assessment of potential waste repository sites were obtained.

  7. Neurological Effects of Bisphenol A and its Analogues

    PubMed Central

    Inadera, Hidekuni

    2015-01-01

    The endocrine disrupting chemical bisphenol A (BPA) is widely used in the production of polycarbonate plastics and epoxy resins. The use of BPA-containing products in daily life makes exposure ubiquitous, and the potential human health risks of this chemical are a major public health concern. Although numerous in vitro and in vivo studies have been published on the effects of BPA on biological systems, there is controversy as to whether ordinary levels of exposure can have adverse effects in humans. However, the increasing incidence of developmental disorders is of concern, and accumulating evidence indicates that BPA has detrimental effects on neurological development. Other bisphenol analogues, used as substitutes for BPA, are also suspected of having a broad range of biological actions. The objective of this review is to summarize our current understanding of the neurobiological effects of BPA and its analogues, and to discuss preventive strategies from a public health perspective. PMID:26664253

  8. New Immunosuppressive Sphingoid Base and Ceramide Analogues in Wild Cordyceps

    PubMed Central

    Mi, Jia-Ning; Han, Yuwei; Xu, Yingqiong; Kou, Junping; Wang, Jing-Rong; Jiang, Zhi-Hong

    2016-01-01

    A comprehensive identification of sphingoid bases and ceramides in wild Cordyceps was performed by integrating a sequential chromatographic enrichment procedure and an UHPLC-ultrahigh definition-Q-TOF-MS based sphingolipidomic approach. A total of 43 sphingoid bases and 303 ceramides were identified from wild Cordyceps, including 12 new sphingoid base analogues and 159 new ceramide analogues based on high-resolution MS and MS/MS data, isotope distribution, matching with the comprehensive personal sphingolipid database, confirmation by sphingolipid standards and chromatographic retention time rule. The immunosuppressive bioassay results demonstrated that Cordyceps sphingoid base fraction exhibits more potent immunosuppressive activity than ceramide fraction, elucidating the immunosuppressive ingredients of wild Cordyceps. This study represented the most comprehensive identification of sphingoid bases and ceramides from a natural source. The findings of this study provided an insight into therapeutic application of wild Cordyceps. PMID:27966660

  9. New Immunosuppressive Sphingoid Base and Ceramide Analogues in Wild Cordyceps.

    PubMed

    Mi, Jia-Ning; Han, Yuwei; Xu, Yingqiong; Kou, Junping; Wang, Jing-Rong; Jiang, Zhi-Hong

    2016-12-14

    A comprehensive identification of sphingoid bases and ceramides in wild Cordyceps was performed by integrating a sequential chromatographic enrichment procedure and an UHPLC-ultrahigh definition-Q-TOF-MS based sphingolipidomic approach. A total of 43 sphingoid bases and 303 ceramides were identified from wild Cordyceps, including 12 new sphingoid base analogues and 159 new ceramide analogues based on high-resolution MS and MS/MS data, isotope distribution, matching with the comprehensive personal sphingolipid database, confirmation by sphingolipid standards and chromatographic retention time rule. The immunosuppressive bioassay results demonstrated that Cordyceps sphingoid base fraction exhibits more potent immunosuppressive activity than ceramide fraction, elucidating the immunosuppressive ingredients of wild Cordyceps. This study represented the most comprehensive identification of sphingoid bases and ceramides from a natural source. The findings of this study provided an insight into therapeutic application of wild Cordyceps.

  10. Synthesis of dehydroepiandrosterone analogues modified with phosphatidic acid moiety.

    PubMed

    Smuga, Damian A; Smuga, Małgorzata; Swizdor, Alina; Panek, Anna; Wawrzeńczyk, Czesław

    2010-12-12

    Dehydroepiandrosterone (DHEA) and its metabolite 7α-OH DHEA have many diverse physiological, biological and biochemical effects encompassing various cell types, tissues and organs. In in vitro studies, DHEA analogues have myriad biological actions, but in vivo, especially in oral administration, DHEA produces far more limited clinical effects. One of the possible solutions of this problem is conversion of DHEA to active analogues and/or its transformation into prodrug form. In this article, the studies on the conversion of DHEA and 7α-OH DHEA into their phosphatides by the phosphodiester approach are described. In this esterification, N,N-dicyclohexylcarbodiimide (DCC) was the most efficient coupling agent as well as p-toluenesulphonyl chloride (TsCl).

  11. Active postoperative acromegaly: sustained remission after discontinuation of somatostatin analogues

    PubMed Central

    Cardenas-Salas, Jersy

    2016-01-01

    Summary In patients with active acromegaly after pituitary surgery, somatostatin analogues are effective in controlling the disease and can even be curative in some cases. After treatment discontinuation, the likelihood of disease recurrence is high. However, a small subset of patients remains symptom-free after discontinuation, with normalized growth hormone (GH) and insulin-like growth factor (IGF1) levels. The characteristics of patients most likely to achieve sustained remission after treatment discontinuation are not well understood, although limited evidence suggests that sustained remission is more likely in patients with lower GH and IGF1 levels before treatment withdrawal, in those who respond well to low-dose treatment, in those without evidence of adenoma on an MRI scan and/or in patients who receive long-term treatment. In this report, we describe the case of a 56-year-old female patient treated with lanreotide Autogel for 11 years. Treatment was successfully discontinued, and the patient is currently disease-free on all relevant parameters (clinical, biochemical and tumour status). The successful outcome in this case adds to the small body of literature suggesting that some well-selected patients who receive long-term treatment with somatostatin analogues may achieve sustained remission. Learning points: The probability of disease recurrence is high after discontinuation of treatment with somatostatin analogues. Current data indicate that remission after treatment discontinuation may be more likely in patients with low GH and IGF1 levels before treatment withdrawal, in those who respond well to low-dose treatment, in those without evidence of adenoma on MRI, and/or in patients receiving prolonged treatment. This case report suggests that prolonged treatment with somatostatin analogues can be curative in carefully selected patients. PMID:27933171

  12. OptZyme: Computational Enzyme Redesign Using Transition State Analogues

    PubMed Central

    Grisewood, Matthew J.; Gifford, Nathanael P.; Pantazes, Robert J.; Li, Ye; Cirino, Patrick C.; Janik, Michael J.; Maranas, Costas D.

    2013-01-01

    OptZyme is a new computational procedure for designing improved enzymatic activity (i.e., kcat or kcat/KM) with a novel substrate. The key concept is to use transition state analogue compounds, which are known for many reactions, as proxies for the typically unknown transition state structures. Mutations that minimize the interaction energy of the enzyme with its transition state analogue, rather than with its substrate, are identified that lower the transition state formation energy barrier. Using Escherichia coli β-glucuronidase as a benchmark system, we confirm that KM correlates (R2 = 0.960) with the computed interaction energy between the enzyme and the para-nitrophenyl- β, D-glucuronide substrate, kcat/KM correlates (R2 = 0.864) with the interaction energy of the transition state analogue, 1,5-glucarolactone, and kcat correlates (R2 = 0.854) with a weighted combination of interaction energies with the substrate and transition state analogue. OptZyme is subsequently used to identify mutants with improved KM, kcat, and kcat/KM for a new substrate, para-nitrophenyl- β, D-galactoside. Differences between the three libraries reveal structural differences that underpin improving KM, kcat, or kcat/KM. Mutants predicted to enhance the activity for para-nitrophenyl- β, D-galactoside directly or indirectly create hydrogen bonds with the altered sugar ring conformation or its substituents, namely H162S, L361G, W549R, and N550S. PMID:24116038

  13. Synthesis of a platform to access bistramides and their analogues.

    PubMed

    Commandeur, Malgorzata; Commandeur, Claude; Cossy, Janine

    2011-11-18

    The platform C14-C40, which can be used to prepare bistramide C and 39-oxobistramide K, was synthesized in 19 steps with an overall yield of 6.2%. Furthermore, the chemoselective reduction of the ketone at C-39 was performed giving an easy access to bistramides A, B, D, K, and L. Finally, the versatility of the synthesis of the C14-C40 fragment can allow the preparation of a large variety of stereoisomers to produce bistramide analogues.

  14. Effect of lipophilicity on the pharmacokinetics of radiolabeled spiperone analogues

    SciTech Connect

    Moerlein, S.M.; Laufer, P.; Stocklin, G.

    1985-05-01

    Several radiolabeled analogues of the butyrophenone neuroleptic spiperone exhibit in vivo localization in D/sub 2/ receptor-rich areas of the brain. A series of N-alkylated spiperone analogues and the corresponding p-brominated compounds were synthesized to ascertain the optimum structure for labeling with /sup 18/F or /sup 75/Br. In vivo studies indicated that all analogues had D/sub 2/ receptor-binding affinity within the same order of magnitude (IC/sub 50/=2.6 nM for SP and 3.9 nM for BPSP), whereas the lipophilicity varied greatly (log P=2.7 for SP and 5.2 for BPSP). In vivo studies in the rat using the radiobrominated analogues were done using compounds labeled with n.c.a. /sup 77/Br via in-situ oxidation by dichloramine-T or H/sub 2/O/sub 2//CH/sub 3/COOH. Alkylation of BSP was found to decrease the striatum-to-cerebellum concentration at 6 hr from 8.2 for BSP to 5.2 for BPSP. Unexpectedly, the cerebral uptake did not increase with log P, the striatal concentration dropping from 390% MBC for BSP to 85% MBC for BPSP. This contrasts with previous results for SP and MSP, where the brain uptake increases slightly with log P. Increasing lipophilicity increases blood faster than brain concentrations, and it is concluded that whereas N-alkylation may be beneficial for /sup 18/F-labeld neuroleptics, non-alkylated spiperone is the optimum labeling substrate for /sup 75/Br.

  15. Bis(vinylenedithio)tetrathiafulvalene analogues of BEDT-TTF

    PubMed Central

    Demirtas, İlknur; Ozturk, Turan

    2015-01-01

    Summary This review aims to give an overview of the current status of our research on the synthesis of π-electron donor bis(ethylenedithio)tetrathiafulvalene (BEDT-TTF, ET) analogues prepared from 1,8-diketones via a ring forming reaction. The new synthesized π-electron donors have vinyl moieties producing extended π-electron delocalization over the substituent phenyl rings at the peripheries. PMID:25977714

  16. Dimerization and DNA recognition rules of mithramycin and its analogues

    PubMed Central

    Weidenbach, Stevi; Hou, Caixia; Chen, Jhong-Min; Tsodikov, Oleg V.; Rohr, Jürgen

    2016-01-01

    The antineoplastic and antibiotic natural product mithramycin (MTM) is used against cancer-related hypercalcemia and, experimentally, against Ewing sarcoma and lung cancers. MTM exerts its cytotoxic effect by binding DNA as a divalent metal ion (Me2+)-coordinated dimer and disrupting the function of transcription factors. A precise molecular mechanism of action of MTM, needed to develop MTM analogues selective against desired transcription factors, is lacking. Although it is known that MTM binds G/C-rich DNA, the exact DNA recognition rules that would allow one to map MTM binding sites remain incompletely understood. Towards this goal, we quantitatively investigated dimerization of MTM and several of its analogues, MTM SDK (for Short side chain, DiKeto), MTM SA-Trp (for Short side chain and Acid), MTM SA-Ala, and a biosynthetic precursor premithramycin B (PreMTM B), and measured the binding affinities of these molecules to DNA oligomers of different sequences and structural forms at physiological salt concentrations. We show that MTM and its analogues form stable dimers even in the absence of DNA. All molecules, except for PreMTM B, can bind DNA with the following rank order of affinities (strong to weak): MTM = MTM SDK > MTM SA-Trp > MTM SA-Ala. An X(G/C)(G/C)X motif, where X is any base, is necessary and sufficient for MTM binding to DNA, without a strong dependence on DNA conformation. These recognition rules will aid in mapping MTM sites across different promoters towards development of MTM analogues as useful anticancer agents. PMID:26760230

  17. Synthesis of phosphonate and phostone analogues of ribose-1-phosphates

    PubMed Central

    Nasomjai, Pitak; Slawin, Alexandra M Z

    2009-01-01

    Summary The synthesis of phosphonate analogues of ribose-1-phosphate and 5-fluoro-5-deoxyribose-1-phosphate is described. Preparations of both the α- and β-phosphonate anomers are reported for the ribose and 5-fluoro-5-deoxyribose series and a synthesis of the corresponding cyclic phostones of each α-ribose is also reported. These compounds have been prepared as tools to probe the details of fluorometabolism in S. cattleya. PMID:19777136

  18. Novel ynamide structural analogues and their synthetic transformations

    PubMed Central

    Lu, Ting; Hsung, Richard P.

    2015-01-01

    This Highlight accounts for a recent phenomenon in which a series of novel ynamide structural analogues have emerged and caught the attention of the synthetic community. Preparations and reactions of these de novo ynamide variants are delineated here to demonstrate their accessibility as well as their reactivity. This Highlight should help reveal that these unique N-containing alkynes can become highly versatile building blocks in organic syntheses. PMID:26280027

  19. Pre-Clinical Testing of New Hydroxybutyrate Analogues

    DTIC Science & Technology

    2011-07-01

    the effects of DHB analogues to ascertain if they are longer-acting compounds than the parent compound. Although obtaining the first and only drug ...useful in the treatment of PD. Body of Work The goal of this study is to fully assess and compare the potency of compounds that are structurally...SARA 313: Carcinogenicity Classification (components present at 0.1% or more): none, unless listed below TSCA (US Toxic Substances Control Act

  20. Differential membrane fluidization by active and inactive cannabinoid analogues.

    PubMed

    Mavromoustakos, T; Papahatjis, D; Laggner, P

    2001-06-06

    The effects of the two cannabinomimetic drugs (-)-2-(6a,7,10,10a-tetrahydro-6,6,9-trimethyl-1-hydroxy-6H-dibenzo[b,d]pyranyl-2-(hexyl)-1,3-dithiolane (AMG-3) and its pharmacologically less active 1-methoxy analogue (AMG-18) on the thermotropic and structural properties of dipalmitoyl-sn-glycero-3-phosphorylcholine (DPPC) liposomes have been studied by X-ray diffraction and differential scanning calorimetry (DSC). DSC data revealed that the incorporation of the drugs affect differently the thermotropic properties of DPPC. The presence of the more active drug distinctly broadened and attenuated both the pretransition and main phase transition of DPPC bilayers, while the inactive analogue had only minor effects. Small and wide angle X-ray diffraction data showed that the two cannabinoids have different effects on the lipid phase structures and on the hydrocarbon chain packing. The pharmacologically active analogue, AMG-3, was found to efficiently fluidize domains of the lipids in the L(beta)' gel phase, and to perturb the regular multibilayer lattice. In the liquid crystalline L(alpha) phase, AMG-3 was also found to cause irregularities in packing, suggesting that the drug induces local curvature. At the same concentration, the inactive AMG-18 had only minor structural effects on the lipids. At about 10-fold or higher concentrations, AMG-18 was found to produce similar but still less pronounced effects in comparison to those observed by AMG-3. The dose-dependent, different thermotropic and structural effects by the two cannabinoid analogues suggest that these may be related to their biological activity.

  1. Evaluation of Anti-HIV-1 Mutagenic Nucleoside Analogues*

    PubMed Central

    Vivet-Boudou, Valérie; Isel, Catherine; El Safadi, Yazan; Smyth, Redmond P.; Laumond, Géraldine; Moog, Christiane; Paillart, Jean-Christophe; Marquet, Roland

    2015-01-01

    Because of their high mutation rates, RNA viruses and retroviruses replicate close to the threshold of viability. Their existence as quasi-species has pioneered the concept of “lethal mutagenesis” that prompted us to synthesize pyrimidine nucleoside analogues with antiviral activity in cell culture consistent with an accumulation of deleterious mutations in the HIV-1 genome. However, testing all potentially mutagenic compounds in cell-based assays is tedious and costly. Here, we describe two simple in vitro biophysical/biochemical assays that allow prediction of the mutagenic potential of deoxyribonucleoside analogues. The first assay compares the thermal stabilities of matched and mismatched base pairs in DNA duplexes containing or not the nucleoside analogues as follows. A promising candidate should display a small destabilization of the matched base pair compared with the natural nucleoside and the smallest gap possible between the stabilities of the matched and mismatched base pairs. From this assay, we predicted that two of our compounds, 5-hydroxymethyl-2′-deoxyuridine and 5-hydroxymethyl-2′-deoxycytidine, should be mutagenic. The second in vitro reverse transcription assay assesses DNA synthesis opposite nucleoside analogues inserted into a template strand and subsequent extension of the newly synthesized base pairs. Once again, only 5-hydroxymethyl-2′-deoxyuridine and 5-hydroxymethyl-2′-deoxycytidine are predicted to be efficient mutagens. The predictive potential of our fast and easy first line screens was confirmed by detailed analysis of the mutation spectrum induced by the compounds in cell culture because only compounds 5-hydroxymethyl-2′-deoxyuridine and 5-hydroxymethyl-2′-deoxycytidine were found to increase the mutation frequency by 3.1- and 3.4-fold, respectively. PMID:25398876

  2. Ungeremine and Its hemisynthesized analogues as bactericides against Flavobacterium columnare.

    PubMed

    Schrader, Kevin K; Avolio, Fabiana; Andolfi, Anna; Cimmino, Alessio; Evidente, Antonio

    2013-02-13

    The Gram-negative bacterium Flavobacterium columnare is the cause of columnaris disease, which can occur in channel catfish ( Ictalurus punctatus ). In a previous study, the betaine-type alkaloid ungeremine, 1, obtained from Pancratium maritimum L. was found to have strong antibacterial activity against F. columnare. In this study, analogues of 1 were evaluated using a rapid bioassay for activity against F. columnare to determine if the analogues might provide greater antibacterial activity and to determine structure-activity relationships of the test compounds. Several ungeremine analogues were prepared by hydrochlorination of the alkaloid and by selenium dioxide oxidation of both lycorine, 7, and pseudolycorine, 8, which yielded the isomer of ungeremine, 3, and zefbetaine, 4, respectively. The treatment of lycorine with phosphorus oxychloride allowed the synthesis of an anhydrolycorine lactam, 5, showing, with respect to 1, the deoxygenation and oxygenation of C-2 and C-7 of the C and B rings, respectively. The results of the structure-activity relationship studies showed that the aromatization of the C ring and the oxidation to an azomethine group of C-7 of the B ring are structural features important for antibacterial activity. In addition, the position of the oxygenation of the C ring as well as the presence of the 1,3-dioxole ring joined to the A ring of the pyrrolo[de]phenanthridine skeleton also plays a significant role in imparting antibacterial activity. On the basis of 24-h 50% inhibition concentration (IC(50)) results, ungeremine hydrochloride, 2, was similar in toxicity to 1, whereas 5 had the lowest activity. Analogue 2 is soluble in water, which may provide the benefit for use as an effective feed additive or therapeutant compared to ungeremine.

  3. Analogue Investigations into Magma-Cryosphere Interactions on Mars

    NASA Astrophysics Data System (ADS)

    Tyson, S.; Wilson, L.; Lane, S. J.; Airey, M. W.; Gilbert, J. S.

    2011-12-01

    Many landforms and morphological features thought to have resulted from magma-cryosphere interactions have been identified on Mars. However, few experimental studies have been conducted to investigate the physical and thermal changes that should occur in the subsurface during these interactions. This project aims to begin to address this by conducting a series of laboratory analogue experiments. We introduce a heat source into a block of analogue cryosphere material (a carefully-prepared mixture of solid grains and ice) and record the thermal development within the block using thermocouples. We use these measurements to interpret the physical activity within the block, such as when and where phase changes occur, what sequence of shapes the developing melt region takes, and the extent of convection of any fluid phase H20. Blocks are also dissected after each run and documented photographically to record any physical movement of grains. Results will be used to constrain variables within a heat flow model that we are developing. This model will then be applied to the interpretation of landforms on Mars to help determine what set of processes could have realistically occurred during their formation. A second series of experiments will investigate surface morphological changes on the cryosphere analogue blocks. Resultant morphologies will be recorded and compared with existing martian landforms to again provide insight into formation processes.

  4. Design and synthesis of biotin analogues reversibly binding with streptavidin.

    PubMed

    Yamamoto, Tomohiro; Aoki, Kiyoshi; Sugiyama, Akira; Doi, Hirofumi; Kodama, Tatsuhiko; Shimizu, Yohei; Kanai, Motomu

    2015-04-01

    Two new biotin analogues, biotin carbonate 5 and biotin carbamate 6, have been synthesized. These molecules were designed to reversibly bind with streptavidin by replacing the hydrogen-bond donor NH group(s) of biotin's cyclic urea moiety with oxygen. Biotin carbonate 5 was synthesized from L-arabinose (7), which furnishes the desired stereochemistry at the 3,4-cis-dihydroxy groups, in 11% overall yield (over 10 steps). Synthesis of biotin carbamate 6 was accomplished from L-cysteine-derived chiral aldehyde 33 in 11% overall yield (over 7 steps). Surface plasmon resonance analysis of water-soluble biotin carbonate analogue 46 and biotin carbamate analogue 47 revealed that KD values of these compounds for binding to streptavidin were 6.7×10(-6)  M and 1.7×10(-10)  M, respectively. These values were remarkably greater than that of biotin (KD =10(-15)  M), and thus indicate the importance of the nitrogen atoms for the strong binding between biotin and streptavidin.

  5. Transdermal delivery of a melanotropic peptide hormone analogue

    SciTech Connect

    Dawson, B.V.; Hadley, M.E.; Kreutzfeld, K.; Dorr, R.T.; Hruby, V.J.; Al-Obeidi, F.; Don, S.

    1988-01-01

    We previously reported that topical application of (Nl3/sup 4/,D-Phe/sup 7/)alpha-MSH, a superpotent analogue of alpha-melanocyte stimulating hormone, to mice induces a darkening of follicular melanocytes throughout the skin. We now report that the melanotropin analogue can be delivered across mouse but not rat skin in an in vitro model system. Passage of the analogue from the topically applied vehicle (polyethylene glycol) across the skin into a subcutaneous receiving vessel was demonstrated by both bioassay as well as by radioimmunoassay. The bioassay data demonstrate that percutaneous absorption of the melanotropin did not result in loss of biological activity of the peptide. The differential penetration of the peptide across rodent skin reveals that one cannot predict percutaneous absorption of a substance across the stratum corneum from studies on a single species. The present results are the first to demonstrate, by direct quantitative measurements, that a bioactive peptide can be delivered across the vertebrate integument in vitro. These studies point out the potential of a topically applied melanotropin for tanning of the skin and possibly for treatment of certain hypopigmentary disorders.

  6. Contact zones and hydrothermal systems as analogues to repository conditions

    SciTech Connect

    Wollenberg, H.A.; Flexser, S.

    1984-10-01

    Radioactive waste isolation efforts in the US are currently focused on examining basalt, tuff, salt, and crystalline rock as candidate rock types to encompass waste repositories. As analogues to near-field conditions, the distributions of radio- and trace-elements have been examined across contacts between these rocks and dikes and stocks that have intruded them. The intensive study of the Stripa quartz monzonite has also offered the opportunity to observe the distribution of uranium and its daughters in groundwater and its relationship to U associated with fracture-filling and alteration minerals. Investigations of intrusive contact zones to date have included (1) a tertiary stock into Precambrian gneiss, (2) a stock into ash flow tuff, (3) a rhyodacite dike into Columbia River basalt, and (4) a kimberlite dike into salt. With respect to temperature and pressure, these contact zones may be considered "worst-case scenario" analogues. Results indicate that there has been no appreciable migration of radioelements from the more radioactive intrusives into the less radioactive country rocks, either in response to the intrusions or in the fracture-controlled hydrological systems that developed following emplacement. In many cases, the radioelements are locked up in accessory minerals, suggesting that artificial analogues to these would make ideal waste forms. Emphasis should now shift to examination of active hydrothermal systems, studying the distribution of key elements in water, fractures, and alteration minerals under pressure and temperature conditions most similar to those expected in the near-field environment of a repository. 14 refs.

  7. THE PENA BLANCA NATURAL ANALOGUE PERFORMANCE ASSESSMENT MODEL

    SciTech Connect

    G. Saulnier and W. Statham

    2006-04-16

    The Nopal I uranium mine in the Sierra Pena Blanca, Chihuahua, Mexico serves as a natural analogue to the Yucca Mountain repository. The Pena Blanca Natural Analogue Performance Assessment Model simulates the mobilization and transport of radionuclides that are released from the mine and transported to the saturated zone. The Pena Blanca Natural Analogue Performance Assessment Model uses probabilistic simulations of hydrogeologic processes that are analogous to the processes that occur at the Yucca Mountain site. The Nopal I uranium deposit lies in fractured, welded, and altered rhyolitic ash-flow tuffs that overlie carbonate rocks, a setting analogous to the geologic formations at the Yucca Mountain site. The Nopal I mine site has the following analogous characteristics as compared to the Yucca Mountain repository site: (1) Analogous source--UO{sub 2} uranium ore deposit = spent nuclear fuel in the repository; (2) Analogous geology--(i.e. fractured, welded, and altered rhyolitic ash-flow tuffs); (3) Analogous climate--Semiarid to arid; (4) Analogous setting--Volcanic tuffs overlie carbonate rocks; and (5) Analogous geochemistry--Oxidizing conditions Analogous hydrogeology: The ore deposit lies in the unsaturated zone above the water table.

  8. An adenosine nucleoside analogue NITD008 inhibits EV71 proliferation.

    PubMed

    Shang, Luqing; Wang, Yaxin; Qing, Jie; Shu, Bo; Cao, Lin; Lou, Zhiyong; Gong, Peng; Sun, Yuna; Yin, Zheng

    2014-12-01

    Enterovirus 71 (EV71), one of the major causative agents of Hand-Foot-Mouth Disease (HFMD), causes severe pandemics and hundreds of deaths in the Asia-Pacific region annually and is an enormous public health threat. However, effective therapeutic antiviral drugs against EV71 are rare. Nucleoside analogues have been successfully used in the clinic for the treatment of various viral infections. We evaluated a total of 27 nucleoside analogues and discovered that an adenosine nucleoside analogue NITD008, which has been reported to be an antiviral reagent that specifically inhibits flaviviruses, effectively suppressed the propagation of different strains of EV71 in RD, 293T and Vero cells with a relatively high selectivity index. Triphosphorylated NITD008 (ppp-NITD008) functions as a chain terminator to directly inhibit the RNA-dependent RNA polymerase activity of EV71, and it does not affect the EV71 VPg uridylylation process. A significant synergistic anti-EV71 effect of NITD008 with rupintrivir (AG7088) (a protease inhibitor) was documented, supporting the potential combination therapy of NITD008 with other inhibitors for the treatment of EV71 infections.

  9. Stereochemical Assignment of Strigolactone Analogues Confirms Their Selective Biological Activity.

    PubMed

    Artuso, Emma; Ghibaudi, Elena; Lace, Beatrice; Marabello, Domenica; Vinciguerra, Daniele; Lombardi, Chiara; Koltai, Hinanit; Kapulnik, Yoram; Novero, Mara; Occhiato, Ernesto G; Scarpi, Dina; Parisotto, Stefano; Deagostino, Annamaria; Venturello, Paolo; Mayzlish-Gati, Einav; Bier, Ariel; Prandi, Cristina

    2015-11-25

    Strigolactones (SLs) are new plant hormones with various developmental functions. They are also soil signaling chemicals that are required for establishing beneficial mycorrhizal plant/fungus symbiosis. In addition, SLs play an essential role in inducing seed germination in root-parasitic weeds, which are one of the seven most serious biological threats to food security. There are around 20 natural SLs that are produced by plants in very low quantities. Therefore, most of the knowledge on SL signal transduction and associated molecular events is based on the application of synthetic analogues. Stereochemistry plays a crucial role in the structure-activity relationship of SLs, as compounds with an unnatural D-ring configuration may induce biological effects that are unrelated to SLs. We have synthesized a series of strigolactone analogues, whose absolute configuration has been elucidated and related with their biological activity, thus confirming the high specificity of the response. Analogues bearing the R-configured butenolide moiety showed enhanced biological activity, which highlights the importance of this stereochemical motif.

  10. TREATMENT OF TYPE 2 DIABETES WITH BIPHASIC INSULIN ANALOGUES

    PubMed Central

    Rizvi, Ali A.

    2016-01-01

    The majority of patients with Type 2 diabetes require insulin therapy for treating hyperglycaemia. There are several regimens available for insulin initiation and maintenance. Insulin analogues have been developed to mimic normal physiology as closely as possible. Biphasic analogues can target both fasting and postprandial hyperglycaemia, with the added advantage of being premixed and thus convenient for the patient. A practical and feasible option is to initiate insulin with one or more biphasic preparations at mealtimes, thus providing both basal and prandial coverage. Individual titration of dose and frequency of daily injections with biphasic insulin preparations has the potential for improving glycaemic control with a high degree of patient acceptance. Drawbacks include a more rigid regimen, a relative lack of flexibility, and a somewhat higher degree of glycaemic variability and hypoglycaemia when compared to multiple daily basal-bolus injections. Awareness of the advantages and limitations of biphasic insulin analogues can assist clinicians in their appropriate use for the treatment of patients with Type 2 diabetes. PMID:27918600

  11. Noble gas encapsulation: clathrate hydrates and their HF doped analogues.

    PubMed

    Mondal, Sukanta; Chattaraj, Pratim Kumar

    2014-09-07

    The significance of clathrate hydrates lies in their ability to encapsulate a vast range of inert gases. Although the natural abundance of a few noble gases (Kr and Xe) is poor their hydrates are generally abundant. It has already been reported that HF doping enhances the stability of hydrogen hydrates and methane hydrates, which prompted us to perform a model study on helium, neon and argon hydrates with their HF doped analogues. For this purpose 5(12), 5(12)6(8) and their HF doped analogues are taken as the model clathrate hydrates, which are among the building blocks of sI, sII and sH types of clathrate hydrate crystals. We use the dispersion corrected and gradient corrected hybrid density functional theory for the calculation of thermodynamic parameters as well as conceptual density functional theory based reactivity descriptors. The method of the ab initio molecular dynamics (AIMD) simulation is used through atom centered density matrix propagation (ADMP) techniques to envisage the structural behaviour of different noble gas hydrates on a 500 fs timescale. Electron density analysis is carried out to understand the nature of Ng-OH2, Ng-FH and Ng-Ng interactions. The current results noticeably demonstrate that the noble gas (He, Ne, and Ar) encapsulation ability of 5(12), 5(12)6(8) and their HF doped analogues is thermodynamically favourable.

  12. Spin Alignment in Analogues of The Local Sheet

    NASA Astrophysics Data System (ADS)

    Conidis, George J.

    2016-10-01

    Tidal torque theory and simulations of large scale structure predict spin vectors of massive galaxies should be coplanar with sheets in the cosmic web. Recently demonstrated, the giants (K s <= -22.5 mag) in the Local Volume beyond the Local Sheet have spin vectors directed close to the plane of the Local Supercluster, supporting the predictions of Tidal Torque Theory. However, the giants in the Local Sheet encircling the Local Group display a distinctly different arrangement, suggesting that the mass asymmetry of the Local Group or its progenitor torqued them from their primordial spin directions. To investigate the origin of the spin alignment of giants locally, analogues of the Local Sheet were identified in the SDSS DR9. Similar to the Local Sheet, analogues have an interacting pair of disk galaxies isolated from the remaining sheet members. Modified sheets in which there is no interacting pair of disk galaxies were identified as a control sample. Galaxies in face-on control sheets do not display axis ratios predominantly weighted toward low values, contrary to the expectation of tidal torque theory. For face-on and edge-on sheets, the distribution of axis ratios for galaxies in analogues is distinct from that in controls with a confidence of 97.6% & 96.9%, respectively. This corroborates the hypothesis that an interacting pair can affect spin directions of neighbouring galaxies.

  13. Four-quadrant analogue multiplier using operational amplifier

    NASA Astrophysics Data System (ADS)

    Riewruja, Vanchai; Rerkratn, Apinai

    2011-04-01

    A method to realise a four-quadrant analogue multiplier using general-purpose operational amplifiers (opamps) as only the active elements is described in this article. The realisation method is based on the quarter-square technique, which utilises the inherent square-law characteristic of class AB output stage of the opamp. The multiplier can be achieved from the proposed structure with using either bipolar or complementary metal-oxide-semiconductor (CMOS) opamps. The operation principle of the proposed multiplier has been confirmed by PSPICE analogue simulation program. Simulation results reveal that the principle of proposed scheme provides an adequate performance for a four-quadrant analogue multiplier. Experimental implementations of the proposed multiplier using bipolar and CMOS opamps are performed to verify the circuit performances. Measured results of the experimental proposed schemes based on the use of bipolar and CMOS opamps with supply voltage ±2.4 V show the worst-case relative errors of 0.32% and 0.47%, and the total harmonic distortions of 0.47% and 0.98%, respectively.

  14. Mammalian folylpoly-. gamma. -glutamate synthetase. 3. Specificity for folate analogues

    SciTech Connect

    George, S.; Cichowicz, D.J.; Shane, B.

    1987-01-27

    A variety of folate analogues were synthesized to explore the specificity of the folate binding site of hog liver folypolyglutamate synthetase and the requirements for catalysis. Modifications of the internal and terminal glutamate moieties of folate cause large drops in on rates and/or affinity for the protein. The only exceptions are glutamine, homocysteate, and ornithine analogues, indicating a less stringent specificity around the delta-carbon of glutamate. It is proposed that initial folate binding to the enzyme involves low-affinity interactions at a pterin and a glutamate site and that the first glutamate bound is the internal residue adjacent to the benzoyl group. Processive movement of the polyglutamate chain through the glutamate site and a possible conformational change in the protein when the terminal residue is bound would result in tight binding and would position the ..gamma..-carboxyl of the terminal glutamate in the correct position for catalysis. The 4-amino substitution of folate increases the on rate for monoglutamate derivatives but severely impairs catalysis with diglutamate derivatives. Pteroylornithine derivatives are the first potent and specific inhibitors of folylpolyglutamate synthetase to be identified and may act as analogues of reaction intermediates. Other folate derivatives with tetrahedral chemistry replacing the peptide bond, such as pteroyl-..gamma..-glutamyl-(psi,CH/sub 2/-NH)-glutamate, retain affinity for the protein but are considerably less effective inhibitors than the ornithine derivatives. Enzyme activity was assayed using (/sup 14/C)glutamate.

  15. Bilateral Choroidal Metastases from Endobronchial Carcinoid Treated with Somatostatin Analogues

    PubMed Central

    De Bruyn, Deborah; Lamont, Jan; Vanderstraeten, Erik; Van Belle, Simon; Platteau, Elise; De Zaeytijd, Julie; Hoornaert, Kristien P.

    2016-01-01

    Objective: To describe a patient with bilateral multifocal choroidal metastases from an endobronchial carcinoid treated with a somatostatin analogue. Method: A 60-year-old woman presenting with photopsia in the left eye underwent an extensive ophthalmic examination, including fluorescein angiography, OCT and ultrasound. Results: Fundoscopy revealed a small retinal tear in the left eye, for which she received laser treatment. In addition, choroidal masses were detected in both eyes. Her medical history of a pneumectomy for a bronchial carcinoid six years earlier together with recent elevated chromogranin A blood levels prompted a diagnosis of choroidal metastases. Subsequently, a Gallium-68 DOTANOC positron emitting tomography/computer tomography scan revealed a spinal cord metastasis and mediastinal as well as mesenterial lymph node invasion. Systemic treatment with Sandostatin®, a somatostatin analogue was started. Up until two years after the initial presentation and treatment, these choroidal lesions remained stable without any signs of growth. Conclusion: Endobronchial carcinoid tumors have an indolent nature and long-term follow-up is recommended for early detection of metastases. Although treatment with somatostatin analogues rarely induces complete tumor regression, tumor stabilization and prevention of symptoms related to hormone secretion is achieved. This well-tolerated systemic treatment provides a worthy alternative treatment for choroidal metastasis compared to classic radiotherapy without any risk of radiation or laser-related visual loss. PMID:27843513

  16. Past and present of analogue modelling, and its future trend

    NASA Astrophysics Data System (ADS)

    Koyi, Hemin

    2015-04-01

    Since Hull (1815) published his article on modelling, analogue modelling has expanded to simulate both a wider range of tectonic regimes and target more challenging set-ups, and has become an integrated part of the fields of tectonics and structural geology. Establishment of new laboratories testifies for the increased attention the technique receives. The ties between modellers and field geoscientists have become stronger with the focus being on understanding the parameters that govern the evolution of a tectonic regime and the processes that dominate it. Since the first sand castle was built with damp sand on a beach, sand has proven to be an appropriate material analogue. Even though granular materials is the most widely used analogue material, new materials are also (re)introduced as rock analogues. Emphasis has been on more precise measurements of the mechanical properties of the materials and on minimizing the preparation effects, which have a great impact on scaling, interpretations and benchmarking. The analytical technique used to quantify model results has also seen a great deal of improvement. In addition to X-ray tomography used to visualise internal structures of models, new techniques (e.g. PIV, high-resolution laser scanning, and interferometry) have enabled monitoring kinematics with a higher precision. Benchmarking exercises have given modelling an additional checking tool by outlining, in addition to the rheology of the modelling materials, the impact of different preparation approaches, the effect of boundary conditions, and the human factor on model results. However, despite the different approaches and deformation rigs, results of models of different tectonic laboratories have shown a great deal of similarities. Even with the introduction of more sophisticated numerical codes and usage of more powerful computers which enable the simulation of more challenging material properties and combinations of those, and 3D model set-up, analogue modelling

  17. THE PENA BLANCA NATURAL ANALOGUE PERFORMANCE ASSESSMENT MODEL

    SciTech Connect

    G.J. Saulnier Jr; W. Statham

    2006-03-10

    The Nopal I uranium mine in the Sierra Pena Blanca, Chihuahua, Mexico serves as a natural analogue to the Yucca Mountain repository. The Pena Blanca Natural Analogue Performance Assessment Model simulates the mobilization and transport of radionuclides that are released from the mine and transported to the saturated zone. the Pena Blanca Natural Analogue Model uses probabilistic simulations of hydrogeologic processes that are analogous to the processes that occur at the Yucca Mountain site. The Nopal I uranium deposit lies in fractured, welded, and altered rhyolitic ash flow tuffs that overlie carbonate rocks, a setting analogous to the geologic formations at the Yucca Mountain site. The Nopal I mine site has the following characteristics as compared to the Yucca Mountain repository site. (1) Analogous source: UO{sub 2} uranium ore deposit = spent nuclear fuel in the repository; (2) Analogous geologic setting: fractured, welded, and altered rhyolitic ash flow tuffs overlying carbonate rocks; (3) Analogous climate: Semiarid to arid; (4) Analogous geochemistry: Oxidizing conditions; and (5) Analogous hydrogeology: The ore deposit lies in the unsaturated zone above the water table. The Nopal I deposit is approximately 8 {+-} 0.5 million years old and has been exposed to oxidizing conditions during the last 3.2 to 3.4 million years. The Pena Blanca Natural Analogue Model considers that the uranium oxide and uranium silicates in the ore deposit were originally analogous to uranium-oxide spent nuclear fuel. The Pena Blanca site has been characterized using field and laboratory investigations of its fault and fracture distribution, mineralogy, fracture fillings, seepage into the mine adits, regional hydrology, and mineralization that shows the extent of radionuclide migration. Three boreholes were drilled at the Nopal I mine site in 2003 and these boreholes have provided samples for lithologic characterization, water-level measurements, and water samples for laboratory

  18. Interglacial analogues of the Holocene and its natural near future

    NASA Astrophysics Data System (ADS)

    Yin, Qiuzhen; Berger, André

    2015-07-01

    In an attempt to find potential interglacial analogues of our present interglacial and its natural future, five interglacials (MIS-1, 5, 9, 11 and 19) are studied in terms of their astronomical characteristics, greenhouse gases concentration and climate simulated using both snapshot and transient experiments. Transient simulations covering a full range of obliquity, precession and eccentricity allow to develop an OPE index to estimate the climate sensitivity to astronomical forcing. They also show that obliquity and precession have different weight on the annual mean temperature and precipitation of different latitudinal zones, leading to varying phasing of these climate variables between different latitudes. However, the variations in boreal summer temperature of different latitudes (except the Southern Ocean) are in phase and are dominated by precession. All the interglacials are shown to be warmer than the natural climate of the present day and of the next centuries during boreal summer and for the annual mean temperature with varying duration and intensity. Such warming is mainly caused by changes in insolation, unlike the present global warming which mainly results from anthropogenic CO2 increase. The exceptionally long duration of MIS-11 is confirmed by our simulations, and it is demonstrated to be related to the long-lasting low eccentricity and high CO2 concentration and to the anti-phase relationship between obliquity maximum and precession minimum during MIS-11. As far as the variations of annual and seasonal temperatures are concerned, both snapshot and transient simulations show that MIS-19 is the best analogue of the present interglacial. MIS-11 is also a decent analogue when the impact of insolation alone is considered, but it is warmer than MIS-1 when the impact of CO2 is additionally included. Due to the large amplitude in the variations of insolation, MIS-5 and MIS-9 can hardly be considered as an analogue of the natural present-day climate and of

  19. Oxygen isotopes in calcite grown under cave-analogue conditions

    NASA Astrophysics Data System (ADS)

    Day, C. C.; Henderson, G. M.

    2011-07-01

    Speleothem oxygen isotopes and growth rates are valuable proxies for reconstructing climate history. There is debate, however, about the conditions that allow speleothems to grow in oxygen isotope equilibrium, and about the correct equilibrium fractionation factors. We report results from a series of carbonate growth experiments in karst-analogue conditions in the laboratory. The setup closely mimics natural processes (e.g. precipitation driven by CO 2-degassing, low ionic strength solution, thin solution film) but with a tight control on growth conditions (temperature, pCO 2, drip rate, calcite saturation index and the composition of the initial solution). Calcite is dissolved in water in a 20,000 ppmV pCO 2 environment. This solution is dripped onto glass plates (coated with seed-carbonate) in a lower pCO 2 environment (<2500 ppmV), where degassing leads to calcite growth. Experiments were performed at 7, 15, 25 and 35 °C. At each temperature, calcite was grown at three drip rates (2, 6 and 10 drips per minute) on separate plates. The mass of calcite grown in these experiments varies with temperature ( T in K) and drip rate ( d_ r in drips min -1) according to the relationship daily growth mass = 1.254 + 1.478 ∗ 10 -9 ∗ e0.0679 T + ( e0.00248 T - 2) ∗ (-0.779 d_ r2 + 10.05 d_ r + 11.69). This relationship indicates a substantial increase of growth mass with temperature, a smaller influence of drip rate on growth mass at low temperature and a non-linear relationship between drip rate and growth mass at higher temperatures. Low temperature, fast dripping conditions are found to be the most favourable for reducing effects associated with evaporation and rapid depletion of the dissolved inorganic carbon reservoir (rapid DIC-depletion). The impact of evaporation can be large so caves with high relative humidity are also preferable for palaeoclimate reconstruction. Even allowing for the maximum offsets that may have been induced by evaporation and rapid DIC

  20. Downscaling of surface moisture flux and precipitation in the Ebro Valley (Spain) using analogues and analogues followed by random forests and multiple linear regression

    NASA Astrophysics Data System (ADS)

    Ibarra-Berastegi, G.; Saénz, J.; Ezcurra, A.; Elías, A.; Diaz Argandoña, J.; Errasti, I.

    2011-06-01

    In this paper, reanalysis fields from the ECMWF have been statistically downscaled to predict from large-scale atmospheric fields, surface moisture flux and daily precipitation at two observatories (Zaragoza and Tortosa, Ebro Valley, Spain) during the 1961-2001 period. Three types of downscaling models have been built: (i) analogues, (ii) analogues followed by random forests and (iii) analogues followed by multiple linear regression. The inputs consist of data (predictor fields) taken from the ERA-40 reanalysis. The predicted fields are precipitation and surface moisture flux as measured at the two observatories. With the aim to reduce the dimensionality of the problem, the ERA-40 fields have been decomposed using empirical orthogonal functions. Available daily data has been divided into two parts: a training period used to find a group of about 300 analogues to build the downscaling model (1961-1996) and a test period (1997-2001), where models' performance has been assessed using independent data. In the case of surface moisture flux, the models based on analogues followed by random forests do not clearly outperform those built on analogues plus multiple linear regression, while simple averages calculated from the nearest analogues found in the training period, yielded only slightly worse results. In the case of precipitation, the three types of model performed equally. These results suggest that most of the models' downscaling capabilities can be attributed to the analogues-calculation stage.

  1. Downscaling of surface moisture flux and precipitation in the Ebro Valley (Spain) using analogues and analogues followed by random forests and multiple linear regression

    NASA Astrophysics Data System (ADS)

    Ibarra-Berastegi, G.; Saénz, J.; Ezcurra, A.; Elías, A.; Diaz de Argandoña, J.; Errasti, I.

    2011-02-01

    In this paper, reanalysis fields from the ECMWF have been statistically downscaled to predict from large-scale atmospheric fields surface moisture flux and daily precipitation at two observatories (Zaragoza and Tortosa, Ebro Valley, Spain) during the 1961-2001 period. Three types of downscaling models have been built (i) analogues, (ii) analogues followed by random forests and (iii) analogues followed by multiple linear regression. The inputs consist of data (predictor fields) taken from the ERA-40 reanalysis. The predicted fields are precipitation and surface moisture flux as measured at the two observatories. With the aim to reduce the dimensionality of the problem, the ERA-40 fields have been decomposed using empirical orthogonal functions. Available daily data has been divided into two parts: a training period used to find a group of about 300 analogues to build the downscaling model (1961-1996) and a test period (1997-2001), where models' performance has been assessed using independent data. In the case of surface moisture flux, the models based on analogues followed by random forests do not clearly outperform those built on analogues plus multiple linear regression, while simple averages calculated from the nearest analogues found in the training period, yielded only slightly worse results. In the case of precipitation, the three types of model performed equally. These results suggest that most of the models' downscaling capabilities can be attributted to the analogues-calculation stage.

  2. Spectrophotometric study of the reaction mechanism between DDQ Pi- and iodine sigma-acceptors and chloroquine and pyrimethamine drugs and their determination in pure and in dosage forms.

    PubMed

    Zayed, M A; Khalil, Shaban M; El-Qudaby, Hoda M

    2005-11-01

    Two simple and accurate spectrophotometric methods are presented for the determination of anti-malarial drugs, chloroquine phosphate (CQP) and pyrimethamine (PYM), in pure and in different pharmaceutical preparations. The charge transphere (CT) reactions between CQP and PYM as electron donors and 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ) pi-acceptor and iodine sigma-acceptor reagents to give highly coloured complex species have been spectrophotometrically studied. The optimum experimental conditions have been studied carefully. Beer' law is obeyed over the concentration range of 1.0-15 microg ml(-1) for CQP and 1.0-40 microg ml(-1) for PYM using I(2) and at 5.0-53 microg ml(-1) for CQP and 1.0-46 microg ml(-1) for PYM using DDQ reagents, respectively. For more accurate results, Ringbom optimum concentration range is calculated and found to be 10-53 and 8-46 microg ml(-1) for CQP and PYM using DDQ, respectively and 5-15 and 8-40 microg ml(-1) for CQP and PYM using iodine, respectively. The Sandell sensitivity is found to be 0.038 and 0.046 g cm(-2) for DDQ method and 0.0078 and 0.056 g cm(-2) for I(2) method for CQP and PYM, respectively which indicates the high sensitivity of both methods. Standard deviation (S.D.=0.012-0.014 and 0.013-0.015) and relative standard deviation (R.S.D.=0.09-1.4 and 1.3-1.5%) (n=5) for DDQ and I(2) methods respectively, refer to the high accuracy and precision of the proposed methods. These results are also confirmed by between day precision of percent recovery of 99-100.6%, and 98-101% for CQP and PYM by DDQ method and 99-102% and 99.2-101.4% for CQP and PYM by I(2) method respectively. These data are comparable to those obtained by British and American pharmacopoeias assay for the determination of CQP and PYM in raw materials and in pharmaceutical preparations.

  3. Spectrophotometric study of the reaction mechanism between DDQ Π- and iodine σ-acceptors and chloroquine and pyrimethamine drugs and their determination in pure and in dosage forms

    NASA Astrophysics Data System (ADS)

    Zayed, M. A.; Khalil, Shaban M.; El-qudaby, Hoda M.

    2005-11-01

    Two simple and accurate spectrophotometric methods are presented for the determination of anti-malarial drugs, chloroquine phosphate (CQP) and pyrimethamine (PYM), in pure and in different pharmaceutical preparations. The charge transphere (CT) reactions between CQP and PYM as electron donors and 2,3-dichloro-5,6-dicyano- p-benzoquinone (DDQ) π-acceptor and iodine σ-acceptor reagents to give highly coloured complex species have been spectrophotometrically studied. The optimum experimental conditions have been studied carefully. Beer' law is obeyed over the concentration range of 1.0-15 μg ml -1 for CQP and 1.0-40 μg ml -1 for PYM using I 2 and at 5.0-53 μg ml -1 for CQP and 1.0-46 μg ml -1 for PYM using DDQ reagents, respectively. For more accurate results, Ringbom optimum concentration range is calculated and found to be 10-53 and 8-46 μg ml -1 for CQP and PYM using DDQ, respectively and 5-15 and 8-40 μg ml -1 for CQP and PYM using iodine, respectively. The Sandell sensitivity is found to be 0.038 and 0.046 g cm -2 for DDQ method and 0.0078 and 0.056 g cm -2 for I 2 method for CQP and PYM, respectively which indicates the high sensitivity of both methods. Standard deviation (S.D. = 0.012-0.014 and 0.013-0.015) and relative standard deviation (R.S.D. = 0.09-1.4 and 1.3-1.5%) ( n = 5) for DDQ and I 2 methods respectively, refer to the high accuracy and precision of the proposed methods. These results are also confirmed by between day precision of percent recovery of 99-100.6%, and 98-101% for CQP and PYM by DDQ method and 99-102% and 99.2-101.4% for CQP and PYM by I 2 method respectively. These data are comparable to those obtained by British and American pharmacopoeias assay for the determination of CQP and PYM in raw materials and in pharmaceutical preparations.

  4. Therapeutic efficacy of chloroquine for the treatment of Plasmodium vivax malaria among outpatients at Shawa Robit Health Care Centre, North-East Ethiopia.

    PubMed

    Seifu, Seble; Zeynudin, Ahmed; Zemene, Endalew; Suleman, Sultan; Biruksew, Abdissa

    2017-03-11

    Nearly 40% of all malaria infection in Ethiopia is caused by Plasmodium vivax. Chloroquine (CQ) is the first line treatment for confirmed P. vivax malaria in the country. However, the efficacy of this drug has been compromised by CQ resistant P. vivax (CRPv) strains. Therefore, the present study was aimed at assessing the therapeutic efficacy of CQ for treatment of P. vivax malaria at Shawa Robit Health Care Centre, North-Ease Ethiopia. A one-arm, 28-day follow-up, in vivo therapeutic efficacy study was conducted from October 2013 to February 2014. Eighty-seven patients with microscopically confirmed P. vivax mono - infection aged between 1 and 65 years were enrolled and treated with a 25mg/kg CQ administered for three consecutive days under supervision. Socio-demographic and clinical information were collected. Blood smears were prepared and examined for parasite clearance or recurrence of parasitaemia. Clinical examination was performed at all follow-up visits. Haematocrit determination was made. Percentages, frequencies, Kaplan-Meier survival probability analysis and statistical associations were computed. P-value of <0.05 was considered statistically significant. From the total 87 patients included in the study 76 (87.4%) completed their 28-day follow-up; four patients were excluded due to P. falciparum infection during the follow up (on day 2, day 7 and day 14) and seven cases were lost to follow-up (on day 3, day 7 and day 14). Among those P. vivax infected individuals, 44 (50.6%) subjects were febrile on day of admission and the remaining had history of fever. From the 76 study participants who completed the 28-day follow up period, late parasitological failure (LPF) was observed in five (6.6%) cases. The geometric mean of parasite density was 8723.9/μl and mean haematocrit value was 35.45%. Besides, survival analysis showed that the cumulative incidence of success and failure rates at day 28 was 93.4% (95% CI=0.849-0.972) and 7.04% (95% CI=0

  5. Linkage disequilibrium between two distinct loci in chromosomes 5 and 7 of Plasmodium falciparum and in vivo chloroquine resistance in Southwest Nigeria.

    PubMed

    Happi, C T; Gbotosho, G O; Folarin, O A; Sowunmi, A; Bolaji, O M; Fateye, B A; Kyle, D E; Milhous, W; Wirth, D F; Oduola, A M J

    2006-12-01

    Chloroquine (CQ) resistance in Plasmodium falciparum is associated with polymorphisms in loci on pfcrt and pfmdr1 genes. In this study, we determined the association and linkage disequilibrium between in vivo CQ resistance and P. falciparum polymorphisms in pfcrt gene at codon 76 and pfmdr1 gene at codon 86 in isolates obtained from 111 children with acute uncomplicated falciparum malaria in Nigeria. Patients were treated with standard dosage of CQ and followed up for 28 days. Filter paper samples were collected at enrollment and during follow-up for parasites genotypes and identification of pfcrt and pfmdr1 mutations. Association and linkage disequilibrium between mutant pfcrtT76 and pfmdr1Y86 alleles in pretreatment isolates of P. falciparum was determined. Fifty-five out of the 111 patients (49.5%) failed treatment. Single mutant pfcrtT76 or pfmdr1Y86 alleles were found in 55 out of 111 P. falciparum isolates screened at enrollment. Of these 55 isolates, the mutant pfcrtT76 and pfmdr1Y86 alleles were found in 84%. Both mutant pfcrtT76 (p=0.0196) and pfmdr1Y86 (p=0.000042) alleles were associated with in vivo CQ resistance. In addition, the mutant pfcrtT76 (p=0.047) and pfmdr1Y86 (p=0.006) alleles were significantly selected by CQ in patients who failed treatment. Association analysis between paired single alleles at pfcrt and pfmdr1 loci showed a significant association (p=0.0349 and chi(2)=4.45) between the pfcrt T76 allele on chromosome 7 and the pfmdr1Y86 allele on chromosome 5 and that these two mutant alleles were in linkage disequilibrium (p=0.000, D'=0.64, and r(2)=0.28). Considering the high level of CQ resistance and drug use in the study area, the observed linkage disequilibrium between the mutant pfcrtT76 and pfmdr1Y86 alleles is maintained epistatically through directional CQ selective pressure.

  6. Phase II randomized, double-blind, placebo-controlled study of whole-brain irradiation with concomitant chloroquine for brain metastases

    PubMed Central

    2013-01-01

    Background and purpose Chloroquine (CLQ), an antimalarial drug, has a lysosomotropic effect associated with increased radiationsensibility, which is mediated by the leakage of hydrolytic enzymes, increased apoptosis, autophagy and increased oxidative stress in vitro. In this phase II study, we evaluated the efficacy and safety of radiosensibilization using CLQ concomitant with 30 Gray (Gy) of whole-brain irradiation (WBI) to treat patients with brain metastases (BM) from solid tumors. Methods Seventy-three eligible patients were randomized. Thirty-nine patients received WBI (30 Gy in 10 fractions over 2 weeks) concomitant with 150 mg of CLQ for 4 weeks (the CLQ arm). Thirty-four patients received the same schedule of WBI concomitant with a placebo for 4 weeks (the control arm). All the patients were evaluated for quality of life (QoL) using the EORTC Quality of Life (QoL) Questionnaire (EORTC QLQ-C30) (Mexican version) before beginning radiotherapy and one month later. Results The overall response rate (ORR) was 54% for the CLQ arm and 55% for the control arm (p=0.92). The progression-free survival of brain metas