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Sample records for chloroquine analogues influence

  1. Recycling antimalarial leads for cancer: Antiproliferative properties of N-cinnamoyl chloroquine analogues.

    PubMed

    Pérez, Bianca C; Fernandes, Iva; Mateus, Nuno; Teixeira, Cátia; Gomes, Paula

    2013-12-15

    Cinnamic acids and quinolines are known as useful scaffolds in the discovery of antitumor agents. Therefore, N-cinnamoylated analogues of chloroquine, recently reported as potent dual-action antimalarials, were evaluated against three different cancer cell lines: MKN-28, Caco-2, and MCF-7. All compounds display anti-proliferative activity in the micromolar range against the three cell lines tested, and most of them were more active than their parent drug, chloroquine, against all cell lines tested. Hence, N-cinnamoyl-chloroquine analogues are a good start towards development of affordable antitumor leads. PMID:24184076

  2. 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.

  3. [Chloroquine influence on lipid metabolism and selected laboratory parameters].

    PubMed

    Woźniacka, Anna; Lesiak, Aleksandra; Smigielski, Janusz; Sysa-Jedrzejowska, Anna

    2005-01-01

    Systemic lupus erythematosus (SLE) is an autoimmune connective tissue disease with complex pathogenesis, various clinical presentation and chronic course with relapses. Mode of treatment depends on the disease activity and kind of internal organ involvement. In most cases clinical remission could be obtained after antimalarials, nonsteroidal anti-inflammatory drugs, corticosteroids, and photoprotection use. Despite the approved antimalarials therapeutic value, the mechanisms by which they provide benefit in lupus, patients are not fully understood. Literature data indicate that they can influence lipid metabolism. The aim of the performed study was the objective evaluation of the influence of 3-month chloroquine treatment (Arechin, 250 mg/day) on lipid metabolism and selected laboratory parameters. In 34 patients with SLE clinical and laboratory evaluation was performed twice, before and after 3-month treatment. After 3 months significantly lower total cholesterol level was observed (mean value 184.91 mg%, 165.26 mg%, p < 0.001). Also LDL level was evidently lowered (111.27 mg%, 99.25 mg%). Similar tendency was noticed in triglycerides, which level after 3 months decreased from the average 152.38 mg% to 104.97 mg%, p < 0.001. Moreover the lowering of sedimentation rate, increasing hemoglobin level and lengthening coagulation time was perceived. The results of the study indicate the influence of chloroquine on decreasing of the disease activity, its anti-inflammatory properties and mainly the drug impact on lipid metabolism. Not only does antimalarials treatment reduce the risk of atherosclerosis development but it also minimizes corticosteroids side effects, which are considered to be the basic medication in lupus patients. PMID:16541717

  4. Investigating the activity of quinine analogues vs. chloroquine resistant Plasmodium falciparum

    PubMed Central

    Dinio, Theresa; Gorka, Alexander P.; McGinniss, Andrew; Roepe, Paul D.; Morgan, Jeremy B.

    2012-01-01

    Plasmodium falciparum, the deadliest malarial parasite species, has developed resistance against nearly all man-made antimalarial drugs within the past century. However, quinine (QN), the first antimalarial drug, remains efficacious worldwide. Some chloroquine resistant (CQR) P. falciparum strains or isolates show mild cross resistance to QN, but many do not. Further optimization of QN may provide well-tolerated therapy with improved activity vs. CQR malaria. Thus, using the Heck reaction, we have pursued a structure-activity relationship study, including vinyl group modifications of QN. Certain derivatives show good antiplasmodial activity in QN-resistant and QN-sensitive strains, with lower IC50 values relative to QN. PMID:22512909

  5. Antimalarial activity of ruthenium(II) and osmium(II) arene complexes with mono- and bidentate chloroquine analogue ligands.

    PubMed

    Ekengard, Erik; Glans, Lotta; Cassells, Irwin; Fogeron, Thibault; Govender, Preshendren; Stringer, Tameryn; Chellan, Prinessa; Lisensky, George C; Hersh, William H; Doverbratt, Isa; Lidin, Sven; de Kock, Carmen; Smith, Peter J; Smith, Gregory S; Nordlander, Ebbe

    2015-11-28

    Eight new ruthenium and five new osmium p-cymene half-sandwich complexes have been synthesized, characterized and evaluated for antimalarial activity. All complexes contain ligands that are based on a 4-chloroquinoline framework related to the antimalarial drug chloroquine. Ligands HL(1-8) are salicylaldimine derivatives, where HL(1) = N-(2-((2-hydroxyphenyl)methylimino)ethyl)-7-chloroquinolin-4-amine, and HL(2-8) contain non-hydrogen substituents in the 3-position of the salicylaldimine ring, viz. F, Cl, Br, I, NO2, OMe and (t)Bu for HL(2-8), respectively. Ligand HL(9) is also a salicylaldimine-containing ligand with substitutions in both 3- and 5-positions of the salicylaldimine moiety, i.e. N-(2-((2-hydroxy-3,5-di-tert-butylphenyl)methyl-imino)ethyl)-7-chloroquinolin-4-amine, while HL(10) is N-(2-((1-methyl-1H-imidazol-2-yl)methylamino)ethyl)-7-chloroquinolin-4-amine) The half sandwich metal complexes that have been investigated are [Ru(η(6)-cym)(L(1-8))Cl] (Ru-1-Ru-8, cym = p-cymene), [Os(η(6)-cym)(L(1-3,5,7))Cl] (Os-1-Os-3, Os-5, and Os-7), [M(η(6)-cym)(HL(9))Cl2] (M = Ru, Ru-HL(9); M = Os, Os-HL(9)) and [M(η(6)-cym)(L(10))Cl]Cl (M = Ru, Ru-10; M = Os, Os-10). In complexes Ru-1-Ru-8 and Ru-10, Os-1-Os-3, Os-5 and Os-7 and Os-10, the ligands were found to coordinate as bidentate N,O- and N,N-chelates, while in complexes Ru-HL(9) and Os-HL(9), monodentate coordination of the ligands through the quinoline nitrogen was established. The antimalarial activity of the new ligands and complexes was evaluated against chloroquine sensitive (NF54 and D10) and chloroquine resistant (Dd2) Plasmodium falciparum malaria parasite strains. Coordination of ruthenium and osmium arene moieties to the ligands resulted in lower antiplasmodial activities relative to the free ligands, but the resistance index is better for the ruthenium complexes compared to chloroquine. Overall, osmium complexes appeared to be less active than the corresponding ruthenium complexes. PMID:26491831

  6. 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.

  7. Influence of LAR and VAR on Para-Aminopyridine Antimalarials Targetting Haematin in Chloroquine-Resistance

    PubMed Central

    Warhurst, David C.; Craig, John C.

    2016-01-01

    Antimalarial chloroquine (CQ) prevents haematin detoxication when CQ-base concentrates in the acidic digestive vacuole through protonation of its p-aminopyridine (pAP) basic aromatic nitrogen and sidechain diethyl-N. CQ export through the variant vacuolar membrane export channel, PFCRT, causes CQ-resistance in Plasmodium falciparum but 3-methyl CQ (sontochin SC), des-ethyl amodiaquine (DAQ) and bis 4-aminoquinoline piperaquine (PQ) are still active. This is determined by changes in drug accumulation ratios in parasite lipid (LAR) and in vacuolar water (VAR). Higher LAR may facilitate drug binding to and blocking PFCRT and also aid haematin in lipid to bind drug. LAR for CQ is only 8.3; VAR is 143,482. More hydrophobic SC has LAR 143; VAR remains 68,523. Similarly DAQ with a phenol substituent has LAR of 40.8, with VAR 89,366. In PQ, basicity of each pAP is reduced by distal piperazine N, allowing very high LAR of 973,492, retaining VAR of 104,378. In another bis quinoline, dichlorquinazine (DCQ), also active but clinically unsatisfactory, each pAP retains basicity, being insulated by a 2-carbon chain from a proximal nitrogen of the single linking piperazine. While LAR of 15,488 is still high, the lowest estimate of VAR approaches 4.9 million. DCQ may be expected to be very highly lysosomotropic and therefore potentially hepatotoxic. In 11 pAP antimalarials a quadratic relationship between logLAR and logResistance Index (RI) was confirmed, while log (LAR/VAR) vs logRI for 12 was linear. Both might be used to predict the utility of structural modifications. PMID:27483471

  8. Influence of LAR and VAR on Para-Aminopyridine Antimalarials Targetting Haematin in Chloroquine-Resistance.

    PubMed

    Warhurst, David C; Craig, John C; Raheem, K Saki

    2016-01-01

    Antimalarial chloroquine (CQ) prevents haematin detoxication when CQ-base concentrates in the acidic digestive vacuole through protonation of its p-aminopyridine (pAP) basic aromatic nitrogen and sidechain diethyl-N. CQ export through the variant vacuolar membrane export channel, PFCRT, causes CQ-resistance in Plasmodium falciparum but 3-methyl CQ (sontochin SC), des-ethyl amodiaquine (DAQ) and bis 4-aminoquinoline piperaquine (PQ) are still active. This is determined by changes in drug accumulation ratios in parasite lipid (LAR) and in vacuolar water (VAR). Higher LAR may facilitate drug binding to and blocking PFCRT and also aid haematin in lipid to bind drug. LAR for CQ is only 8.3; VAR is 143,482. More hydrophobic SC has LAR 143; VAR remains 68,523. Similarly DAQ with a phenol substituent has LAR of 40.8, with VAR 89,366. In PQ, basicity of each pAP is reduced by distal piperazine N, allowing very high LAR of 973,492, retaining VAR of 104,378. In another bis quinoline, dichlorquinazine (DCQ), also active but clinically unsatisfactory, each pAP retains basicity, being insulated by a 2-carbon chain from a proximal nitrogen of the single linking piperazine. While LAR of 15,488 is still high, the lowest estimate of VAR approaches 4.9 million. DCQ may be expected to be very highly lysosomotropic and therefore potentially hepatotoxic. In 11 pAP antimalarials a quadratic relationship between logLAR and logResistance Index (RI) was confirmed, while log (LAR/VAR) vs logRI for 12 was linear. Both might be used to predict the utility of structural modifications. PMID:27483471

  9. Experimental chloroquine retinopathy.

    PubMed

    Matsumura, M; Ohkuma, M; Tsukahara, I

    1986-01-01

    Chloroquine retinopathy was produced experimentally in the eye of the albino corydoras (one of the tropical fish) by daily administration of chloroquine (0.1 mg per os). The enucleated eyes were examined from the 14th day to 3 months after the beginning of drug administration under light and electron microscopy. The first change of retina was the appearance of membraneous cytoplasmic body (MCB) in the cytoplasm of ganglion, amacrine, bipolar and horizontal cells. MCB might be degenerated lysosome. They showed lamellar figures or crystalline lattice-like structures. Secondarily, these MCB appeared in the inner segments of photoreceptor cells. The outer segments of rod cells disappeared, and then those of cone cells. Although photoreceptor cells were diminished in number in advanced degeneration, the cells of inner nuclear layer and ganglion cells were maintained in number. The presence of MCB dose not mean death of cells. The retinal pigment epithelial cells contained MCB in its cytoplasm only in severe degenerative cases, and did not show other remarkable changes. MCB also appeared in the cytoplasm of pericytes of retinal vessels. Chloroquine is considered to damage directly photoreceptor cells most severely. PMID:3018650

  10. 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.

  11. 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

  12. 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. PMID:20504815

  13. Effects of chloroquine on the adrenocortical function. II. Histological, histochemical and biochemical changes in the suprarenal gland of rats on long-term administration of chloroquine.

    PubMed

    Grundmann, M; Bayer, A

    1976-01-01

    White female Wistar rats were used in order to study the influence of long-term oral application of 7-chloro-4-(4-diethylamino-1-methylbutylamino) quinoline (chloroquine) in doses of 30, 40 and 80 mg of base/kg upon the suprarenal gland. Histological, histochemical and biochemical findings give evidence of adrenocortical activation induced by chloroquine at all dose levels tested. The differences between the signs of adrenocortical activation as observed after the various doses were only those of quantity and time onset. The results indicate that the stimulation of the suprarenal cortex produced by repeated administration of chloroquine is not solely a manifestation of toxic action of chloroquine.

  14. Research influence on antimalarial drug policy change in Tanzania: case study of replacing chloroquine with sulfadoxine-pyrimethamine as the first-line drug

    PubMed Central

    Mubyazi, Godfrey M; Gonzalez-Block, Miguel A

    2005-01-01

    Introduction Research is an essential tool in facing the challenges of scaling up interventions and improving access to services. As in many other countries, the translation of research evidence into drug policy action in Tanzania is often constrained by poor communication between researchers and policy decision-makers, individual perceptions or attitudes towards the drug and hesitation by some policy decision-makers to approve change when they anticipate possible undesirable repercussions should the policy change as proposed. Internationally, literature on the role of researchers on national antimalarial drug policy change is limited. Objectives To describe the (a) role of researchers in producing evidence that influenced the Tanzanian government replace chloroquine (CQ) with sulfadoxine-pyrimethamine (SP) as the first-line drug and the challenges faced in convincing policy-makers, general practitioners, pharmaceutical industry and the general public on the need for change (b) challenges ahead before a new drug combination treatment policy is introduced in Tanzania. Methods In-depth interviews were held with national-level policy-makers, malaria control programme managers, pharmaceutical officers, general medical practitioners, medical research library and publications officers, university academicians, heads of medical research institutions and district and regional medical officers. Additional data were obtained through a review of malaria drug policy documents and participant observations were also done. Results In year 2001, the Tanzanian Government officially changed its malaria treatment policy guidelines whereby CQ – the first-line drug for a long time was replaced with SP. This policy decision was supported by research evidence indicating parasite resistance to CQ and clinical CQ treatment failure rates to have reached intolerable levels as compared to SP and amodiaquine (AQ). Research also indicated that since SP was also facing rising resistance trend

  15. Conformationally restricted (+)-cacospongionolide B analogues. Influence on secretory phospholipase A2 inhibition.

    PubMed

    Murelli, Ryan P; Cheung, Atwood K; Snapper, Marc L

    2007-03-01

    A new approach to (+)-cacospongionolide was developed to access conformationally restricted variants of the natural product. The flexible aliphatic region between the decalin and side chain portion of the natural product was replaced with alkenyl and alkynyl linkers to probe the influence of structural rigidity in the inhibition of secretary phospholipase A2 (sPLA2). It was found that when the aliphatic section is replaced with a Z-olefin or an alkyne, sPLA2 inhibitory activity suffered relative to the natural product; however, an E-olefin-containing analogue led to an enhanced activity. These results suggest that preferred sPLA2 binding conformation of the natural product is similar to the geometry of the E-olefin-containing analogue.

  16. Chloroquine impairs visual transduction via modulation of acid sensing ion channel 1a.

    PubMed

    Li, Xiaoyu; Fei, Jianchun; Lei, Zhen; Liu, Kejing; Wu, Jianbo; Meng, Tao; Yu, Jingui; Li, Jingxin

    2014-08-01

    Acid-sensing ion channels (ASICs) are extracellular pH sensors activated by protons, which influence retinal activity and phototransduction. Among all ASICs, ASIC1a is abundantly expressed in the retina and involved in normal retinal activity. Chloroquine, which has been used in the treatment of malaria, rheumatoid arthritis and systemic lupus erythematosus, has been shown to be toxic to the retina. However, the underlying mechanisms remain unclear. In this study, we investigated the role of chloroquine in phototransduction by measuring the electroretinogram (ERG). The effect of chloroquine on acid-evoked currents in either isolated rat retinal ganglion neurons (RGNs) or Chinese hamster ovary (CHO) cells transfected with ASIC1a were assessed using a whole-cell patch-clamp technique. Chloroquine reduced the b-wave of scotopic 0.01 and photopic 3.0 and amplitudes of oscillatory potentials (OPs), an effect which was almost completely reversed by PcTx1, an ASIC1a-specific channel blocker. Further, patch-clamp experiments demonstrated that chloroquine reduced the peak current amplitude and prolonged the activation and desensitization of ASIC1a currents. These chloroquine-induced effects on the kinetics of ASIC 1a were dose-, pH- and Ca(2+)-dependent. Taken together, these results demonstrate that chloroquine affects vision conduction by directly modifying the kinetics of ASIC1a. Such a mechanism, may, in part, explain the retinal toxicity of chloroquine.

  17. 3-Halo Chloroquine Derivatives Overcome Plasmodium falciparum Chloroquine Resistance Transporter-Mediated Drug Resistance in P. falciparum.

    PubMed

    Edaye, Sonia; Tazoo, Dagobert; Bohle, D Scott; Georges, Elias

    2015-12-01

    Polymorphism in the Plasmodium falciparum chloroquine resistance transporter (PfCRT) was shown to cause chloroquine resistance. In this report, we examined the antimalarial potential of novel 3-halo chloroquine derivatives (3-chloro, 3-bromo, and 3-iodo) against chloroquine-susceptible and -resistant P. falciparum. All three derivatives inhibited the proliferation of P. falciparum; with 3-iodo chloroquine being most effective. Moreover, 3-iodo chloroquine was highly effective at potentiating and reversing chloroquine toxicity of drug-susceptible and -resistant P. falciparum.

  18. Antifungal activity of eugenol analogues. Influence of different substituents and studies on mechanism of action.

    PubMed

    Carrasco, Héctor; Raimondi, Marcela; Svetaz, Laura; Di Liberto, Melina; Rodriguez, María V; Espinoza, Luis; Madrid, Alejandro; Zacchino, Susana

    2012-01-19

    Twenty one phenylpropanoids (including eugenol and safrole) and synthetic analogues, thirteen of them new compounds, were evaluated for antifungal properties, first with non-targeted assays against a panel of human opportunistic pathogenic fungi. Some structure-activity relationships could be observed, mainly related to the influence of an allyl substituent at C-4, an OH group at C-1 and an OCH(3) at C-2 or the presence of one or two NO(2) groups in different positions of the benzene ring. All active compounds were tested in a second panel of clinical isolates of C. albicans and non-albicans Candida spp., Cryptococcus neoformans and dermatophytes. The eugenol derivative 4-allyl-2-methoxy-5-nitrophenol (2) was the most active structure against all strains tested, and therefore it was submitted to targeted assays. These studies showed that the antifungal activity of 2 was not reversed in the presence of an osmotic support such as sorbitol, suggesting that it does not act by inhibiting the fungal cell wall synthesis or assembly. On the other hand, the Ergosterol Assay showed that 2 did not bind to the main sterol of the fungal membrane up to 250 µg mL-1. In contrast, a 22% of fungal membrane damage was observed at concentrations = 1 × MIC and 71% at 4× MIC, when 2 was tested in the Cellular Leakage assay. The comparison of log P and MICs for all compounds revealed that the antifungal activity of the eugenol analogues would not to be related to lipophilicity.

  19. Influence of methane concentration on the optical indices of Titan's aerosols analogues

    NASA Astrophysics Data System (ADS)

    Mahjoub, A.; Dahoo, P. R.; Gautier, T.; Carrasco, N.; Szopa, C.; Cernogora, G.

    2012-04-01

    Titan’s haze is one of the main drivers of the radiative transfer in the atmosphere of Titan and strongly influences its thermal structure (Rannou et al.2010). In Titan’s atmosphere, CH4 concentration may have varied through time during the evolution of this planet (Atreya et al. 2006). So it is of utmost importance to determine the optical constants of tholins synthesized from N2-CH4 mixtures with different CH4 concentration to understand the evolution of Titan atmosphere through time. This work deals with the optical constant characterization of Titan aerosol analogues produced with a radio frequency experimental setup and deposited as thin films onto a silicon substrate (Mahjoub et al. 2012). Tholins were produced in different N2-CH4 gaseous mixtures to study the effect of the initial methane concentration on their optical constants. The real and imaginary parts of the complex refractive index were determined using the spectroscopic ellipsometry in the 0.37-1 µm range. We find that optical indices depend strongly on the methane concentrations of the gas phase: imaginary index (k) decreases by an order of magnitude with initial CH4 concentration at 1 µm wavelength, while the real index (n) increases from 1.48 up to 1.56 at 1 µm wavelength. The larger absorption in the visible range of tholins produced at lower methane percentage is explained by an increase of amines signatures in tholins, measured by absorption spectroscopy in the mid-IR range. According to the methane concentration in Titan’s atmosphere, the evolution of the visible optical signature of Titan’s aerosols may have influenced very differently Titan’s climate through time. References: Atreya et al., Titan’s methane cycle, PSS, vol 54, 1177-1187 Mahjoub et al., Influence of methane concentration on the optical indices of Titan’s aerosols analogues submitted to ICARUS Rannou et al. Titan haze distribution and optical properties retrieved from recent observations, Icarus, 208, 850-867.

  20. Synthesis and biological evaluation of febrifugine analogues.

    PubMed

    Mai, Huong Doan Thi; Thanh, Giang Vo; Tran, Van Hieu; Vu, Van Nam; Vu, Van Loi; Le, Cong Vinh; Nguyen, Thuy Linh; Phi, Thi Dao; Truong, Bich Ngan; Chau, Van Minh; Pham, Van Cuong

    2014-12-01

    A series of febrifugine analogues were designed and synthesized. Antimalarial activity evaluation of the synthetic compounds indicated that these derivatives had a strong inhibition against both chloroquine-sensitive and -resistant Plasmodium falciparum parasites. Many of them were found to be more active than febrifugine hydrochloride. The tested analogues had also a significant cytotoxicity against four cancer cell lines (KB, MCF7, LU1 and HepG2). Among the synthetic analogues, two compounds 17b and 17h displayed a moderate cytotoxicity while they exhibited a remarkable antimalarial activity. PMID:25632466

  1. Determination of chloroquine and monodesethylchloroquine in hair.

    PubMed

    Viala, A; Deturmeny, E; Aubert, C; Estadieu, M; Durand, A; Cano, J P; Delmont, J

    1983-10-01

    Using thin-layer and gas chromatography and mass spectrometry, chloroquine and its major metabolite (monodesethylchloroquine) were identified in hair samples of numerous patients who received this antimalarial drug for several months. In two patients the amounts of chloroquine were, respectively, 310 and 145 mg/kg hair and those of the monodesethylchloroquine 23 and 11 mg/kg. The respective proportions (93 and 7%) are the same in the two subjects. The chloroquine percentage was near those in the spleen or stomach wall after poisoning. Other metabolites in hair are being identified. Hair analysis may provide a good toxicologic and forensic science complement to the blood, urine, and tissues. It may be useful for the control of chloroquine therapy. PMID:6631371

  2. 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

  3. 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

  4. Structural influences on preferential oxazolone versus diketopiperazine b(2+) ion formation for histidine analogue-containing peptides.

    PubMed

    Gucinski, Ashley C; Chamot-Rooke, Julia; Nicol, Edith; Somogyi, Árpád; Wysocki, Vicki H

    2012-05-01

    Studies of peptide fragment ion structures are important to aid in the accurate kinetic modeling and prediction of peptide fragmentation pathways for a given sequence. Peptide b(2)(+) ion structures have been of recent interest. While previously studied b(2)(+) ions that contain only aliphatic or simple aromatic residues are oxazolone structures, the HA b(2)(+) ion consists of both oxazolone and diketopiperazine structures. The structures of a series of histidine-analogue-containing Xxx-Ala b(2)(+) ions were studied by using action infrared multiphoton dissociation (IRMPD) spectroscopy, fragment ion hydrogen-deuterium exchange (HDX), and density functional theory (DFT) calculations to systematically probe the influence of different side chain structural elements on the resulting b(2)(+) ion structures formed. The b(2)(+) ions studied include His-Ala (HA), methylated histidine analogues, including π-methyl-HA and τ-methyl-HA, pyridylalanine (pa) analogues, including 2-(pa)A, 3-(pa)A, and 4-(pa)A, and linear analogues, including diaminobutanoic acid-Ala (DabA) and Lys-Ala (KA). The location and accessibility of the histidine π-nitrogen, or an amino nitrogen on an aliphatic side chain, were seen to be essential for diketopiperazine formation in addition to the more typical oxazolone structure formation, while blocking or removal of the τ-nitrogen did not change the b(2)(+) ion structures formed. Linear histidine analogues, DabA and KA, formed only diketopiperazine structures, suggesting that a steric interaction in the HisAla case may interfere with the complete trans-cis isomerization of the first amide bond that is necessary for diketopiperazine formation.

  5. 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.

  6. Single dose disposition of chloroquine in kwashiorkor and normal children--evidence for decreased absorption in kwashiorkor.

    PubMed

    Walker, O; Dawodu, A H; Salako, L A; Alván, G; Johnson, A O

    1987-04-01

    The single dose disposition of chloroquine was studied in five children with kwashiorkor and six normal control children after an oral dose of 10 mg kg-1 of chloroquine base. Plasma concentrations of chloroquine and its main metabolite were assayed by high performance liquid chromatography (h.p.l.c.). Chloroquine was detectable for up to 21 days in all the subjects. Chloroquine was detectable in all the subjects within 30 min after giving the drug except in one subject. Peak levels were reached between 0.5 and 8 h in all the subjects (with no significant difference in the tmax between the two groups of children). Peak plasma chloroquine concentrations in the children with kwashiorkor varied from 9 ng ml-1 to 95 ng ml-1 (mean 40 +/- 34 ng ml-1). Peak chloroquine concentrations in the controls varied between 69 ng ml-1 and 330 ng ml-1 (mean 134 +/- 99 ng ml-1). The mean AUC in the kwashiorkor children was significantly lower than the mean AUC in the control children (P less than 0.001). Peak plasma desethylchloroquine concentrations in the children with kwashiorkor varied between 3 and 13 ng ml-1 (mean 6 +/- 9 ng ml-1) while in the controls the concentrations varied between 14 and 170 ng ml-1 (mean 50 +/- 61 ng ml-1). There was no significant difference in the half-life of chloroquine between the kwashiorkor children and the normal control children. The possible influence of a different binding and distribution pattern of chloroquine in kwashiorkor could not be assessed in this study.(ABSTRACT TRUNCATED AT 250 WORDS)

  7. Chloroquine cardiomyopathy: beyond ocular adverse effects

    PubMed Central

    Lopez-Ruiz, Nilson; Uribe, Carlos Esteban

    2014-01-01

    A 36-year-old woman who had received long-term treatment with chloroquine for systemic lupus erythematosus developed a third degree atrioventricular block and required a permanent pacemaker. Notably, left ventricular thickening and mild systolic dysfunction were noticed on echocardiography as well as on cardiac MRI. As there was no clear explanation for myocardial findings, the patient underwent an endomyocardial biopsy that demonstrated vacuolar degeneration of myocytes on light microscopy and curvilinear bodies on electron microscopy, both findings consistent with chloroquine toxicity. The drug was withheld and treatment with candesartan and carvedilol was prescribed. At 2-year follow-up, the patient remained asymptomatic and left ventricular systolic function had improved. Physicians who prescribe antimalarial drugs for rheumatic diseases should be aware of the potentially life-threatening effects of chloroquine on the heart. PMID:25225192

  8. 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.

  9. Chloroquine resistance of Plasmodium berghei: biochemical basis and countermeasures*

    PubMed Central

    Salganik, R. I.; Pankova, T. G.; Chekhonadskikh, T. V.; Igonina, T. M.

    1987-01-01

    Microsomal monooxygenases, enzymes that metabolize xenobiotics, may be responsible for the chloroquine resistance of malarial parasites. Plasmodium cells contain cytochrome P-450 and exhibit aryl hydrocarbon hydroxylase and aminopyrine N-dimethylase activity, two monooxygenases that inactivate chloroquine. The activities of these monooxygenases are considerably higher in chloroquine-resistant strains of Plasmodium berghei than in the chloroquine-sensitive strain of the parasite. Inhibitors of microsomal monooxygenases have the potential to overcome the chloroquine resistance of Plasmodium spp., and, of those inhibitors tested, the copper-lysine complex, copper(lysine)2, was the most effective. PMID:3117393

  10. The influence of fluorinated molecules (semiochemicals and enzyme substrate analogues) on the insect communication system.

    PubMed

    Pesenti, Cristina; Viani, Fiorenza

    2004-05-01

    Can the introduction of fluorine atoms affect the bioactivity of natural semiochemicals? Can fluorine contribute in the creation of specific enzyme inhibitors to interrupt or disrupt the insect communication system? The first step for the bioactivity of a molecule is interaction with the biological sensor. Hydrogen and fluorine are almost bioisosteric and the receptor site of the enzyme can still recognize and accept the fluoro analogue of its natural substrate. However, the peculiar electronegativity of the fluorine atom can affect the binding, absorption, and transport of the molecule. The differences in the molecule's electronic properties can lead to differences in the chemical interactions between the receptor and the fluorinated substrate. Fluorine introduction can modify the metabolic stability and pathway of the semiochemicals in many different ways. Fluorinated analogues can show synergism, inhibition, or hyperagonism effects on insect behaviors, that is, the activity of the nonfluorinated parent compounds can be mimicked, lost, or increased. In any case, the fluorinated molecules can interact with the bioreceptors in a new and disrupting way. The semiochemicals are olfactory substances: fluorine can affect their volatility or smell. Production of semiochemicals from exogenous substances, perception at antennal receptors, and processing of biological responses are the main steps of communication among insects. In the production step, the fluorinated molecules can interact with enzymes that catalyze the biosynthesis of the natural pheromones. In the perception step, fluorinated semiochemicals can interact with the olfactory receptor cells; this often leads to totally unpredictable behaviors. Fluorinated molecules have been developed as probes to elucidate the complex chemorecognition processes of insects. Many of these molecules have been tested to find highly effective behavior-modifying chemicals. New analogues have been synthesized to investigate the

  11. 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

  12. Structural differences in diarylheptanoids analogues from Alnus viridis and Alnus glutinosa influence their activity and selectivity towards cancer cells.

    PubMed

    Dinić, Jelena; Novaković, Miroslav; Podolski-Renić, Ana; Vajs, Vlatka; Tešević, Vele; Isaković, Aleksandra; Pešić, Milica

    2016-04-01

    Diarylheptanoids represent a group of plant secondary metabolites that possess multiple biological properties and are increasingly recognized for their therapeutic potential. A comparative study was performed on structurally analogous diarylheptanoids isolated from the bark of green (Alnus viridis) and black alder (Alnus glutinosa) to address their biological effects and determine structure-activity relationship. The structures and configurations of all compounds were elucidated by NMR, HR-ESI-MS, UV and IR. Diarylheptanoids actions were studied in human non-small cell lung carcinoma cells (NCI-H460) and normal keratinocytes (HaCaT). A. viridis compounds 3v, 5v, 8v and 9v that possess a carbonyl group at C-3 were considerably more potent than compounds without this group. A. viridis/A. glutinosa analogue pairs, 5v/5g and 9v/9g, which differ in the presence of 3' and 3″-OH groups, were evaluated for anticancer activity and selectivity. 5v and 9v that do not possess 3' and 3″-OH groups showed significantly higher cytotoxicity compared to analogues 5g and 9g. In addition, these two A. viridis compounds induced a more prominent apoptosis in both cell lines and an increase in subG0 cell cycle phase, compared to their A. glutinosa analogues. 5v and 9v treatment triggered intracellular superoxide anion accumulation and notably decreased mitochondrial transmembrane potential. In HaCaT cells, 9v and 9g with a 4,5 double bond caused a more prominent loss of mitochondrial transmembrane potential compared to 5v and 5g which possess a 5-methoxy group instead. Although green alder diarylheptanoids 5v and 9v displayed higher cytotoxicity, their analogues from black alder 5g and 9g could be more favorable for therapeutic use since they were more active in cancer cells than in normal keratinocytes. These results indicate that minor differences in the chemical structure can greatly influence the effect of diarylheptanoids on apoptosis and redox status and determine their

  13. Phosphonic analogues of tyrosine and 3,4-dihydroxyphenylalanine (dopa) influence mushroom tyrosinase activity.

    PubMed

    Lejczak, B; Kafarski, P; Makowiecka, E

    1987-02-15

    A series of phosphonic analogues of tyrosine and 3,4-dihydroxyphenylalanine (dopa) were synthesized in order to study their interaction with mushroom tyrosinase. 1-Amino-2-(3,4-dihydroxyphenyl)ethylphosphonic acid and 1-amino-2-(3,4-dimethoxyphenyl)ethylphosphonic acid turned out to be substrates for mushroom tyrosinase with Km values of 3.3 mM and 9.3 mM respectively. Shortening of the alkyl chain by one methylene group gave amino-(3,4-dihydroxyphenyl)methylphosphonic acid, one of the most powerful known inhibitors of this enzyme. This compound, racemic as well as in its optically active forms, exerts a mixed type of inhibition with an affinity for the enzyme one order of magnitude greater than that of the natural substrate. PMID:3109385

  14. Phosphonic analogues of tyrosine and 3,4-dihydroxyphenylalanine (dopa) influence mushroom tyrosinase activity.

    PubMed Central

    Lejczak, B; Kafarski, P; Makowiecka, E

    1987-01-01

    A series of phosphonic analogues of tyrosine and 3,4-dihydroxyphenylalanine (dopa) were synthesized in order to study their interaction with mushroom tyrosinase. 1-Amino-2-(3,4-dihydroxyphenyl)ethylphosphonic acid and 1-amino-2-(3,4-dimethoxyphenyl)ethylphosphonic acid turned out to be substrates for mushroom tyrosinase with Km values of 3.3 mM and 9.3 mM respectively. Shortening of the alkyl chain by one methylene group gave amino-(3,4-dihydroxyphenyl)methylphosphonic acid, one of the most powerful known inhibitors of this enzyme. This compound, racemic as well as in its optically active forms, exerts a mixed type of inhibition with an affinity for the enzyme one order of magnitude greater than that of the natural substrate. PMID:3109385

  15. Interaction between chloroquine and diverse pharmacological agents in chloroquine resistant Plasmodium yoelii nigeriensis.

    PubMed

    Singh, N; Puri, S K

    2000-11-01

    The effect of a number of pharmacological agents on the enhancement of antimalarial activity of chloroquine was evaluated against chloroquine resistant line of Plasmodium yoelii nigeriensis (N-67). The response after combination therapy was monitored on the basis of alteration in the course of parasitaemia, the extension of mean survival time and the percent cure rate in different groups. The study was designed to compare the in vivo efficacy of a number of resistance modulating agents found effective in several in vitro studies against chloroquine resistant P. falciparum isolates. Based on their efficacy in this rodent model, the response of combination of chloroquine with agents representing diverse chemical moieties has been categorised as curative, moderately active and inactive. Out of the 22 agents evaluated, only cyproheptadine-chloroquine combination produced curative response. Ketotifen, azatadine, pheniramine, amitriptyline, fluoxetine, verapamil, penfluridol and trifluoperazine demonstrated moderate activity while loratadine, terfenadine, promethazine, ranitidine, nifedipine, diltiazem, chlorpromazine, amiodarone, tamoxifen, dipyridamol, propranolol, acyclovir and amantidine were inactive. The study advocates the suitability of proposed rodent model to shortlist potential resistance reversal agents. PMID:11080509

  16. Physicochemical equivalence of chloroquine phosphate tablets.

    PubMed

    Bamiro, O A; Odeniyi, M A; Idowu, O B; Jaiyeoba, K T

    2004-12-01

    Seven brands of chloroquine phosphate tablets sourced from different retail outlets in the South-West Nigerian market were analysed in order to determine their physicochemical equivalence. The assessment parameters included uniformity of weight, friability, crushing strength, disintegration and dissolution tests and chemical assay of the tablets. All the brands passed the British Pharmacopoeia tests for weight uniformity, disintegration time and dissolution rate. Two brands, C and E passed the minimum criterion for crushing strength, four brands passed the friability test and two brands exceeded the specified amount of active drug content for chloroquine tablets. Only one brand C out of the seven brands that were analysed passed all the BP quality specifications. Hence none of the seven brands analysed could said to be physically and chemically equivalent. This study highlights the need for constant market monitoring of new products in order to ascertain their quality. PMID:15977447

  17. Chloroquine and hydroxychloroquine for cancer therapy.

    PubMed

    Manic, Gwenola; Obrist, Florine; Kroemer, Guido; Vitale, Ilio; Galluzzi, Lorenzo

    2014-01-01

    Macroautophagy (herein referred to as autophagy) is a highly conserved mechanism for the lysosomal degradation of cytoplasmic components. Autophagy is critical for the maintenance of intracellular homeostasis, both in baseline conditions and in the context of adaptive responses to stress. In line with this notion, defects in the autophagic machinery have been etiologically associated with various human disorders including infectious, inflammatory and neoplastic conditions. Once tumors are established, however, autophagy sustains the survival of malignant cells, hence representing an appealing target for the design of novel anticancer regimens. Accordingly, inhibitors of autophagy including chloroquine and hydroxychloroquine have been shown to mediate substantial antineoplastic effects in preclinical models, especially when combined with chemo- or radiotherapeutic interventions. The pharmacological profile of chloroquine and hydroxychloroquine, however, appear to involve mechanisms other than autophagy inhibition. Here, we discuss the dual role of autophagy in oncogenesis and tumor progression, and summarize the results or design of clinical studies recently completed or initiated to evaluate the therapeutic activity of chloroquine derivatives in cancer patients. PMID:27308318

  18. Chloroquine and hydroxychloroquine for cancer therapy

    PubMed Central

    Manic, Gwenola; Obrist, Florine; Kroemer, Guido; Vitale, Ilio; Galluzzi, Lorenzo

    2014-01-01

    Macroautophagy (herein referred to as autophagy) is a highly conserved mechanism for the lysosomal degradation of cytoplasmic components. Autophagy is critical for the maintenance of intracellular homeostasis, both in baseline conditions and in the context of adaptive responses to stress. In line with this notion, defects in the autophagic machinery have been etiologically associated with various human disorders including infectious, inflammatory and neoplastic conditions. Once tumors are established, however, autophagy sustains the survival of malignant cells, hence representing an appealing target for the design of novel anticancer regimens. Accordingly, inhibitors of autophagy including chloroquine and hydroxychloroquine have been shown to mediate substantial antineoplastic effects in preclinical models, especially when combined with chemo- or radiotherapeutic interventions. The pharmacological profile of chloroquine and hydroxychloroquine, however, appear to involve mechanisms other than autophagy inhibition. Here, we discuss the dual role of autophagy in oncogenesis and tumor progression, and summarize the results or design of clinical studies recently completed or initiated to evaluate the therapeutic activity of chloroquine derivatives in cancer patients. PMID:27308318

  19. Identification of a chloroquine importer in Plasmodium falciparum. Differences in import kinetics are genetically linked with the chloroquine-resistant phenotype.

    PubMed

    Sanchez, C P; Wünsch, S; Lanzer, M

    1997-01-31

    We demonstrate that uptake of the antimalarial drug chloroquine is temperature-dependent, saturable, and inhibitable in Plasmodium falciparum. These features are indicative of carrier-mediated transport and suggest that a P. falciparum-encoded protein facilitates chloroquine import. Although both chloroquine-resistant and susceptible parasite isolates exhibit facilitated chloroquine uptake, the kinetics differ. Chloroquine-resistant parasite isolates consistently have an import mechanism with a lower transport activity and a reduced affinity for chloroquine. These differences in uptake kinetics are linked with chloroquine resistance in a genetic cross. These data suggest that changes in chloroquine import kinetics constitute a minimal and necessary event in the generation of the resistant phenotype. Competitive inhibition of chloroquine uptake by amiloride derivatives further suggests that chloroquine import is mediated by a plasmodial Na+/H+ exchanger.

  20. Influence of methane concentration on the optical indices of Titan’s aerosols analogues

    NASA Astrophysics Data System (ADS)

    Mahjoub, A.; Carrasco, N.; Dahoo, P.-R.; Gautier, T.; Szopa, C.; Cernogora, G.

    2012-11-01

    This work deals with the optical constant characterization of Titan aerosol analogues or “tholins” produced with the PAMPRE experimental setup and deposited as thin films onto a silicon substrate. Tholins were produced in different N2-CH4 gaseous mixtures to study the effect of the initial methane concentration on their optical constants. The real (n) and imaginary (k) parts of the complex refractive index were determined using the spectroscopic ellipsometry technique in the 370-1000 nm wavelength range. We found that optical constants depend strongly on the methane concentrations of the gas phase in which tholins are produced: imaginary optical index (k) decreases with initial CH4 concentration from 2.3 × 10-2 down to 2.7 × 10-3 at 1000 nm wavelength, while the real optical index (n) increases from 1.48 up to 1.58 at 1000 nm wavelength. The larger absorption in the visible range of tholins produced at lower methane percentage is explained by an increase of the secondary and primary amines signature in the mid-IR absorption. Comparison with results of other tholins and data from Titan observations are presented. We found an agreement between our values obtained with 10% methane concentration, and Imanaka et al. (Imanaka, H., Khare, B.N., Elsila, J.E., Bakes, E.L.O., McKay, C.P., Cruikshank, D.P., Sugita, S., Matsui, T., Zare, R.N. [2004]. Icarus, 168, 344-366) values, in spite of the difference in the analytical method. This confirms a reliability of the optical properties of tholins prepared with various setups but with similar plasma conditions. Our comparison with Titan’s observations also raises a possible inconsistency between the mid-IR aerosol signature by VIMS and CIRS Cassini instruments and the visible Huygens-DISR derived data. The mid-IR VIMS and CIRS signatures are in agreement with an aerosol dominated by an aliphatic carbon content, whereas the important visible absorption derived from the DISR measurement seems to be incompatible with such

  1. Opioids and efflux transporters. Part 4: influence of N-substitution on P-glycoprotein substrate activity of noroxymorphone analogues.

    PubMed

    Metcalf, Matthew D; Rosicky, Andrew D; Hassan, Hazem E; Eddington, Natalie D; Coop, Andrew; Cunningham, Christopher W; Mercer, Susan L

    2014-08-01

    The efflux transporter protein P-glycoprotein (P-gp) is capable of affecting the central distribution of diverse neurotherapeutics, including opioid analgesics, through their active removal from the brain. P-gp located at the blood brain barrier has been implicated in the development of tolerance to opioids and demonstrated to be up-regulated in rats tolerant to morphine and oxycodone. We have previously examined the influence of hydrogen-bonding oxo-substitutents on the P-gp-mediated efflux of 4,5-epoxymorphinan analgesics, as well as that of N-substituted analogues of meperidine. Structure-activity relationships (SAR) governing N-substituent effects on opioid efficacy is well-established, however the influence of such structural modifications on P-gp-mediated efflux is unknown. Here, we present SAR describing P-gp recognition of a short series of N-modified 4,5-epoxymorphinans. Oxymorphone, naloxone, naltrexone, and nalmexone all failed to demonstrate P-gp substrate activity, indicating these opioid scaffolds contain structural features that preclude recognition by the transporter. These results are examined using mathematical molecular modeling and discussed in comparison to other opioid scaffolds bearing similar N-substituents. PMID:24915880

  2. Comparison of Analogue Strategies for Investigating the Influence of Counselors' Physical Attractiveness.

    ERIC Educational Resources Information Center

    Zlotlow, Susan F.; Allen, George J.

    1981-01-01

    Assessed the validity of examining the influence of counselors' physical attractiveness via observation of videotapes. Reactions to audio-only and video-only videotape segments were compared with in vivo contact. In vivo contact yielded more positive impressions than videotape observations. Technical skill was more predictive of counselor…

  3. Antimuscarinic effects of chloroquine in rat pancreatic acini

    SciTech Connect

    Habara, Y.; Williams, J.A.; Hootman, S.R.

    1986-06-13

    Chloroquine inhibited carbachol-induced amylase release in a dose-dependent fashion in rat pancreatic acini; cholecystokinin- and bombesin-induced secretory responses were almost unchanged by the antimalarial drug. The inhibition of carbachol-induced amylase release by chloroquine was competitive in nature with a K/sub i/ of 11.7 ..mu..M. Chloroquine also inhibited (/sup 3/H)N-methylscopolamine binding to acinar muscarinic receptors. The IC/sub 50/ for chloroquine inhibition of (/sup 3/H)N-methylscopolamine binding was lower than that for carbachol or the other antimalarial drugs, quinine and quinidine. These results demonstrate that chloroquine is a muscarinic receptor antagonist in the exocrine pancreas.

  4. Influence of the Convergence and Stepover Angles in the Structural Style of Strike-Slip Systems: Analogue Models

    NASA Astrophysics Data System (ADS)

    Gonzalez, D.; Pinto, L.

    2008-12-01

    The presented results of analogue models analyze the influence of the relation between the convergence angle and the stepover angle on strike-slip systems. The experiments include 2 stepovers arrays to generate both transpressional and transtensional zones. These experiments were prepared using 5 cm thick sandpack (sand diameter <500 μm, internal friction angle 30°, density 1,400 kg/m3) to simulate brittle deformation; the base of the model was formed by thin zinc base plates, one of them mobile, cut in such a way so as to produce restraining and releasing strike-slip stepovers; the rate convergence was constant. We carried out 3 series of experiments in which the convergence angles (0°-60°) and stepover angles (30°-60°) were varied systematically. Preliminary results indicate that by increasing the angle between the stepover and the convergence vector: a) the restraining area generated a positive flower structure that is progressively wider; b) progressively more reverse faults which absorb more shortening were generated. Locally, strike-slip faults in the positive flowers were accommodated by the geometry of the stepover base. Areas most complex involved the development of normal faults, which subsequently were inverted. In conclusion, the relation between the convergence and stepover angles is a main factor that determines the structural style of flowers structures on strike-slip systems. This work was done through the ACT-18 PBCT project.

  5. [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.

  6. Effect of chloroquine wash-out period of photosensitizers in the skin and selected organs in rats.

    PubMed

    Zima, T; Jirsa, M; Jirsa, M; Jirásková, M; Bradová, V; Stádník, B

    2004-01-01

    In the last decade, photodynamic therapy has become an alternative method for the diagnosis and therapy of tumors. In human medicine hematoporphyrin derivatives, sulfonated hydrophilic meso-tetraphenylporphyrin (TPPS4) and an oligomer of hematoporphyrin (Photosan 3), are widely used. Chloroquine is used for the treatment of porphyria cutanea tarda for its power to release porphyrins from the liver tissue. The kinetics of two porphyrin photosensitizers TPPS4 and Photosan 3 in the skin and some organs as well as the effect of chloroquine on the porphyrin excretion and their accumulation in skin and organs of Wistar rats were studied. TPPS4 exhibited maximum fluorescence in skin 48 h after application with decreasing to basal level from the 8th to the 14th day. Maximum fluorescence was reached at 72 hours after Photosan 3 application and it decreased to basal level during 96 hours after application. TPPS4 caused significantly higher fluorescence compared to Photosan 3. Chloroquine after oral administration did not change the fluorescence of skin, but it significantly decreased the TPPS4 concentration in rat organs if chloroquine treatment started 3 days or 2 weeks after TPPS4 application. Chloroquine significantly decreased the serum TPPS4 concentration during the period of 28 days. Fluorescence of skin was significantly higher and lasted longer after application of TPPS4 compared to Photosan 3. Chloroquine after oral administration did not influence the fluorescence of the skin, but it significantly decreased the TPPS4 concentration in rat organs. This effect could be useful in photodynamic therapy for mobilizing exogenous porphyrins from tissues after parenteral photodynamic therapy. PMID:14984321

  7. Chloroquine induces empty capsid formation during poliovirus eclipse.

    PubMed Central

    Kronenberger, P; Vrijsen, R; Boeyé, A

    1991-01-01

    The poliovirus capsid (160S) is modified during eclipse in HeLa cells, which results in at least three types of particles having sedimentation coefficients of 135, 110, and 80S. The lysosomotropic agent chloroquine redirected the production of eclipse products from 135 and 110S particles (containing RNA) to 80S particles (without RNA). The effect started at 5 microM and was fully developed with 20 microM chloroquine. Viral protein synthesis and virion production remained unaffected. The results show that chloroquine can redirect the processing of input virions without interfering with productive uncoating. Images PMID:1658391

  8. 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. PMID:26980246

  9. 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. PMID:23602464

  10. Quality of chloroquine tablets available in Africa

    PubMed Central

    SAWADOGO, C W; AMOOD AL-KAMARANY, M; AL-MEKHLAFI, H M; ELKARBANE, M; AL-ADHROEY, A H; CHERRAH, Y; BOUKLOUZE, A

    2011-01-01

    Malaria is the biggest killer of African children, yet it is cheaply preventable and curable with insecticides spraying, impregnated bednets and effective drugs. This study aimed to evaluate the quality of Chloroquine (CQ) tablets available in selected African countries. Twenty-six samples of antimalarial CQ tablet of 100, 150 and 250 mg were collected from 12 African countries and evaluated for their quality in the Drugs Quality Control Laboratory of Rabat, Morocco. The identification and dosage of active pharmaceutical ingredients in the tablets, dissolution rate, hardness and the friability of CQ tablets were performed according to the United States Pharmacopeia (USP) and European Pharmacopoeia (Eur.Ph.) recommended methods. The results showed that 7.7% of the sampled CQ tablets available in Burkina Faso were of low quality. Failure in dissolution profile was found in 50% of CQ tablets sampled from Benin, Burkina Faso, Comoros Union, Mali and Senegal. The findings showed poor quality of CQ tablets available in the African market. This problem may affect the efforts to control malaria in Africa. Efficient regulatory systems of drugs quality control should be implemented. PMID:22117854

  11. 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.

  12. 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. PMID:18806516

  13. 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

  14. Characterization of the chloroquine resistance transporter homologue in Toxoplasma gondii.

    PubMed

    Warring, Sally D; Dou, Zhicheng; Carruthers, Vern B; McFadden, Geoffrey I; van Dooren, Giel G

    2014-11-01

    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.

  15. Ecotoxicological evaluation of the antimalarial drug chloroquine.

    PubMed

    Zurita, Jorge L; Jos, Angeles; del Peso, Ana; Salguero, Manuel; López-Artíguez, Miguel; Repetto, Guillermo

    2005-10-15

    There is limited information available about the potential environmental effects of chloroquine (CQ), a widely used antimalarial agent and a promising inexpensive drug in the management of HIV disease. The acute effects of CQ were studied using four ecotoxicological model systems. The most sensitive bioindicator was the immobilization of the cladoceran Daphnia magna, with an EC50 of 12 microM CQ at 72 h and a non-observed adverse effect level of 2.5 microM CQ, followed very closely by the decrease of the uptake of neutral red and the reduction of the lysosomal function in the fish cell line PLHC-1 derived from the top minnow Poeciliopsis lucida, probably due to the selective accumulation of the drug into the lysosomes. There was significant cellular stress as indicated by the increases on metallothionein and glucose-6P dehydrogenase levels after 24 h of exposure and succinate dehydrogenase activity mainly after 48 h. No changes were observed for ethoxyresorufin-O-deethylase (EROD) activity. The least sensitive model was the inhibition of bioluminescence in the bacterium Vibrio fischeri. An increase of more than five-fold in the toxicity from 24 to 72 h of exposure was observed for the inhibition of the growth in the alga Chlorella vulgaris and the content of total protein and MTS tetrazolium salt metabolization in PLHC-1 cells. At the morphological level, the most evident alterations in PLHC-1 cultures were hydropic degeneration from 25 microM CQ after 24h of exposure and the presence of many cells with pyknotic nuclei, condensed cytoplasm and apoptosis with concentrations higher than 50 microM CQ after 48 h of exposure. In conclusion, CQ should be classified as harmful to aquatic organisms. PMID:16153718

  16. 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

  17. An investigation into the suitability of amidated pectin hydrogel beads as a delivery matrix for chloroquine.

    PubMed

    Munjeri, O; Hodza, P; Osim, E E; Musabayane, C T

    1998-08-01

    The aim of the present study was to delay the release of chloroquine to distal parts of the gastrointestinal tract by using a multiparticulate hydrogel formulation. Amidated pectin chloroquine beads (PC) with varying pectin-to-chloroquine ratios (PC) w/w loadings of 4:1, 2:1, and 1:1 in the dried beads were prepared by the gelation of drug-loaded pectin solutions in the presence of calcium. In vitro release studies of chloroquine from pectin-chloroquine hydrogel beads and chloroquine diphosphate powder were carried out in simulated gastric and intestinal fluids. The total release of the entrapped chloroquine from the hydrogel beads was achieved between 4 and 7 h in simulated intestinal fluid, but total release was not achieved in simulated gastric fluid. However, total release from chloroquine diphosphate powder was achieved by 1.5 and 2 h in gastric and intestinal fluids, respectively. The plasma pharmacokinetics of chloroquine from pectin hydrogel beads and chloroquine diphosphate solution following single or repeated dosing were compared in male Sprague-Dawley rats over a period of 60 h. Oral administration of the hyrogel beads to rats produced maximum plasma concentrations by 7 h, but highest plasma concentrations following chloroquine solution administration were observed by 2 h. The dissolution data and appearance of significant plasma concentrations of chloroquine 2 to 4 h after oral administration suggests release in duodenum, jejunum, or ileum.

  18. Chloroquine resistance of Plasmodium falciparum is associated with severity of disease in Nigerian children.

    PubMed

    Olumese, P E; Amodu, O K; Björkman, A; Adeyemo, A A; Gbadegesin, R A; Walker, O

    2002-01-01

    Chloroquine resistance of Plasmodium falciparum in vitro was significantly higher in isolates from patients with severe malaria than those with uncomplicated disease. This association may be due to either progression of uncomplicated to severe disease following chloroquine failure or increased virulence of chloroquine-resistant parasites. The implication of this for antimalarial treatment policy is discussed. PMID:12497979

  19. Exploring Microstructural Changes in Structural Analogues of Ibuprofen-Hosted In Situ Gelling System and Its Influence on Pharmaceutical Performance.

    PubMed

    Patil, Sharvil S; Venugopal, Edakkal; Bhat, Suresh; Mahadik, Kakasaheb R; Paradkar, Anant R

    2015-10-01

    The present work explores inner structuration of in situ gelling system consisting of glyceryl monooleate (GMO) and oleic acid (OA). The system under study involves investigation of microstructural changes which are believed to govern the pharmaceutical performance of final formulation. The changes which are often termed mesophasic transformation were analysed by small angle X-ray scattering (SAXS), differential scanning calorimetry (DSC), rheology and plane polarised light (PPL) microscopy. The current work revealed transformation of blank system from W/O emulsion to reverse hexagonal structure upon addition of structural analogues of ibuprofen. Such transformations are believed to occur due to increased hydrophobic volume within system as probed by SAXS analysis. The findings of SAXS studies were well supported by DSC, rheology and PPL microscopy. The study established inverse relationship between log P value of structural analogues of ibuprofen and the degree of binding of water molecules to surfactant chains. Such relationship had pronounced effect on sol-gel transformation process. The prepared in situ gelling system showed sustained drug release which followed Higuchi model.

  20. Photoaffinity Labeling of the Plasmodium falciparum Chloroquine Resistance Transporter with a Novel Perfluorophenylazido Chloroquine†

    PubMed Central

    Lekostaj, Jacqueline K.; Natarajan, Jayakumar K.; Paguio, Michelle F.; Wolf, Christian; Roepe, Paul D.

    2009-01-01

    Several models describing how amino acid substitutions in the Plasmodium falciparum chloroquine resistance transporter (PfCRT) confer resistance to chloroquine (CQ) and other antimalarial drugs have been proposed. Further progress requires molecular analysis of interactions between purified reconstituted PfCRT protein and these drugs. We have thus designed and synthesized several perfluorophenyl azido (pfpa) CQ analogues for PfCRT photolabeling studies. One particularly useful probe (AzBCQ) places the pfpa group at the terminal aliphatic N of CQ via a flexible four-carbon ester linker and includes a convenient biotin tag. This probe photolabels PfCRT in situ with high specificity. Using reconstituted proteoliposomes harboring partially purified recombinant PfCRT, we analyze AzBCQ photolabeling versus competition with CQ and other drugs to probe the nature of the CQ binding site. We also inspect how pH, the chemoreversal agent verapamil (VPL), and various amino acid mutations in PfCRT that cause CQ resistance (CQR) affect the efficiency of AzBCQ photolabeling. Upon gel isolation of AzBCQ-labeled PfCRT followed by trypsin digestion and mass spectrometry analysis, we are able to define a single AzBCQ covalent attachment site lying within the digestive vacuolar-disposed loop between putative helices 9 and 10 of PfCRT. Taken together, the data provide important new insight into PfCRT function and, along with previous results, allow us to propose a model for a single CQ binding site in the PfCRT protein. PMID:18767816

  1. 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. 522.810 Section 522.810 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN... euthanasia. (3) Limitations. Not for use in animals intended for food. Federal law restricts this drug to...

  2. 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. 522.810 Section 522.810 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN... euthanasia. (3) Limitations. Not for use in animals intended for food. Federal law restricts this drug to...

  3. 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. 522.810 Section 522.810 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN... euthanasia. (3) Limitations. Not for use in animals intended for food. Federal law restricts this drug to...

  4. 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. 522.810 Section 522.810 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN... euthanasia. (3) Limitations. Not for use in animals intended for food. Federal law restricts this drug to...

  5. 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. 522.810 Section 522.810 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN... euthanasia. (3) Limitations. Not for use in animals intended for food. Federal law restricts this drug to...

  6. Chloroquine treatment of severe malaria in children. Pharmacokinetics, toxicity, and new dosage recommendations.

    PubMed

    White, N J; Miller, K D; Churchill, F C; Berry, C; Brown, J; Williams, S B; Greenwood, B M

    1988-12-01

    Although empirical regimens of parenteral chloroquine have been used extensively to treat severe malaria for 40 years, recent recommendations state that parenteral chloroquine should no longer be used because of potential toxicity. We studied prospectively the pharmacokinetics and toxicity of seven chloroquine regimens in 58 Gambian children with severe chloroquine-sensitive falciparum malaria. In all regimens the total cumulative dose was 25 mg of chloroquine base per kilogram of body weight. Chloroquine was rapidly absorbed after either intramuscular or subcutaneous administration (5 mg of base per kilogram every 12 hours), producing high peak blood concentrations but transient hypotension in 5 of 18 patients (28 percent). Intermittent intravenous infusion (5 mg of base per kilogram over 4 hours, repeated every 12 hours) also produced wide fluctuations in chloroquine levels, suggesting incomplete distribution from a small central compartment. Continuous infusion (0.83 mg of base per kilogram per hour for 30 hours) and smaller, more frequent intramuscular or subcutaneous injections of chloroquine (3.5 mg of base per kilogram every 6 hours) produced smoother blood-concentration profiles with lower early peak levels and no adverse cardiovascular or neurologic effects. Chloroquine given by nasogastric tube (initial dose, 10 mg of base per kilogram) was absorbed well, even in comatose children. We conclude that simple alterations in dosage and frequency of administration can give parenteral chloroquine an acceptable therapeutic ratio and reinstate it as the treatment of choice for severe malaria in areas where chloroquine resistance is not a major problem.

  7. 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.

  8. 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

  9. Activities of Various 4-Aminoquinolines Against Infections with Chloroquine-Resistant Strains of Plasmodium falciparum1

    PubMed Central

    Schmidt, L. H.; Vaughan, Dennis; Mueller, Donna; Crosby, Ruth; Hamilton, Rebecca

    1977-01-01

    The studies reported here stemmed from a personal report by Geiman on the capacity of the 4-aminoquinoline amodiaquin to inhibit in vitro maturation of ring stages of the chloroquine-resistant Monterey strain of Plasmodium falciparum. This observation, confirmed in owl monkeys infected with this strain, led to a comparison of the activities of chloroquine, amodiaquin, amopyroquin, and dichlorquinazine (12,278 RP) against infections with various chloroquine-susceptible and chloroquine-resistant strains. The results showed that: (i) these 4-aminoquinolines were essentially equally active against infections with chloroquine-susceptible strains and (ii) the activities of amodiaquin, amopyroquin, and dichlorquinazine were reduced significantly in the face of chloroquine resistance, but (iii) well-tolerated doses of these compounds would cure infections with strains that fully resisted treatment with maximally tolerated doses of chloroquine. Two other 4-aminoquinolines, SN-8137 and SN-9584, which also exhibited activity against chloroquine-resistant parasites in vitro, displayed curative activity in monkeys infected with a chloroquine-resistant strain. These observations show that there is cross-resistance among the 4-aminoquinolines, confirming earlier findings, but indicate that the dimensions of this phenomenon are sufficiently limited so that some derivatives are therapeutically effective against infections refractory to maximally tolerated doses of chloroquine. PMID:406829

  10. An analogue study of the influence of solidification on the advance and surface thermal signature of lava flows

    NASA Astrophysics Data System (ADS)

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

    2014-06-01

    The prediction of lava flow advance and velocity is crucial during an effusive volcanic crisis. The effusion rate is a key control of lava dynamics, and proxies have been developed to estimate it in near real-time. The thermal proxy in predominant use links the satellite-measured thermal radiated power to the effusion rate. It lacks however a robust physical basis to allow time-dependent modeling. We investigate here through analogue experiments the coupling between the spreading of a solidifying flow and its surface thermal signal. We extract a first order behavior from experimental results obtained using polyethylene glycol (PEG) wax, that solidifies abruptly during cooling. We find that the flow advance is discontinuous, with relatively low supply rates yielding long stagnation phases and compound flows. Flows with higher supply rates are less sensitive to solidification and display a spreading behavior closer to that of purely viscous currents. The total power radiated from the upper surface also grows by stages, but the signal radiated by the hottest and liquid part of the flow reaches a quasi-steady state after some time. This plateau value scales around half of the theoretical prediction of a model developed previously for the spreading and cooling of isoviscous gravity currents. The corrected scaling yields satisfying estimates of the effusion rate from the total radiated power measured on a range of basaltic lava flows. We conclude that a gross estimate of the supply rate of solidifying flows can be retrieved from thermal remote-sensing, but the predictions of lava advance as a function of effusion rate appears a more difficult task due to chaotic emplacement of solidifying flows.

  11. Solvent H-bond accepting ability induced conformational change and its influence towards fluorescence enhancement and dual fluorescence of hydroxy meta-GFP chromophore analogue.

    PubMed

    Chatterjee, Tanmay; Mandal, Mrinal; Mandal, Prasun K

    2016-09-21

    The effect of structural rigidity towards enhancement of fluorescence quantum yield of GFP chromophore analogues has been documented. In the present study, a new way of enhancing the fluorescence quantum yield of two ortho-meta GFP chromophore analogues meta-methoxy-ortho-hydroxy-benzylimidazolidinone (abbreviated as mOMe-HBDI) and meta-diethylamino-ortho-hydroxyl imidazolidinone (abbreviated as MOHIM) has been reported. This enhancement is controlled by the H-bond accepting ability (denoted as β value) of the solvent and happens only in the case of GFP chromophore analogues having ortho (hydroxyl)-meta (electron donating group) and not in the case of analogues having a para electron donating group. The ground state (solid) conformation of mOMe-HBDI has been obtained from single crystal X-ray analysis, exhibiting the existence of strong intramolecular H-bonding. However, in solution phase, as the solvent β value increases, the strength of intramolecular H-bonding decreases. This process has strong influence on the relative conformational orientation of phenyl and imidazolidinone rings. For mOMe-HBDI, fluorescence quantum yield increases with increase in β value of the solvents. However, the effect of solvent polarity cannot be completely ruled out. The lower wavelength emission band (∼480 nm) has been assigned to the normal charge-transferred (CT) species, whereas the highly Stokes shifted emission band (∼660 nm) has been assigned to the proton-transferred (PT) tautomer species for mOMe-HBDI. In solvents of low β value (say hexane) only the PT band and in solvents of high β value (say DMSO) only the CT band is observed. Quite interestingly, in solvents of intermediate β value both CT and PT bands, thus dual emission, are observed. For mOMe-HBDI when fluorescence decay is monitored at the normal CT emission band, it is observed to be biexponential in nature. The short component increases from ∼0.2 ns to 0.6 ns and the long component increases from 1 to 3

  12. 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.

  13. Synergistic activity of chloroquine with fluconazole against fluconazole-resistant isolates of Candida species.

    PubMed

    Li, Yali; Wan, Zhe; Liu, Wei; Li, Ruoyu

    2015-02-01

    The in vitro activity of chloroquine and the interactions of chloroquine combined with fluconazole against 37 Candida isolates were tested using the broth microdilution, disk diffusion, and Etest susceptibility tests. Synergistic effect was detected with 6 of 9 fluconazole-resistant Candida albicans isolates, with Candida krusei ATCC 6258, and with all 12 fluconazole-resistant Candida tropicalis isolates.

  14. Synergistic Activity of Chloroquine with Fluconazole against Fluconazole-Resistant Isolates of Candida Species

    PubMed Central

    Li, Yali; Wan, Zhe; Li, Ruoyu

    2014-01-01

    The in vitro activity of chloroquine and the interactions of chloroquine combined with fluconazole against 37 Candida isolates were tested using the broth microdilution, disk diffusion, and Etest susceptibility tests. Synergistic effect was detected with 6 of 9 fluconazole-resistant Candida albicans isolates, with Candida krusei ATCC 6258, and with all 12 fluconazole-resistant Candida tropicalis isolates. PMID:25512426

  15. Confirmed Plasmodium vivax Resistance to Chloroquine in Central Vietnam

    PubMed Central

    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

    2015-01-01

    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. PMID:26392501

  16. 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.

  17. Transdermal delivery of chloroquine by amidated pectin hydrogel matrix patch in the rat.

    PubMed

    Musabayane, C T; Munjeri, O; Matavire, T P

    2003-07-01

    The aim of the present study was to investigate the suitability of amidated pectin matrix patch for transdermal chloroquine delivery in an effort to mask the bitter taste when orally administered. Chloroquine has easily measurable outputs that are linked to increased renal Na+ excretion. We thus monitored urinary Na+ output in separate groups intravenously administered chloroquine or topically applied pectin hydrogel chloroquine matrix patch. Male groups of anesthetized Sprague-Dawley rats were placed on a continuous jugular infusion of 0.077 M NaCl at 150 microL min(-1). After 3 h equilibration period, consecutive 20 min urine collections were made over the subsequent 4 h of 1 h control, 1 h 20 min treatment, and 1 h 40 min recovery periods for measurements of urine flow and Na+ and K+ excretion rates. The effects of intravenous chloroquine infusion or topical application of pectin hydrogel chloroquine matrix patch were examined in rats in which the drug was added to the infusate or patch applied onto the shaved area during the 1 h 20 min treatment period. The animals were switched back to the infusate alone for the final 1 h 40 min recovery period. Vehicle infused animals acted as controls. Trunk blood was collected after the treatment period from parallel groups for chloroquine measurements. The plasma chloroquine concentrations following iv chloroquine or application of pectin chloroquine hydrogel matrix patch were 9.3 +/- 0.8 mg L(-1) and 7.3 +/- 1.1 mg L(-1) respectively (n = 7 in both groups). Chloroquine infusion and pectin chloroquine patch significantly (p < 0.01) increased Na+ excretion to peak values of 14.1 +/- 0.9 micromol min(-1). and 20.35 +/- 1.0 micromol min(-1), respectively by comparison with controls (9.1 +/- 0.9 micromol min(-1)), at the corresponding period. The results suggest that the pectin chloroquine patch matrix preparation has potential applications for transdermal delivery of chloroquine and perhaps in the management of malaria.

  18. Overcoming chloroquine resistance in malaria: Design, synthesis and structure-activity relationships of novel chemoreversal agents.

    PubMed

    Boudhar, Aicha; Ng, Xiao Wei; Loh, Chiew Yee; Chia, Wan Ni; Tan, Zhi Ming; Nosten, Francois; Dymock, Brian W; Tan, Kevin S W

    2016-08-25

    Malaria remains a significant infectious disease with even artemisinin-based therapies now facing resistance in the field. Development of new therapies is urgently needed, either by finding new compounds with unique modes of action, or by reversing resistance towards known drugs with 'chemosensitizers' or 'chemoreversal' agents (CRA). Concerning the latter, we have focused on the resistance mechanisms developed against chloroquine (CQ). We have synthesized a series of compounds related to previously identified CRAs, and found promising novel compounds. These compounds show encouraging results in a coumarin labeled chloroquine uptake assay, exhibiting a dose response in resensitising parasites to the antimalarial effects of chloroquine. Selected compounds show consistent potency across a panel of chloroquine and artemisinin sensitive and resistant parasites, and a wide therapeutic window. This data supports further study of CRAs in the treatment of malaria and, ultimately, their use in chloroquine-based combination therapies. PMID:27173385

  19. Diverse mutational pathways converge on saturable chloroquine transport via the malaria parasite’s chloroquine resistance transporter

    PubMed Central

    Summers, Robert L.; Dave, Anurag; Dolstra, Tegan J.; Bellanca, Sebastiano; Marchetti, Rosa V.; Nash, Megan N.; Richards, Sashika N.; Goh, Valerie; Schenk, Robyn L.; Stein, Wilfred D.; Kirk, Kiaran; Sanchez, Cecilia P.; Lanzer, Michael; Martin, Rowena E.

    2014-01-01

    Mutations in the chloroquine resistance transporter (PfCRT) are the primary determinant of chloroquine (CQ) resistance in the malaria parasite Plasmodium falciparum. A number of distinct PfCRT haplotypes, containing between 4 and 10 mutations, have given rise to CQ resistance in different parts of the world. Here we present a detailed molecular analysis of the number of mutations (and the order of addition) required to confer CQ transport activity upon the PfCRT as well as a kinetic characterization of diverse forms of PfCRT. We measured the ability of more than 100 variants of PfCRT to transport CQ when expressed at the surface of Xenopus laevis oocytes. Multiple mutational pathways led to saturable CQ transport via PfCRT, but these could be separated into two main lineages. Moreover, the attainment of full activity followed a rigid process in which mutations had to be added in a specific order to avoid reductions in CQ transport activity. A minimum of two mutations sufficed for (low) CQ transport activity, and as few as four conferred full activity. The finding that diverse PfCRT variants are all limited in their capacity to transport CQ suggests that resistance could be overcome by reoptimizing the CQ dosage. PMID:24728833

  20. 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

  1. 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. PMID:25114131

  2. Chloroquine-induced bull's eye maculopathy in rheumatoid arthritis: related to disease duration?

    PubMed

    Shinjo, Samuel K; Maia, Otacílio O; Tizziani, Vivian A P; Morita, Celso; Kochen, Jussara A L; Takahashi, Walter Y; Laurindo, Ieda M M

    2007-08-01

    Chloroquine diphosphate has been used in the treatment of various rheumatic diseases, including rheumatoid arthritis. The most important of its side effects is retinopathy. If not diagnosed early, this lesion can evolve into irreversible bull's eye maculopathy and visual loss. The aim of this study was to define the outcome of chloroquine-induced maculopathy after cessation of chloroquine therapy and also to identify the risk factors involved in case of retinopathy evolution. The design of this cohort study was longitudinal and retrospective. Over the period spanning 2000 to 2005, out of 607 medical records of patients with rheumatoid arthritis followed in our Division of Rheumatology, 27 had been diagnosed with chloroquine-induced maculopathy through clinical funduscopy with pupil dilation. In all cases, there was immediate chloroquine intake cessation. After a mean time of 5 years, 16 of these patients were available for follow-up and underwent a new ophthalmologic evaluation by funduscopy, using biomicroscopy and angiofluorescein when necessary. Sequelae maculopathy were reconfirmed in all 16 cases, but progression to advanced stage (bull's eye maculopathy) was found in half of the cohort, even though chloroquine had been suspended. All patients complained of visual alterations, but without progression. Comparison between patient groups with and without bull's eye maculopathy revealed a statistically significant longer rheumatoid arthritis disease history in the former group. Also, the bull's eye group had higher dose intakes of chloroquine and over a longer period compared to the other group, but not statistically significant. This study corroborates the progression of maculopathy even after cessation of chloroquine intake, pointing out the need for careful screening in the high-risk patients. Furthermore, it indicates that duration of rheumatoid arthritis disease could be a possible factor linked to worse prognosis of chloroquine-induced maculopathy.

  3. Frequency of pruritus in Plasmodium vivax malaria patients treated with chloroquine in Thailand.

    PubMed

    Bussaratid, V; Walsh, D S; Wilairatana, P; Krudsood, S; Silachamroon, U; Looareesuwan, S

    2000-10-01

    Chloroquine-induced itch in black-skinned African malaria patients is common and frequently leads to poor compliance or treatment defaulting.To assess the frequency and severity of chloroquine-induced pruritus in an Asian population, we reviewed case records of 1189 Plasmodium vivax malaria patients treated with chloroquine (25 mg/kg over 3 days) at the Bangkok Hospital for Tropical Diseases from 1992 through 1997. The majority of patients were Thais or ethnic Burmese (light brown skin), referred from the western border of Thailand. Overall, there were 23 patients (1.9%) with complaints of pruritus during chloroquine therapy. Of these, 12 (52%) had palm and sole involvement, eight (35%) had generalized pruritus including the palms and soles, and three (13%) had palm itching only. One patient developed pruritus on the palms and soles on two consecutive admissions. The pruritus did not interfere with daily activity, was reduced in intensity by anti-histamine therapy, and did not affect the patient's willingness to complete the chloroquine regimen. Therapeutic responses in the 23 patients with chloroquine itch was similar to those without itch. Among the itch patients, there was no association with gender or level of parasitaemias. Our findings indicate that the frequency of chloroquine-induced pruritus in Asian patients treated with chloroquine for P. vivax malaria is low in comparison with black-skinned Africans.This may be related to pharmacogenetic factors, the infective Plasmodium species, drug metabolism or drug-parasite interactions, or a lower affinity of chloroquine for less pigmented skin.

  4. Diverse supramolecular arrangement of substituted oxopyrrolidine analogues influenced by weak intermolecular interactions (Csbnd H⋯O/Csbnd H⋯π/H⋯H)

    NASA Astrophysics Data System (ADS)

    Samipillai, Marivel; Bhatt, Nilay; Kruger, Hendrik G.; Govender, Thavendran; Naicker, Tricia

    2016-10-01

    Three analogues of 3-oxopyrrolidines; (S)-1-tert-butyl 2-ethyl-2-((S)-2-nitro-1-p-tolylethyl)-3-oxopyrrolidine-1,2-dicarboxylate, 1, (S)-1-tert-butyl 2-ethyl 2-((S)-1-(4-methoxyphenyl)-2-nitroethyl)-3-oxopyrrolidine-1,2-dicarboxylate 2, and Ethyl 1-((S)-2-(((benzyloxy)carbonyl)amino)-3-phenylpropanoyl)-2-(2-nitro-1-phenylethyl)-3-oxopyrrolidine-2-carboxylate 3, were synthesized and crystallized in suitable solvents. Crystal structure analysis was carried out by single crystal X-ray diffraction to provide a detailed investigation of the packing and supramolecular arrangement of these analogues. The weak interactions such as Csbnd H⋯O/Csbnd H⋯π present in the crystal structure of all these analogues (1-3) played a vital role in controlling the conformation of the molecules and construction of dissimilar supramolecular assemblies. This study provides some insight; that even though these oxopyrrolidine analogues, lack a hydrogen bond donor and acceptor system, that upon bulky substitutions, this scaffold can still form fascinating supramolecular assemblies through various weak interactions. The surface interaction was carried out by means of Hirshfeld surface analysis, which depicted the significant intermolecular interactions of a molecule with its neighbor within the structures.

  5. Synthesis of New 4-Aminoquinolines and Evaluation of Their In Vitro Activity against Chloroquine-Sensitive and Chloroquine-Resistant Plasmodium falciparum.

    PubMed

    Rajapakse, Chandima S K; Lisai, Maryna; Deregnaucourt, Christiane; Sinou, Véronique; Latour, Christine; Roy, Dipankar; Schrével, Joseph; Sánchez-Delgado, Roberto A

    2015-01-01

    The efficacy of chloroquine, once the drug of choice in the fight against Plasmodium falciparum, is now severely limited due to widespread resistance. Amodiaquine is one of the most potent antimalarial 4-aminoquinolines known and remains effective against chloroquine-resistant parasites, but toxicity issues linked to a quinone-imine metabolite limit its clinical use. In search of new compounds able to retain the antimalarial activity of amodiaquine while circumventing quinone-imine metabolite toxicity, we have synthesized five 4-aminoquinolines that feature rings lacking hydroxyl groups in the side chain of the molecules and are thus incapable of generating toxic quinone-imines. The new compounds displayed high in vitro potency (low nanomolar IC50), markedly superior to chloroquine and comparable to amodiaquine, against chloroquine-sensitive and chloroquine-resistant strains of P. falciparum, accompanied by low toxicity to L6 rat fibroblasts and MRC5 human lung cells, and metabolic stability comparable or higher than that of amodiaquine. Computational studies indicate a unique mode of binding of compound 4 to heme through the HOMO located on a biphenyl moeity, which may partly explain the high antiplasmodial activity observed for this compound. PMID:26473363

  6. [Monitoring delagil (chloroquine) efficacy against imported Plasmodium vivax strains].

    PubMed

    Rabinovich, S A; Tokmalaev, A K; Kukina, I V; Morozov, E N; Maksakovskaia, E V; Sadykova, V D; Burchik, M A; Ivanova, T N; Sergiev, V P

    2010-01-01

    The efficiency of P. vivax malaria treatment with delagil (chloroquine) was evaluated in 122 patients, including 82 cases in Moscow and the Moscow region. The origin of the cases was malaria endemic areas in Asia, Africa, the Pacific Region, South America, and Transcaucasia. Forty other cases were imported malaria cases (secondary to imported ones), detected in Moscow and the Moscow region. Standard treatment with delagil (2.5 g) resulted in clinical improvement during 3 days in the majority of cases. Initial signs of degradation of asexual stages of P. vivax--kernels of nucleus, refinement of cytoplasm and its vacuolization, aggregation of pigment in isolated instances, its pushing out from cytoplasm--were observed after 1-2 hours after administration of delagil. Thereafter, parasite degradation was increasing, and it disappeared within 48 hours. Disappearance of fever slowed down in a few cases. However, degradation of parasites occurred during the same period among the rest of cases. It can not be excluded that fever was determined by the pyrogenic effect of remnants of degraded parasites and by the products of destroyed infected erythrocytes. It is probable that the findings of gametocytes, not completely degraded after disappearance of asexual forms in conjunction with prolonged fever, could result in a wrong conclusion of drug resistance. Negative results of microscopy and nested PCR on the last day of treatment, as well as in the following 10 days and absence of complains during 45 days, suggest the absence of resistance to delagil in P. vivax strains imported from different regions of the world. It is also probable that the literature on P. vivax resistance to chloroquine is limited to sporadic cases. PMID:21395044

  7. Functional Comparison of 45 Naturally Occurring Isoforms of the Plasmodium falciparum Chloroquine Resistance Transporter (PfCRT).

    PubMed

    Callaghan, Paul S; Hassett, Matthew R; Roepe, Paul D

    2015-08-18

    At least 53 distinct isoforms of Plasmodium falciparum chloroquine resistance transporter (PfCRT) protein are expressed in strains or isolates of P. falciparum malarial parasites from around the globe. These parasites exhibit a range of sensitivities to chloroquine (CQ) and other drugs. Mutant PfCRT is believed to confer cytostatic CQ resistance (CQR(CS)) by transporting CQ away from its DV target (free heme released upon hemoglobin digestion). One theory is that variable CQ transport catalyzed by these different PfCRT isoforms is responsible for the range of CQ sensitivities now found for P. falciparum. Alternatively, additional mutations in drug-selected parasites, or additional functions of PfCRT, might complement PfCRT-mediated CQ transport in conferring the range of observed resistance phenotypes. To distinguish between these possibilities, we recently optimized a convenient method for measuring PfCRT-mediated CQ transport, involving heterologous expression in Saccharomyces cerevisiae. Here, we use this method to quantify drug transport activity for 45 of 53 of the naturally occurring PfCRT isoforms. Data show that variable levels of CQR likely depend upon either additional PfCRT functions or additional genetic events, including perhaps changes that influence DV membrane potential. The data also suggest that the common K76T PfCRT mutation that is often used to distinguish a P. falciparum CQR phenotype is not, in and of itself, a fully reliable indicator of CQR status.

  8. 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.

  9. 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.

  10. Effects of chloroquine on viral infections: an old drug against today's diseases?

    PubMed

    Savarino, Andrea; Boelaert, Johan R; Cassone, Antonio; Majori, Giancarlo; Cauda, Roberto

    2003-11-01

    Chloroquine is a 9-aminoquinoline known since 1934. Apart from its well-known antimalarial effects, the drug has interesting biochemical properties that might be applied against some viral infections. Chloroquine exerts direct antiviral effects, inhibiting pH-dependent steps of the replication of several viruses including members of the flaviviruses, retroviruses, and coronaviruses. Its best-studied effects are those against HIV replication, which are being tested in clinical trials. Moreover, chloroquine has immunomodulatory effects, suppressing the production/release of tumour necrosis factor alpha and interleukin 6, which mediate the inflammatory complications of several viral diseases. We review the available information on the effects of chloroquine on viral infections, raising the question of whether this old drug may experience a revival in the clinical management of viral diseases such as AIDS and severe acute respiratory syndrome, which afflict mankind in the era of globalisation.

  11. Chloroquine resistant Plasmodium falciparum malaria in Osogbo Nigeria: efficacy of amodiaquine + sulfadoxine-pyrimethamine and chloroquine + chlorpheniramine for treatment.

    PubMed

    Ogungbamigbe, T O; Ojurongbe, O; Ogunro, P S; Okanlawon, B M; Kolawole, S O

    2008-02-01

    Chloroquine (CQ) resistance in Plasmodium falciparum contributes to increasing malaria-attributable morbidity and mortality in Sub-Saharan Africa. Despite a change in drug policy, continued prescription of CQ did not abate. Therefore the therapeutic efficacy of CQ in uncomplicated falciparum malaria patients was assessed in a standard 28-day protocol in 116 children aged between six and 120 months in Osogbo, Southwest Nigeria. Parasitological and clinical assessments of response to treatment showed that 72 (62.1%) of the patients were cured and 44 (37.9%) failed the CQ treatment. High initial parasite density and young age were independent predictors for early treatment failure. Out of the 44 patients that failed CQ, 24 received amodiaquine + sulphadoxine/pyrimethamine (AQ+SP) and 20 received chlorpheniramine + chloroquine (CH+CQ) combinations. Mean fever clearance time in those treated with AQ+SP was not significantly different from those treated with CH+CQ (p = 0.05). There was no significant difference in the mean parasite density of the two groups. The cure rate for AQ+SP group was 92% while those of CH+CQ was 85%. There was a significant difference in parasite clearance time (p = 0.01) between the two groups. The 38% treatment failure for CQ reported in this study is higher than the 10% recommended by World Health Organization in other to effect change in antimalarial treatment policy. Hence we conclude that CQ can no more be solely relied upon for the treatment of falciparum malaria in Osogbo, Nigeria. AQ+SP and CH+CQ are effective in the treatment of acute uncomplicated malaria and may be considered as useful alternative drugs in the absence of artemisinin-based combination therapies.

  12. In vitro response of chloroquine-resistant Plasmodium falciparum to mefloquine.

    PubMed

    López Antuñano, F J; Wernsdorfer, W H

    1979-01-01

    The present study was conducted to evaluate the application of the in vitro microtechnique system in determining the response of chloroquine-resistant Plasmodium falciparum to mefloquine.Using isolates of P. falciparum from Boa Vista, Brazil, and Villavicencio, Colombia, mefloquine was more than 7.7, 7.1, 7.1, and 6.4 times more effective than chloroquine in vitro at the ED(90), ED(95), ED(99), and ED(99.9) levels, respectively.

  13. Chloroquine has tumor-inhibitory and tumor-promoting effects in triple-negative breast cancer.

    PubMed

    Tuomela, Johanna; Sandholm, Jouko; Kauppila, Joonas H; Lehenkari, Petri; Harris, Kevin W; Selander, Katri S

    2013-12-01

    Toll-like receptor-9 (TLR9) is an intracellular DNA receptor that is widely expressed in breast and other cancers. We previously demonstrated that low tumor TLR9 expression upon diagnosis is associated with significantly shortened disease-specific survival times in patients with triple-negative breast cancer (TNBC). There are no targeted therapies for this subgroup of patients whose prognosis is among the worst in breast cancer. Due to the previously detected in vitro anti-invasive effects of chloroquine in these cell lines, the present study aimed to investigate the in vivo effects of chloroquine against two clinical subtypes of TNBC that differ in TLR9 expression. Chloroquine suppressed matrix metalloproteinase (MMP)-2 and MMP-9 mRNA expression and protein activity, whereas MMP-13 mRNA expression and proteolytic activity were increased. Despite enhancing TLR9 mRNA expression, chloroquine suppressed TLR9 protein expression in vitro. Daily treatment of mice with intraperitoneal (i.p.) chloroquine (80 mg/kg/day) for 22 days, did not inhibit the growth of control siRNA or TLR9 siRNA MDA-MB-231 breast cancer cells. In conclusion, despite the favorable in vitro effects on TNBC invasion and viability, particularly in hypoxic conditions, chloroquine does not prevent the growth of the triple-negative MDA-MB-231 cells with high or low TLR9 expression levels in vivo. This may be explained by the activating effects of chloroquine on MMP-13 expression or by the fact that chloroquine, by suppressing TLR9 expression, permits the activation of currently unknown molecular pathways, which allow the aggressive behavior of TNBC cells with low TLR9 expression in hypoxia. PMID:24273604

  14. Time to use a dose of Chloroquine as an adjuvant to anti-cancer chemotherapies.

    PubMed

    Pascolo, Steve

    2016-01-15

    Chloroquine, a drug used for over 80 years to treat and prevent malaria and, more recently, to treat autoimmune diseases, is very safe but has a plethora of dose-dependent effects. By increasing pH in acidic compartments it inhibits for example lysosomal enzymes. In the context of cancer, Chloroquine was found to have direct effects on different types of malignancies that could potentiate chemotherapies. For example, the anti-malaria drug may inhibit both the multidrug-resistance pump and autophagy (mechanisms that tumor cells may use to resist chemotherapies), intercalate in DNA and enhance the penetration of chemotherapeutic drugs in cells or solid cancer tissues. However, these activities were mostly demonstrated at high doses of Chloroquine (higher than 10mg/kg or 10mg/l i.e. ca. 31μM). Nevertheless, it was reported that daily uptake of clinically acceptable doses (less than 10mg/kg) of Chloroquine in addition to chemo-radio-therapy increases the survival of glioblastoma patients (Sotelo et al., 2006; Briceno et al., 2007). However, the optimal dose and schedule of this multi-active drug with respect to chemotherapy has never been experimentally determined. The present article reviews the several known direct and indirect effects of different doses of Chloroquine on cancer and how those effects may indicate that a fine tuning of the dose/schedule of Chloroquine administration versus chemotherapy may be critical to obtain an adjuvant effect of Chloroquine in anti-cancer treatments. We anticipate that the appropriate (time and dose) addition of Chloroquine to the standard of care may greatly and safely potentiate current anti-cancer treatments. PMID:26687632

  15. Chloroquine has tumor-inhibitory and tumor-promoting effects in triple-negative breast cancer

    PubMed Central

    TUOMELA, JOHANNA; SANDHOLM, JOUKO; KAUPPILA, JOONAS H.; LEHENKARI, PETRI; HARRIS, KEVIN W.; SELANDER, KATRI S.

    2013-01-01

    Toll-like receptor-9 (TLR9) is an intracellular DNA receptor that is widely expressed in breast and other cancers. We previously demonstrated that low tumor TLR9 expression upon diagnosis is associated with significantly shortened disease-specific survival times in patients with triple-negative breast cancer (TNBC). There are no targeted therapies for this subgroup of patients whose prognosis is among the worst in breast cancer. Due to the previously detected in vitro anti-invasive effects of chloroquine in these cell lines, the present study aimed to investigate the in vivo effects of chloroquine against two clinical subtypes of TNBC that differ in TLR9 expression. Chloroquine suppressed matrix metalloproteinase (MMP)-2 and MMP-9 mRNA expression and protein activity, whereas MMP-13 mRNA expression and proteolytic activity were increased. Despite enhancing TLR9 mRNA expression, chloroquine suppressed TLR9 protein expression in vitro. Daily treatment of mice with intraperitoneal (i.p.) chloroquine (80 mg/kg/day) for 22 days, did not inhibit the growth of control siRNA or TLR9 siRNA MDA-MB-231 breast cancer cells. In conclusion, despite the favorable in vitro effects on TNBC invasion and viability, particularly in hypoxic conditions, chloroquine does not prevent the growth of the triple-negative MDA-MB-231 cells with high or low TLR9 expression levels in vivo. This may be explained by the activating effects of chloroquine on MMP-13 expression or by the fact that chloroquine, by suppressing TLR9 expression, permits the activation of currently unknown molecular pathways, which allow the aggressive behavior of TNBC cells with low TLR9 expression in hypoxia. PMID:24273604

  16. 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

    SciTech Connect

    Vandevoorde, Severine; Saha, Bijali; Mahadevan, Anu; Razdan, Raj K.; Pertwee, Roger G.; Martin, Billy R.; Fowler, Christopher J. . E-mail: cf@pharm.umu.se

    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 (IC{sub 50} values in the range 5.1-8.2 {mu}M), whereas the two compounds with a single unsaturated bond were less potent (IC{sub 50} values 19 and 21 {mu}M). 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 IC{sub 50} values of 12 and 32 {mu}M, respectively. The 22-carbon chain analogue of 1-AG was also potent (IC{sub 50} value 4.5 {mu}M). 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.

  17. Antitumor and antimetastatic activities of chloroquine diphosphate in a murine model of breast cancer.

    PubMed

    Jiang, Pei-Du; Zhao, Ying-Lan; Deng, Xiao-Qiang; Mao, Yong-Qiu; Shi, Wei; Tang, Qing-Qing; Li, Zheng-Guang; Zheng, Yu-Zhu; Yang, Sheng-Yong; Wei, Yu-Quan

    2010-11-01

    Metastatic breast cancers are hard to treat and almost always fatal. Chloroquine diphosphate, a derivative of quinine, has long been used as a potent and commonly used medicine against different human diseases. We therefore investigated the effects of chloroquine diphosphate on a highly metastatic mouse mammary carcinoma cell line. In vitro treatment of 4T1 mouse breast cancer cells with chloroquine diphosphate resulted in significant inhibition of cellular proliferation and viability, and induction of apoptosis in 4T1 cells in a time- and dose-dependent manner. Further analysis indicated that induction of apoptosis was associated with the loss of mitochondrial membrane potential, release of cytochrome c, and activation of caspase-9 and caspase-3, and cleavage of poly(ADP-ribose) polymerase. The effect of chloroquine diphosphate was then examined using a mice model in which 4T1 cells were implanted subcutaneously. Chloroquine diphosphate (25mg/kg and 50mg/kg, respectively) significantly inhibited the growth of the implanted 4T1 tumor cells and induced apoptosis in the tumor microenvironment. Moreover, the metastasis of tumor cells to the lungs was inhibited significantly and the survival of the mice enhanced. These data suggested that chloroquine diphosphate might have chemotherapeutic efficacy against breast cancer including inhibition of metastasis. PMID:20888174

  18. Nonstationary analogue black holes

    NASA Astrophysics Data System (ADS)

    Eskin, Gregory

    2014-12-01

    We study the existence of analogue nonstationary spherically symmetric black holes. The prime example is the acoustic model see Unruh (1981 Phys. Rev. Lett. 46 1351). We consider also a more general class of metrics that could be useful in other physical models of analogue black and white holes. We give examples of the appearance of black holes and of disappearance of white holes. We also discuss the relation between the apparent and the event horizons for the case of analogue black holes. In the end we study the inverse problem of determination of black or white holes by boundary measurements for the spherically symmetric nonstationary metrics.

  19. Simple Molecular Methods for Early Detection of Chloroquine Drug Resistance in Plasmodium vivax and Plasmodium falciparum

    PubMed Central

    Singh, Raksha; Urhehar, Anant Dattatraya

    2016-01-01

    Introduction Malaria is a human disease of which causes high morbidity and mortality. In Plasmodium falciparum malaria, the resistance to antimalarial drugs, especially chloroquine (CQ) is one of the paramount factors contributing to the global increase in morbidity and mortality, due to malaria. Hence, there is a need for detection of chloroquine drug resistance genes i.e., pfcrt-o (Plasmodium falciparum chloroquine resistance transporter-o) and pfmdr-1 (Plasmodium falciparum multidrug resistance-1) of P. falciparum and pvcrt-o (Plasmodium vivax chloroquine resistance transporter-o) and pvmdr-1 (Plasmodium vivax multidrug resistance-1) of P. vivax by using molecular methods to prevent mortality in malarial cases. Aim To standardize chloroquine drug sensitivity testing by molecular method so as to provide reports of chloroquine within 6-8 hours to physicians for better treatment. Materials and Methods This study was conducted over a period of one year from January to December 2014. A Total of 300 blood samples were collected from malaria suspected patient attending MGM Hospital, Kamothe, Navi Mumbai, India. Out of 300 blood samples, 44 were malaria positive as assessed by Thick and Thin blood smear stained, by Leishman’s method and examination with light microscope. Chloroquine drug sensitivity testing was performed using WHO III plate method (micro test). Nested PCR was done for detection of pfcrt-o and pfmdr-1 for P. falciparum and pvcrt-o, pvmdr-1 genes for P. vivax. Results Total 44 samples were included in this study, out of which 22 samples confirmed for Plasmodium falciparum and 22 samples confirmed for Plasmodium vivax. Out of 22 P. falciparum 15 (68.18%) samples were chloroquine resistant. P. vivax showed chloroquine resistance to 5 samples (22.73%) by method similar to WHO III plate method (micro test) and nested PCR. Conclusion Drug resistance testing by molecular methods is useful for early detection of antimalarial drug resistance. pfmdr-1 along with

  20. Simple Molecular Methods for Early Detection of Chloroquine Drug Resistance in Plasmodium vivax and Plasmodium falciparum

    PubMed Central

    Singh, Raksha; Urhehar, Anant Dattatraya

    2016-01-01

    Introduction Malaria is a human disease of which causes high morbidity and mortality. In Plasmodium falciparum malaria, the resistance to antimalarial drugs, especially chloroquine (CQ) is one of the paramount factors contributing to the global increase in morbidity and mortality, due to malaria. Hence, there is a need for detection of chloroquine drug resistance genes i.e., pfcrt-o (Plasmodium falciparum chloroquine resistance transporter-o) and pfmdr-1 (Plasmodium falciparum multidrug resistance-1) of P. falciparum and pvcrt-o (Plasmodium vivax chloroquine resistance transporter-o) and pvmdr-1 (Plasmodium vivax multidrug resistance-1) of P. vivax by using molecular methods to prevent mortality in malarial cases. Aim To standardize chloroquine drug sensitivity testing by molecular method so as to provide reports of chloroquine within 6-8 hours to physicians for better treatment. Materials and Methods This study was conducted over a period of one year from January to December 2014. A Total of 300 blood samples were collected from malaria suspected patient attending MGM Hospital, Kamothe, Navi Mumbai, India. Out of 300 blood samples, 44 were malaria positive as assessed by Thick and Thin blood smear stained, by Leishman’s method and examination with light microscope. Chloroquine drug sensitivity testing was performed using WHO III plate method (micro test). Nested PCR was done for detection of pfcrt-o and pfmdr-1 for P. falciparum and pvcrt-o, pvmdr-1 genes for P. vivax. Results Total 44 samples were included in this study, out of which 22 samples confirmed for Plasmodium falciparum and 22 samples confirmed for Plasmodium vivax. Out of 22 P. falciparum 15 (68.18%) samples were chloroquine resistant. P. vivax showed chloroquine resistance to 5 samples (22.73%) by method similar to WHO III plate method (micro test) and nested PCR. Conclusion Drug resistance testing by molecular methods is useful for early detection of antimalarial drug resistance. pfmdr-1 along with

  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. Photophysical properties and photobiological behavior of amodiaquine, primaquine and chloroquine.

    PubMed

    Viola, Giampietro; Salvador, Alessia; Cecconet, Laura; Basso, Giuseppe; Vedaldi, Daniela; Dall'Acqua, Francesco; Aloisi, Gian Gaetano; Amelia, Matteo; Barbafina, Arianna; Latterini, Loredana; Elisei, Fausto

    2007-01-01

    This article describes the results of a coupled photophysical and photobiological study aimed at understanding the phototoxicity mechanism of the antimalarial drugs amodiaquine (AQ), primaquine (PQ) and chloroquine (CQ). Photophysical experiments were carried out in aqueous solutions by steady-state and time-resolved spectrometric techniques to obtain information on the different decay pathways of the excited states of the drugs and on the transient species formed upon laser irradiation. The results showed that all three drugs possess very low fluorescence quantum yields (10(-2)-10(-4)). Laser flash photolysis experiments proved the occurrence of photoionization processes leading to the formation of a radical cation in all three systems. In the case of AQ the lowest triplet state was also detected. Together with the photophysical properties the photobiological properties of the antimalarial drugs were investigated under UV irradiation, on various biological targets through a series of in vitro assays. Phototoxicity on mouse 3T3 fibroblast and human keratinocyte cell lines NCTC-2544 was detected for PQ and CQ but not for AQ. In particular, PQ- and CQ-induced apoptosis was revealed by the externalization of phosphatidylserine. Furthermore, upon UV irradiation, the drugs caused significant variations of the mitochondrial potential (Deltapsi(mt)) measured by flow cytometry. The photodamages produced by the drugs were also evaluated on proteins, lipids and DNA. The combined approaches were useful in understanding the mechanism of phototoxicity induced by these antimalarial drugs. PMID:18028216

  3. Properties of binding sites for chloroquine in liver lysosomal membranes.

    PubMed

    Colombo, M I; Bertini, F

    1988-12-01

    Chloroquine (CQ) is an antimalarial and antirheumatic drug that accumulates in lysosomes. We purified liver lysosomal membranes of tritosomes from albino mice injected with Triton WR 1339. The membranes were used for the binding assay with CQ in 0.01 M Tris-HCl buffer (pH 7.4). This binding was saturable, with a KD value of 6.2 microM. To understand the nature of CQ affinity, the binding was done under conditions that alter membrane structure and composition. Changes in pH, high ionic strength, and bivalent cations reversibly decreased the binding, while the effect of non-ionic detergents was partially reversed. The cationic detergent Hyamine strongly decreased the binding, and its effect was trypsin and neuraminidase had no effect. The results indicate the existence of binding sites for CQ in liver lysosomal membranes, which were strongly affected by changes of charge in the molecules involved in the binding. The treatment with the enzymes suggests that loss of polar groups of phospholipids increases the affinity of CQ by exposing protein sites located deep in the membrane, or by permiting a closer interaction between the drug and membrane lipids. CQ lysosomotropism and other effects of CQ on the lysosomal apparatus studied by other authors may be due not only to its accumulation inside the acid milieu of the lysosomes, in the same manner as other weak bases, but also to the affinity of CQ for binding sites in the lysosomal membrane. PMID:3192634

  4. 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.

  5. Biphasic activity of chloroquine in human colorectal cancer cells.

    PubMed

    Park, Deokbae; Lee, Youngki

    2014-12-01

    Autophagy is a homeostatic degradation process that is involved in tumor development and normal development. Autophagy is induced in cancer cells in response to chemotherapeutic agents, and inhibition of autophagy results in enhanced cancer cell death or survival. Chloroquine (CQ), an anti-malarial devrepug, is a lysosomotropic agent and is currently used as a potential anticancer agent as well as an autophagy inhibitor. Here, we evaluate the characteristics of these dual activities of CQ using human colorectal cancer cell line HCT15. The results show that CQ inhibited cell viability in dose-and time-dependent manner in the range between 20 to 80 uM, while CQ did not show any antiproliferative activity at 5 and 10 uM. Cotreatment of CQ with antitumor agent NVP-BEZ235, a dual inhibitor of PI3K/mTOR, rescued the cell viability at low concentrations meaning that CQ acted as an autophagy inhibitor, but CQ induced the lethal effect at high concentrations. Acridine orange staining revealed that CQ at high doses induced lysosomal membrane permeabilization (LMP). High doses of CQ produced cellular reactive oxygen species (ROS) and cotreatment of antioxidants, such as NAC and trolox, with high doses of CQ rescued the cell viability. These results suggest that CQ may exert its dual activities, as autophagy inhibitor or LMP inducer, in concentration-dependent manner. PMID:25949192

  6. Biphasic Activity of Chloroquine in Human Colorectal Cancer Cells

    PubMed Central

    Park, Deokbae; Lee, Youngki

    2014-01-01

    Autophagy is a homeostatic degradation process that is involved in tumor development and normal development. Autophagy is induced in cancer cells in response to chemotherapeutic agents, and inhibition of autophagy results in enhanced cancer cell death or survival. Chloroquine (CQ), an anti-malarial devrepug, is a lysosomotropic agent and is currently used as a potential anticancer agent as well as an autophagy inhibitor. Here, we evaluate the characteristics of these dual activities of CQ using human colorectal cancer cell line HCT15. The results show that CQ inhibited cell viability in dose-and time-dependent manner in the range between 20 to 80 uM, while CQ did not show any antiproliferative activity at 5 and 10 uM. Cotreatment of CQ with antitumor agent NVP-BEZ235, a dual inhibitor of PI3K/mTOR, rescued the cell viability at low concentrations meaning that CQ acted as an autophagy inhibitor, but CQ induced the lethal effect at high concentrations. Acridine orange staining revealed that CQ at high doses induced lysosomal membrane permeabilization (LMP). High doses of CQ produced cellular reactive oxygen species (ROS) and cotreatment of antioxidants, such as NAC and trolox, with high doses of CQ rescued the cell viability. These results suggest that CQ may exert its dual activities, as autophagy inhibitor or LMP inducer, in concentration-dependent manner. PMID:25949192

  7. Pentacycloundecylamines and conjugates thereof as chemosensitizers and reversed chloroquine agents.

    PubMed

    Joubert, Jacques; Fortuin, Elton E; Taylor, Dale; Smith, Peter J; Malan, Sarel F

    2014-12-01

    The control of malaria has been complicated by increased resistance of the malaria parasite to existing antimalarials such as chloroquine (CQ). Herein, we report the ability of NGP1-01, the prototype pentacycloundecylamine (PCU), to reverse CQ resistance (>50%) and act as a chemosensitizer. Based on this finding we set out to synthesize a small series of novel agents comprising of a PCU moiety as the reversal agent conjugated to a CQ-like aminoquinoline (AM) molecule and evaluate the potential of these PCU-AM derivatives as reversed CQ agents. PCU-AM derivatives 1-3 showed anti-plasmodial IC50 values in the ranges of 3.74-17.6 nM and 27.6-253.5 nM against CQ-sensitive (D10) and CQ-resistant strains (Dd2) of Plasmodium falciparum, respectively. Compound 1 presented with the best antiplasmodial activity at low nM concentrations against both strains and was found to be 5 fold more active against the resistant strain than CQ. Compound 1 can be considered as a lead compound to develop reversed CQ agents with improved pharmacodynamic and pharmacokinetic properties. PMID:25451997

  8. Contrasting ex vivo efficacies of "reversed chloroquine" compounds in chloroquine-resistant Plasmodium falciparum and P. vivax isolates.

    PubMed

    Wirjanata, Grennady; Sebayang, Boni F; Chalfein, Ferryanto; Prayoga; Handayuni, Irene; Noviyanti, Rintis; Kenangalem, Enny; Poespoprodjo, Jeanne Rini; Burgess, Steven J; Peyton, David H; Price, Ric N; Marfurt, Jutta

    2015-09-01

    Chloroquine (CQ) has been the mainstay of malaria treatment for more than 60 years. However, the emergence and spread of CQ resistance now restrict its use to only a few areas where malaria is endemic. The aim of the present study was to investigate whether a novel combination of a CQ-like moiety and an imipramine-like pharmacophore can reverse CQ resistance ex vivo. Between March to October 2011 and January to September 2013, two "reversed chloroquine" (RCQ) compounds (PL69 and PL106) were tested against multidrug-resistant field isolates of Plasmodium falciparum (n = 41) and Plasmodium vivax (n = 45) in Papua, Indonesia, using a modified ex vivo schizont maturation assay. The RCQ compounds showed high efficacy against both CQ-resistant P. falciparum and P. vivax field isolates. For P. falciparum, the median 50% inhibitory concentrations (IC50s) were 23.2 nM for PL69 and 26.6 nM for PL106, compared to 79.4 nM for unmodified CQ (P < 0.001 and P = 0.036, respectively). The corresponding values for P. vivax were 19.0, 60.0, and 60.9 nM (P < 0.001 and P = 0.018, respectively). There was a significant correlation between IC50s of CQ and PL69 (Spearman's rank correlation coefficient [r s] = 0.727, P < 0.001) and PL106 (rs = 0.830, P < 0.001) in P. vivax but not in P. falciparum. Both RCQs were equally active against the ring and trophozoite stages of P. falciparum, but in P. vivax, PL69 and PL106 showed less potent activity against trophozoite stages (median IC50s, 130.2 and 172.5 nM) compared to ring stages (median IC50s, 17.6 and 91.3 nM). RCQ compounds have enhanced ex vivo activity against CQ-resistant clinical isolates of P. falciparum and P. vivax, suggesting the potential use of reversal agents in antimalarial drug development. Interspecies differences in RCQ compound activity may indicate differences in CQ pharmacokinetics between the two Plasmodium species.

  9. Factors associated with regional bias of pfcrt (plasmodium falciparum chloroquine resistance transporter) haplotypes in Nepal.

    PubMed

    Banjara, Megha Raj; Imwong, Mallika; Petmitr, Songsak; Sirawaraporn, Worachart; Joshi, Anand B; Chavalitshewinkoon-Petmitr, Porntip

    2011-01-01

    Evidences of reappearance of chloroquine sensitive Plasmodium falciparum haplotypes after cessation of chloroquine in many countries provide a rationale for the search of chloroquine sensitive haplotypes in P. falciparum isolates in Nepal where the use of chloroquine for falciparum malaria treatment has been ceased since 1988. P. falciparum chloroquine resistant transporter gene (pfcrt) haplotypes were determined and the factors associated with pfcrt haplotypes in the Eastern and Central regions of Nepal were identified. Blood samples from 106 microscopy-positive falciparum malaria patients (62 from the Eastern and 44 from the Central region) were collected on filter paper. Pfcrt region covering codons 72-76 was amplified by PCR and sequenced. SVMNT haplotype was predominant in the Central region, whereas CVIET haplotype significantly more common in the Eastern region. In multivariable analysis of factors associated with CVIET haplotype, the Eastern region and parasite isolates from patients visiting India within one month are significant at 5% level of significance. These findings suggest that antimalarial pressure is different between Eastern and Central regions of Nepal and there is a need of an effective malaria control program in the border areas between India and Nepal.

  10. Sontochin as a Guide to the Development of Drugs against Chloroquine-Resistant Malaria

    PubMed Central

    Pou, Sovitj; Winter, Rolf W.; Nilsen, Aaron; Kelly, Jane Xu; Li, Yuexin; Doggett, J. Stone; Riscoe, Erin W.; Wegmann, Keith W.; Hinrichs, David J.

    2012-01-01

    Sontochin was the original chloroquine replacement drug, arising from research by Hans Andersag 2 years after chloroquine (known as “resochin” at the time) had been shelved due to the mistaken perception that it was too toxic for human use. We were surprised to find that sontochin, i.e., 3-methyl-chloroquine, retains significant activity against chloroquine-resistant strains of Plasmodium falciparum in vitro. We prepared derivatives of sontochin, “pharmachins,” with alkyl or aryl substituents at the 3 position and with alterations to the 4-position side chain to enhance activity against drug-resistant strains. Modified with an aryl substituent in the 3 position of the 7-chloro-quinoline ring, Pharmachin 203 (PH-203) exhibits low-nanomolar 50% inhibitory concentrations (IC50s) against drug-sensitive and multidrug-resistant strains and in vivo efficacy against patent infections of Plasmodium yoelii in mice that is superior to chloroquine. Our findings suggest that novel 3-position aryl pharmachin derivatives have the potential for use in treating drug resistant malaria. PMID:22508305

  11. Chloroquine activates the p53 pathway and induces apoptosis in human glioma cells

    PubMed Central

    Kim, Ella L.; Wüstenberg, Robin; Rübsam, Anne; Schmitz-Salue, Christoph; Warnecke, Gabriele; Bücker, Eva-Maria; Pettkus, Nadine; Speidel, Daniel; Rohde, Veit; Schulz-Schaeffer, Walter; Deppert, Wolfgang; Giese, Alf

    2010-01-01

    Glioblastoma is the most common malignant brain tumor in adults. The currently available treatments offer only a palliative survival advantage and the need for effective treatments remains an urgent priority. Activation of the p53 growth suppression/apoptotic pathway is one of the promising strategies in targeting glioma cells. We show that the quinoline derivative chloroquine activates the p53 pathway and suppresses growth of glioma cells in vitro and in vivo in an orthotopic (U87MG) human glioblastoma mouse model. Induction of apoptosis is one of the mechanisms underlying the effects of chloroquine on suppressing glioma cell growth and viability. siRNA-mediated downregulation of p53 in wild-type but not mutant p53 glioblastoma cells substantially impaired chloroquine-induced apoptosis. In addition to its p53-activating effects, chloroquine may also inhibit glioma cell growth via p53-independent mechanisms. Our results clarify the mechanistic basis underlying the antineoplastic effect of chloroquine and reveal its therapeutic potential as an adjunct to glioma chemotherapy. PMID:20308316

  12. Chloroquine targets pancreatic cancer stem cells via inhibition of CXCR4 and hedgehog signaling.

    PubMed

    Balic, Anamaria; Sørensen, Morten Dræby; Trabulo, Sara Maria; Sainz, Bruno; Cioffi, Michele; Vieira, Catarina R; Miranda-Lorenzo, Irene; Hidalgo, Manuel; Kleeff, Joerg; Erkan, Mert; Heeschen, Christopher

    2014-07-01

    Pancreatic ductal adenocarcinoma is one of the deadliest carcinomas and is characterized by highly tumorigenic and metastatic cancer stem cells (CSC). CSCs evade available therapies, which preferentially target highly proliferative and more differentiated progenies, leaving behind CSCs as a putative source for disease relapse. Thus, to identify potentially more effective treatment regimens, we screened established and new compounds for their ability to eliminate CSCs in primary pancreatic cancer (stem) cells in vitro and corresponding patient-derived pancreatic cancer tissue xenografts in vivo. Intriguingly, we found that in vitro treatment with the antimalarial agent chloroquine significantly decreased CSCs, translating into diminished in vivo tumorigenicity and invasiveness in a large panel of pancreatic cancers. In vivo treatment in combination with gemcitabine was capable of more effectively eliminating established tumors and improved overall survival. The inhibitory effect of chloroquine was not related to inhibition of autophagy, but was due to inhibition of CXCL12/CXCR4 signaling, resulting in reduced phosphorylation of ERK and STAT3. Furthermore, chloroquine showed potent inhibition of hedgehog signaling by decreasing the production of Smoothened, translating into a significant reduction in sonic hedgehog-induced chemotaxis and downregulation of downstream targets in CSCs and the surrounding stroma. Our study demonstrates that via to date unreported effects, chloroquine is an effective adjuvant therapy to chemotherapy, offering more efficient tumor elimination and improved cure rates. Chloroquine should be further explored in the clinical setting as its success may help to more rapidly improve the poor prognosis of patients with pancreatic cancer. PMID:24785258

  13. 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. PMID:23288916

  14. 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. PMID:27178823

  15. 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.

  16. Chloroquine sensitizes breast cancer cells to chemotherapy independent of autophagy.

    PubMed

    Maycotte, Paola; Aryal, Suraj; Cummings, Christopher T; Thorburn, Jacqueline; Morgan, Michael J; Thorburn, Andrew

    2012-02-01

    Chloroquine (CQ) is a 4-aminoquinoline drug used for the treatment of diverse diseases. It inhibits lysosomal acidification and therefore prevents autophagy by blocking autophagosome fusion and degradation. In cancer treatment, CQ is often used in combination with chemotherapeutic drugs and radiation because it has been shown to enhance the efficacy of tumor cell killing. Since CQ and its derivatives are the only inhibitors of autophagy that are available for use in the clinic, multiple ongoing clinical trials are currently using CQ or hydroxychloroquine (HCQ) for this purpose, either alone, or in combination with other anticancer drugs. Here we show that in the mouse breast cancer cell lines, 67NR and 4T1, autophagy is induced by the DNA damaging agent cisplatin or by drugs that selectively target autophagy regulation, the PtdIns3K inhibitor LY294002, and the mTOR inhibitor rapamycin. In combination with these drugs, CQ sensitized to these treatments, though this effect was more evident with LY294002 and rapamycin treatment. Surprisingly, however, in these experiments CQ sensitization occurred independent of autophagy inhibition, since sensitization was not mimicked by Atg12, Beclin 1 knockdown or bafilomycin treatment, and occurred even in the absence of Atg12. We therefore propose that although CQ might be helpful in combination with cancer therapeutic drugs, its sensitizing effects can occur independently of autophagy inhibition. Consequently, this possibility should be considered in the ongoing clinical trials where CQ or HCQ are used in the treatment of cancer, and caution is warranted when CQ treatment is used in cytotoxic assays in autophagy research. PMID:22252008

  17. Chloroquine sensitizes breast cancer cells to chemotherapy independent of autophagy

    PubMed Central

    Maycotte, Paola; Aryal, Suraj; Cummings, Christopher T; Thorburn, Jacqueline; Morgan, Michael J

    2012-01-01

    Chloroquine (CQ) is a 4-aminoquinoline drug used for the treatment of diverse diseases. It inhibits lysosomal acidification and therefore prevents autophagy by blocking autophagosome fusion and degradation. In cancer treatment, CQ is often used in combination with chemotherapeutic drugs and radiation because it has been shown to enhance the efficacy of tumor cell killing. Since CQ and its derivatives are the only inhibitors of autophagy that are available for use in the clinic, multiple ongoing clinical trials are currently using CQ or hydroxychloroquine (HCQ) for this purpose, either alone, or in combination with other anticancer drugs. Here we show that in the mouse breast cancer cell lines, 67NR and 4T1, autophagy is induced by the DNA damaging agent cisplatin or by drugs that selectively target autophagy regulation, the PtdIns3K inhibitor LY294002, and the mTOR inhibitor rapamycin. In combination with these drugs, CQ sensitized to these treatments, though this effect was more evident with LY294002 and rapamycin treatment. Surprisingly, however, in these experiments CQ sensitization occurred independent of autophagy inhibition, since sensitization was not mimicked by Atg12, Beclin 1 knockdown or bafilomycin treatment, and occurred even in the absence of Atg12. We therefore propose that although CQ might be helpful in combination with cancer therapeutic drugs, its sensitizing effects can occur independently of autophagy inhibition. Consequently, this possibility should be considered in the ongoing clinical trials where CQ or HCQ are used in the treatment of cancer, and caution is warranted when CQ treatment is used in cytotoxic assays in autophagy research. PMID:22252008

  18. Biodegradable analogues of DDT*

    PubMed Central

    Metcalf, Robert L.; Kapoor, Inder P.; Hirwe, Asha S.

    1971-01-01

    Despite the immense utility of DDT for vector control its usefulness is prejudiced by its stability in the environment and by the low rate at which it can be degraded biologically. Metabolic studies in insects, in mice, and in a model ecosystem with several food chains have shown that DDT analogues with substituent groups readily attacked by multifunction oxidases undergo a substantial degree of biological degradation and do not appear to be stored readily in animal tissues or concentrated in food chains. Detailed metabolic pathways have been worked out and it is clear that comparative biochemistry can be used to develop DDT analogues that are adequately persistent yet biodegradable. A number of new DDT analogues have been evaluated for insecticidal activity against flies and mosquitos and for their potential usefulness as safe, persistent, and biodegradable insecticides. PMID:5315354

  19. Menhaden-fish oil in a vitamin E-deficient diet: protection against chloroquine-resistant malaria in mice.

    PubMed

    Levander, O A; Ager, A L; Morris, V C; May, R G

    1989-12-01

    Feeding a vitamin E-deficient diet containing 5% menhaden oil to mice affords significant protection against both a chloroquine-sensitive and a chloroquine-resistant line of the malarial parasite. Nutritional manipulation may offer a new approach to the problem of drug-resistant malaria, a rapidly emerging global threat to public health. PMID:2688393

  20. 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.

  1. Chloroquine enhanced the anticancer capacity of VNP20009 by inhibiting autophagy

    PubMed Central

    Zhang, Xiaoxin; Xu, Qiaoqiao; Zhang, Zhuangzhuang; Cheng, Wei; Cao, Wenmin; Jiang, Chizhou; Han, Chao; Li, Jiahuang; Hua, Zichun

    2016-01-01

    Bacteria-based living anticancer agents have emerged as promising therapeutics. However, the functional role of autophagy in bacterial cancer therapy has been little investigated. In this study, Salmonella VNP20009 induced autophagy in B16F10 cells, which is an unfavorable factor in bacterial cancer therapy. Inhibiting the induction of autophagy by chloroquine or siRNA in bacterial cancer therapy dose- and time-dependently promoted cell death. The combined therapy of VNP20009 and chloroquine not only enhanced the bacterial tumor targeting ability but also facilitated the infiltration of immune cells into the tumor. Our results showed that the combined therapy of VNP20009 and chloroquine could significantly inhibit tumor growth and prolong mouse survival time. This study provides a novel strategy for improving the anti-cancer efficacy of bacterial cancer therapy. PMID:27412722

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

    PubMed

    Boudhar, Aicha; Ng, Xiao Wei; Loh, Chiew Yee; Chia, Wan Ni; Tan, Zhi Ming; Nosten, Francois; Dymock, Brian W; Tan, Kevin S W

    2016-05-01

    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.

  3. 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

  4. Synthesis and antimalarial activity of new isotebuquine analogues.

    PubMed

    Miroshnikova, Olga V; Hudson, Thomas H; Gerena, Lucia; Kyle, Dennis E; Lin, Ai J

    2007-02-22

    Amodiaquine (AQ) and tebuquine are 4-aminoquinoline antimalarials with Mannich base side chain and are highly effective against chloroquine (CQ)-resistant strains of Plasmodium falciparum. Clinical use of AQ has been severely restricted due to hepatoxicity and agranulocytosis side effects associated with its long term use. Lysosomal accumulation and bioactivation to generate reactive quinoneimine metabolite are implicated to be the cause of the observed AQ toxicities. To avoid the quinoneimine formation and thus the toxicity, a series of isotebuquine analogues and their Nomega-oxides with hydroxy group meta to the amino rather than in para position of the aniline moiety were prepared. The new Mannich bases are highly active against both CQ-sensitive (D6) and -resistant (W2 and TM91C235) clones of P. falciparum with IC50 in the range of 0.3-120 ng/mL. New compounds are1000-fold less toxic (IC50 = 0.7-6 microg/mL) to mouse macrophage cell line than to parasite cell lines. Mono-Mannich bases are more active than bis-Mannich bases. Mono-Mannich base 1a (IC50 = 0.3 ng/mL) is 20-fold more active than the corresponding trifluoromethyl analogue 1b. No appreciable difference in either toxicity or efficacy were observed between the new Mannich bases (m-hydroxyaniline derivatives) 1a or 2a and the corresponding p-hydroxyaniline derivatives.

  5. Chloroquine resistance and Plasmodium falciparum in Punjab, Pakistan during 2000-2001.

    PubMed

    Rana, Muhammad Saleem; Tanveer, Akhtar

    2004-06-01

    During the years 2000-2001, the rural populations of 5 districts in Punjab were examined for malarial parasites. The incidence of Plasmodium falciparum was more than double (8.98%) that of P. vivax (4.06%). The incidence was higher among male subjects (53.5%) than females (46.9%). The largest number of infected male subjects was found in Sheikhupura district (77.78%). Chloroquine resistance was only checked in the subjects harboring P. falciparum, using in vivo techniques. Overall chloroquine sensitivity was 63.8%. Overall frequency of chloroquine resistance in the 5 Punjabi districts was 35%, with 30.6% RI and 4.4% RII. It is important that RIII was not found in the present study. Among the five districts, maximum RI (35.1%) and RII (5.4%) were noted in Multan. By age, maximum chloroquine resistance was noted in the 1-5 year age group (ie RI, 41%; RII 8%). A similar RI value (41%) was noted for the 6-14 age group, but with a low RII (3%) value. Although, the present finding is an outcome of a survey conducted in only 5 districts of Punjab, it reflects an alarming situation, as not only RI and RII resistance against chloroquine is increasing, but at the same time the incidence of P. falciparum is increasing two-fold that of P. vivax. The findings warrant that top priority be given to determining the exact status of chloroquine resistance among P. falciparum in this region, which is now hosting a heavy influx of refugees from Afghanistan, a country endemic for P. falciparum. PMID:15691126

  6. Chloroquine retinopathy: pattern of presentation in Ibadan, Sub-Sahara Africa.

    PubMed

    Oluleye, T S; Babalola, Y; Ijaduola, M

    2016-01-01

    BackgroundSelf-medication with chloroquine is common in Ibadan, Sub-Sahara Africa. Retinopathy from chloroquine is not uncommon. The aim was to determine the pattern of presentation.MethodologyCases of Chloroquine retinopathy seen at the Retina and Vitreous Unit of the University College Hospital, Ibadan between 2008 and 2014 were reviewed. Information on age, sex, duration of chloroquine use, and visual loss were retrieved. Visual acuity at presentation, anterior, and posterior segment findings were documented. The results were analyzed using proportions and percentages.ResultsFourteen cases were seen during the study period. Mean age was 50.7 years. Male to female ratio was 3.5 : 1. Average duration of visual loss before presentation was 2.7 years. Average duration of self-medication with chloroquine was 5.3 years. Presenting visual acuity showed 2(14%) cases of bilateral blindness(VA<3/60 in both eyes); 5(35.7%) cases of uniocular blindness; three cases of bilateral low vision(VA worse than 6/18 but better than 3/60). Anterior segment examination showed abnormal sluggish pupillary reaction in those with severe affectation. Dilated fundoscopy showed features ranging from mild macular pigmentary changes and bulls eye maculopathy to overt extensive retinal degeneration involving the posterior pole, attenuation of retinal vessels, optic atrophy, and beaten bronze appearance of atrophic maculopathy.ConclusionChloroquine retinopathy is not uncommon in Ibadan, Sub-Sahara Africa. Bulls eye maculopathy, extensive retinal, and macular degeneration with optic atrophy are the main presentations. Public health education is imperative. PMID:26427986

  7. Combination treatment with ABT-737 and chloroquine in preclinical models of small cell lung cancer

    PubMed Central

    2013-01-01

    Background New therapies are urgently needed for patients with small cell lung cancer (SCLC). Chemotherapy and targeted therapies, including the Bcl-2 inhibitor ABT-737, may induce tumor cell autophagy. Autophagy can promote survival of cancer cells under stress and comprise a pathway of escape from cytotoxic therapies. Methods We explored the combination of ABT-737 and chloroquine, an inhibitor of autophagy, in preclinical models of SCLC. These included cell culture analyses of viability and of autophagic and apoptotic pathway induction, as well as in vivo analyses of efficacy in multiple xenograft models. Results Combination treatment of SCLC lines with ABT-737 and chloroquine decreased viability and increased caspase-3 activation over treatment with either single agent. ABT-737 induced several hallmarks of autophagy. However, knockdown of beclin-1, a key regulator of entry into autophagy, diminished the efficacy of ABT-737, suggesting either that the effects of chloroquine were nonspecific or that induction but not completion of autophagy is necessary for the combined effect of ABT-737 and chloroquine. ABT-737 and chloroquine in SCLC cell lines downregulated Mcl-1 and upregulated NOXA, both of which may promote apoptosis. Treatment of tumor-bearing mice demonstrated that chloroquine could enhance ABT-737-mediated tumor growth inhibition against NCI-H209 xenografts, but did not alter ABT-737 response in three primary patient-derived xenograft models. Conclusion These data suggest that although ABT-737 can induce autophagy in SCLC, autophagic inhibition by choroquine does not markedly alter in vivo response to ABT-737 in relevant preclinical models, arguing against this as a treatment strategy for SCLC. PMID:23452820

  8. In vitro antimalarial activity and chloroquine potentiating action of two bisbenzylisoquinoline enantiomer alkaloids isolated from Strychnopsis thouarsii and Spirospermum penduliflorum.

    PubMed

    Ratsimamanga-Urverg, S; Rasoanaivo, P; Ramiaramanana, L; Milijaona, R; Rafatro, H; Verdier, F; Rakoto-Ratsimamanga, A; Le Bras, J

    1992-12-01

    The bisbenzylisoquinolines 7-O-demethyltetrandrine and limacine, respectively, isolated from Strychnopsis thouarsii Baill. and Spirospermum penduliflorum Thou. were evaluated for their intrinsic antimalarial activity in vitro and chloroquine potentiating action against the chloroquine-resistant Plasmodium falciparum FCM 29 originating from Cameroon. They both showed significant antiplasmodial potency in vitro with very similar IC50 values of respectively, 740 nM and 789 nM (IC50 = 214 nM for chloroquine used as standard drug), which demonstrated that the stereochemistry of the C-1 and C-1' configuration likely plays a role in the chloroquine potentiating effect of these drugs. If confirmed in vivo, these results may account for the traditional use of the two plants as antimalarials and adjuvant to chloroquine in Madagascan folklore remedies. PMID:1484894

  9. Inhibition of cyanide-resistant respiration in pea cotyledon mitochondria by chloroquine.

    PubMed

    James, T W; Spencer, M S

    1982-05-01

    The action on mitochondrial respiration of a ubiquinone analog, chloroquine, has been studied using purified mitochondria from the cotyledons of germinating peas (Pisum sativum L. var. Homesteader). Chloroquine at 3 millimolar did not inhibit malate or succinate oxidation at pH 7.2, but it did inhibit malate (but not succinate) oxidation at pH 8.2. Cyanide-resistant respiration was also inhibited.The implications of these experiments on the role of ubiquinone in the cyanide-resistant respiratory pathway and on the location of the alternate oxidase are discussed.

  10. Inhibition of Cyanide-Resistant Respiration in Pea Cotyledon Mitochondria by Chloroquine 1

    PubMed Central

    James, Terrance W.; Spencer, Mary S.

    1982-01-01

    The action on mitochondrial respiration of a ubiquinone analog, chloroquine, has been studied using purified mitochondria from the cotyledons of germinating peas (Pisum sativum L. var. Homesteader). Chloroquine at 3 millimolar did not inhibit malate or succinate oxidation at pH 7.2, but it did inhibit malate (but not succinate) oxidation at pH 8.2. Cyanide-resistant respiration was also inhibited. The implications of these experiments on the role of ubiquinone in the cyanide-resistant respiratory pathway and on the location of the alternate oxidase are discussed. PMID:16662353

  11. 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

  12. Chloroquine enhances the chemotherapeutic activity of 5-fluorouracil in a colon cancer cell line via cell cycle alteration.

    PubMed

    Choi, Jung-Hye; Yoon, Jin Sun; Won, Young-Woong; Park, Byeong-Bae; Lee, Young Yiul

    2012-07-01

    Autophagy is a conserved catabolic process that degrades cytoplasmic proteins and organelles for recycling. The role of autophagy in tumorigenesis is controversial because autophagy can be either protective or damaging to tumor cells, and its effects may change during tumor progression. A number of cancer cell lines have been exposed to chloroquine, an anti-malarial drug, with the aim of inhibiting cell growth and inducing cell death. In addition, chloroquine inhibits a late phase of autophagy. This study was conducted to investigate the anti-cancer effect of autophagy inhibition, using chloroquine together with 5-fluorouracil (5-FU) in a colon cancer cell line. Human colon cancer DLD-1 cells were treated with 5-FU (10 μΜ) or chloroquine (100 μΜ), or a combination of both. Autophagy was evaluated by western blot analysis of microtubule-associated protein light chain3 (LC3). Proliferative activity, alterations of the cell cycle, and apoptosis were measured by MTT assays, flow cytometry, and western blotting. LC3-II protein increased after treatment with 5-FU, and chloroquine potentiated the cytotoxicity of 5-FU. MTT assays showed that 5-FU inhibited proliferation of the DLD-1 cells and that chloroquine enhanced this inhibitory effect of 5-FU. The combination of 5-FU and chloroquine induced G1 arrest, up-regulation of p27 and p53, and down-regulation of CDK2 and cyclin D1. These results suggest that chloroquine may potentiate the anti-cancer effect of 5-FU via cell cycle inhibition. Chloroquine potentiates the anti-cancer effect of 5-FU in colon cancer cells. Supplementation of conventional chemotherapy with chloroquine may provide a new cancer therapy modality. PMID:22716215

  13. Natural Analogue Synthesis Report

    SciTech Connect

    A. M. Simmons

    2002-05-01

    The purpose of this report is to present analogue studies and literature reviews designed to provide qualitative and quantitative information to test and provide added confidence in process models abstracted for performance assessment (PA) and model predictions pertinent to PA. This report provides updates to studies presented in the ''Yucca Mountain Site Description'' (CRWMS M and O 2000 [151945], Section 13) and new examples gleaned from the literature, along with results of quantitative studies conducted specifically for the Yucca Mountain Site Characterization Project (YMP). The intent of the natural analogue studies was to collect corroborative evidence from analogues to demonstrate additional understanding of processes expected to occur during postclosure at a potential Yucca Mountain repository. The report focuses on key processes by providing observations and analyses of natural and anthropogenic (human-induced) systems to improve understanding and confidence in the operation of these processes under conditions similar to those that could occur in a nuclear waste repository. The process models include those that represent both engineered and natural barrier processes. A second purpose of this report is to document the various applications of natural analogues to geologic repository programs, focusing primarily on the way analogues have been used by the YMP. This report is limited to providing support for PA in a confirmatory manner and to providing corroborative inputs for process modeling activities. Section 1.7 discusses additional limitations of this report. Key topics for this report are analogues to emplacement drift degradation, waste form degradation, waste package degradation, degradation of other materials proposed for the engineered barrier, seepage into drifts, radionuclide flow and transport in the unsaturated zone (UZ), analogues to coupled thermal-hydrologic-mechanical-chemical processes, saturated zone (SZ) transport, impact of radionuclide

  14. Implications of Glutathione Levels in the Plasmodium berghei Response to Chloroquine and Artemisinin

    PubMed Central

    Vega-Rodríguez, Joel; Pastrana-Mena, Rebecca; Crespo-Lladó, Keila N.; Ortiz, José G.; Ferrer-Rodríguez, Iván; Serrano, Adelfa E.

    2015-01-01

    Malaria is one of the most devastating parasitic diseases worldwide. Plasmodium drug resistance remains a major challenge to malaria control and has led to the re-emergence of the disease. Chloroquine (CQ) and artemisinin (ART) are thought to exert their anti-malarial activity inducing cytotoxicity in the parasite by blocking heme degradation (for CQ) and increasing oxidative stress. Besides the contribution of the CQ resistance transporter (PfCRT) and the multidrug resistant gene (pfmdr), CQ resistance has also been associated with increased parasite glutathione (GSH) levels. ART resistance was recently shown to be associated with mutations in the K13-propeller protein. To analyze the role of GSH levels in CQ and ART resistance, we generated transgenic Plasmodium berghei parasites either deficient in or overexpressing the gamma-glutamylcysteine synthetase gene (pbggcs) encoding the rate-limiting enzyme in GSH biosynthesis. These lines produce either lower (pbggcs-ko) or higher (pbggcs-oe) levels of GSH than wild type parasites. In addition, GSH levels were determined in P. berghei parasites resistant to CQ and mefloquine (MQ). Increased GSH levels were detected in both, CQ and MQ resistant parasites, when compared to the parental sensitive clone. Sensitivity to CQ and ART remained unaltered in both pgggcs-ko and pbggcs-oe parasites when tested in a 4 days drug suppressive assay. However, recrudescence assays after the parasites have been exposed to a sub-lethal dose of ART showed that parasites with low levels of GSH are more sensitive to ART treatment. These results suggest that GSH levels influence Plasmodium berghei response to ART treatment. PMID:26010448

  15. 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

  16. Chitosan conjugated chloroquine: proficient to protect the induction of liver apoptosis during malaria.

    PubMed

    Tripathy, Satyajit; Chattopadhyay, Sourav; Dash, Sandeep Kumar; Chowdhuri, Angshuman Ray; Das, Sabyasachi; Sahu, Sumanta Kumar; Majumdar, Subrata; Roy, Somenath

    2015-03-01

    Chitosan has impelled continuous motion by its unique physicochemical and biological characteristics. In our study, chitosan-tripolyphosphate (CS-TPP) particles was conjugated with an undervalued antimalarial drug, chloroquine to find out the proficiency against ROS mediated caspase activation and apoptosis in liver during Plasmodium berghei NK65 infection. The transmission electron microscopic image illustrated the size range of particle was less than 50 nm and the particle showed the blood compatibility. ROS generation, mitochondrial membrane potential, anti apoptotic and pro apoptotic protein level of CS-TPP conjugated chloroquine treated group revealed that CS-TPP conjugation amplified the protective capability of chloroquine. FACS study by annexin v-FITC and PI staining reveals chloroquine treatment reduces significantly (P<0.05) the apoptotic cells by 25.31%; whereas chitosan-tripolyphosphate conjugated nanochloroquine decreases by 61.56% apoptotic cell against P. berghei induced liver apoptosis. This study suggests that proficiency of conventional antimalarial drug may escalate by delivery with chitosan nanoparticles to portray defense possessions against malarial damage.

  17. Non-selective cation channels mediate chloroquine-induced relaxation in precontracted mouse airway smooth muscle.

    PubMed

    Zhang, Ting; Luo, Xiao-Jing; Sai, Wen-Bo; Yu, Meng-Fei; 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.

  18. Chloroquine stimulates nitric oxide synthesis in murine, porcine, and human endothelial cells.

    PubMed Central

    Ghigo, D; Aldieri, E; Todde, R; Costamagna, C; Garbarino, G; Pescarmona, G; Bosia, A

    1998-01-01

    Nitric oxide (NO) is a free radical involved in the regulation of many cell functions and in the expression of several diseases. We have found that the antimalarial and antiinflammatory drug, chloroquine, is able to stimulate NO synthase (NOS) activity in murine, porcine, and human endothelial cells in vitro: the increase of enzyme activity is dependent on a de novo synthesis of some regulatory protein, as it is inhibited by cycloheximide but is not accompanied by an increased expression of inducible or constitutive NOS isoforms. Increased NO synthesis is, at least partly, responsible for chloroquine-induced inhibition of cell proliferation: indeed, NOS inhibitors revert the drug-evoked blockage of mitogenesis and ornithine decarboxylase activity in murine and porcine endothelial cells. The NOS-activating effect of chloroquine is dependent on its weak base properties, as it is exerted also by ammonium chloride, another lysosomotropic agent. Both compounds activate NOS by limiting the availability of iron: their stimulating effects on NO synthesis and inhibiting action on cell proliferation are reverted by iron supplementation with ferric nitrilotriacetate, and are mimicked by incubation with desferrioxamine. Our results suggest that NO synthesis can be stimulated in endothelial cells by chloroquine via an impairment of iron metabolism. PMID:9691096

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

    PubMed Central

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

    2015-01-01

    Summary 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. PMID:25898991

  20. 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. PMID:20074103

  1. 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.

  2. Mutations in the Plasmodium falciparum chloroquine resistance transporter, PfCRT, enlarge the parasite's food vacuole and alter drug sensitivities.

    PubMed

    Pulcini, Serena; Staines, Henry M; Lee, Andrew H; Shafik, Sarah H; Bouyer, Guillaume; Moore, Catherine M; Daley, Daniel A; Hoke, Matthew J; Altenhofen, Lindsey M; Painter, Heather J; Mu, Jianbing; Ferguson, David J P; Llinás, Manuel; Martin, Rowena E; Fidock, David A; Cooper, Roland A; Krishna, Sanjeev

    2015-09-30

    Mutations in the Plasmodium falciparum chloroquine resistance transporter, PfCRT, are the major determinant of chloroquine resistance in this lethal human malaria parasite. Here, we describe P. falciparum lines subjected to selection by amantadine or blasticidin that carry PfCRT mutations (C101F or L272F), causing the development of enlarged food vacuoles. These parasites also have increased sensitivity to chloroquine and some other quinoline antimalarials, but exhibit no or minimal change in sensitivity to artemisinins, when compared with parental strains. A transgenic parasite line expressing the L272F variant of PfCRT confirmed this increased chloroquine sensitivity and enlarged food vacuole phenotype. Furthermore, the introduction of the C101F or L272F mutation into a chloroquine-resistant variant of PfCRT reduced the ability of this protein to transport chloroquine by approximately 93 and 82%, respectively, when expressed in Xenopus oocytes. These data provide, at least in part, a mechanistic explanation for the increased sensitivity of the mutant parasite lines to chloroquine. Taken together, these findings provide new insights into PfCRT function and PfCRT-mediated drug resistance, as well as the food vacuole, which is an important target of many antimalarial drugs.

  3. 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.

  4. 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.

  5. Disposition of chloroquine in man after single intravenous and oral doses.

    PubMed

    Gustafsson, L L; Walker, O; Alván, G; Beermann, B; Estevez, F; Gleisner, L; Lindström, B; Sjöqvist, F

    1983-04-01

    1 Chloroquine was given in 300 mg single doses as an i.v. infusion, an oral solution and as tablets at intervals of at least 56 days to 11 healthy volunteers. Concentrations of chloroquine and its metabolite desethylchloroquine were measured in plasma, erythrocytes and urine using h.p.l.c. 2 Chloroquine was detectable in all plasma samples up to 23 days and occasionally up to 52 days after dosage. Urinary concentrations were monitored up to 119 days. The disposition pattern was multiexponential reflecting extensive tissue binding of the drug. 3 After i.v. dosing the volume of distribution ranged from 116 to 285 l/kg and the apparent terminal half-life from 146 to 333 h. Total plasma clearance +/- s.d. was 712 +/- 166 ml/min and renal clearance 412 +/- 139 ml/min. The mean estimated urinary recovery of chloroquine was 47%, 42% and 46% after i.v., oral solution and tablets indicating nearly complete bioavailability. The corresponding figures for the metabolite were 7%, 10% and 12%. 4 The disposition of chloroquine in erythrocytes was parallel to that in plasma. The concentrations in erythrocytes were consistently 2 to 5 times higher than in plasma. 5 Subjective side effects like difficulties with swallowing and accommodation, diplopia and fatigue occurred during intravenous infusion and were closely related to plasma concentrations. No effect was seen on the electrocardiogram, mean arterial blood pressure and pulse rate. No adverse reactions were observed after the oral doses. High frequency audiometry did not reveal any significant hearing impairment for the group as a whole.

  6. 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.

  7. The influence of double-diffusive processes on the melting of ice in the Arctic Ocean: laboratory analogue experiments and their interpretation

    NASA Astrophysics Data System (ADS)

    Turner, J. S.; Veronis, G.

    2004-03-01

    This study has been motivated by two oceanographic observations: an increased rate of melting of sea ice in the Arctic Ocean, and the advance of an anomalously warm tongue of Atlantic water across the Arctic below the halocline over the last few decades. A series of laboratory experiments has been carried out in order to explore the physical principles underlying these phenomena, and the possibility that the extra heating at depth is responsible for the enhanced melting rate. A tank was filled with salt solution having various constant vertical density gradients. A block of ice one third of the length of the tank was floated on the surface at one end, and the rest of the surface and the walls of the tank were insulated. When no extra heat was supplied the melting rate (loss of weight of the ice in 1 h) systematically decreased as the stratification was changed from homogeneous fluid to increasingly large density gradients, while keeping the salinity of the solution in contact with the ice constant. An analogue of the intruding Atlantic water was produced by heating the lower portion of the vertical end wall at the end of the tank opposite to the ice end, keeping its temperature constant, and using the same range of salinity gradients as in the unheated experiments. Again the melting rate decreased as the density gradient was increased, but for low gradients it was larger than that in the unheated experiments. Above a certain intermediate gradient there was no significant difference in melting rate between the unheated and heated runs. The melting data were supplemented by photographs and vertical temperature and salinity profiles. The upward transfer of heat from the body of the fluid to melt the ice was clearly double-diffusive: overturning layers, separated by 'diffusive' interfaces, were visible on shadowgraphs, and the thickness of the layers decreased as the density gradient increased. The mean thickness of the layers through the depth of the tank also

  8. 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

  9. The influence of N-acetyl-L-cysteine on oxidative stress and nitric oxide synthesis in stimulated macrophages treated with a mustard gas analogue

    PubMed Central

    Paromov, Victor; Qui, Min; Yang, Hongsong; Smith, Milton; Stone, William L

    2008-01-01

    Background Sulphur mustard gas, 2, 2'-dichlorodiethyl sulphide (HD), is a chemical warfare agent. Both mustard gas and its monofunctional analogue, 2-chloroethyl ethyl sulphide (CEES), are alkylating agents that react with and diminish cellular thiols and are highly toxic. Previously, we reported that lipopolysaccharide (LPS) significantly enhances the cytotoxicity of CEES in murine RAW 264.7 macrophages and that CEES transiently inhibits nitric oxide (NO) production via suppression of inducible NO synthase (iNOS) protein expression. NO generation is an important factor in wound healing. In this paper, we explored the hypotheses that LPS increases CEES toxicity by increasing oxidative stress and that treatment with N-acetyl-L-cysteine (NAC) would block LPS induced oxidative stress and protect against loss of NO production. NAC stimulates glutathione (GSH) synthesis and also acts directly as a free radical scavenger. The potential therapeutic use of the antibiotic, polymyxin B, was also evaluated since it binds to LPS and could thereby block the enhancement of CEES toxicity by LPS and also inhibit the secondary infections characteristic of HD/CEES wounds. Results We found that 10 mM NAC, when administered simultaneously or prior to treatment with 500 μM CEES, increased the viability of LPS stimulated macrophages. Surprisingly, NAC failed to protect LPS stimulated macrophages from CEES induced loss of NO production. Macrophages treated with both LPS and CEES show increased oxidative stress parameters (cellular thiol depletion and increased protein carbonyl levels). NAC effectively protected RAW 264.7 cells simultaneously treated with CEES and LPS from GSH loss and oxidative stress. Polymyxin B was found to partially block nitric oxide production and diminish CEES toxicity in LPS-treated macrophages. Conclusion The present study shows that oxidative stress is an important mechanism contributing to CEES toxicity in LPS stimulated macrophages and supports the notion

  10. Influence of a permanent low-friction boundary on rotation and flow in rigid inclusion/viscous matrix systems from an analogue perspective

    NASA Astrophysics Data System (ADS)

    Marques, Fernando O.; Bose, Santanu

    2004-04-01

    Natural occurrences and recent experimental work show that a low-friction inclusion/matrix boundary can be responsible for antithetical rotation and development of stable shape preferred orientations in simple shear. The flow of a viscous matrix around a rigid inclusion to which it may or may not be adherent is still not well studied, but it is relevant to the understanding of the behaviour of structural elements in mylonite zones. We used two-dimensional (2-D) analogue experiments to address these issues. The experimental results with a permanent low-friction inclusion/matrix boundary (nonadherent mode) show the following. (1) The rotation behaviour of inclusions in this mode is markedly different from the theoretical predictions and experimental results for the adherent mode. (2) Inclusions with aspect ratio equal to 1 rotate synthetically at a rate that depends upon inclusion shape and orientation. (3) Ellipse-, rectangle- and lozenge-shaped inclusions rotate antithetically when starting with their greatest axis parallel to the shear direction. (4) Back rotation is limited in all cases studied, and the angle between the inclusion greatest axis and the shear direction represents a stable orientation, which depends on inclusion aspect ratio and shape. (5) A metastable orientation exists, which is strongly dependent upon inclusion shape and aspect ratio, and separates fields of antithetic and synthetic rotation. Our experimental results show that the overall flow pattern is bow tie-shaped in adherent and nonadherent modes. However, there are major differences in the way the matrix flows near the inclusion. (i) In the nonadherent mode, the nearby matrix flows past the inclusion, whereas in the adherent mode, the nearby matrix flows with and follows the inclusion. Therefore, in the adherent mode, passive marker lines parallel to the shear direction and streamlines show considerable deflections at the inclusion crests, in marked contrast with their straight character

  11. Using and interpreting analogue designs.

    PubMed

    Cook, Bryan G; Rumrill, Phillip D

    2005-01-01

    Researchers in rehabilitation counseling and disability studies sometimes use analogue research, which involves materials that approximate or describe reality (e.g., written vignettes, videotaped exemplars) rather than investigating phenomena in real-world settings. Analogue research often utilizes experimental designs, and it thereby frequently possesses a high degree of internal validity. Analogue research allows investigators to exercise tight control over the implementation of the independent or treatment variable and over potentially confounding variables, which enables them to isolate the effects of those treatment variables on selected outcome measures. However, the simulated nature of analogue research presents an important threat to external validity. As such, the generalizability of analogue research to real-life settings and situations may be problematic. These and other issues germane to analogue research in vocational rehabilitation are discussed in this article, illustrated with examples from the contemporary literature.

  12. Chloroquine inhibits colon cancer cell growth in vitro and tumor growth in vivo via induction of apoptosis.

    PubMed

    Zheng, Yuzhu; Zhao, Ying-Lan; Deng, Xiaoqiang; Yang, Shengyong; Mao, Yongqiu; Li, Zhengguang; Jiang, Peidu; Zhao, Xia; Wei, Yuquan

    2009-03-01

    The present study was to investigate the anticancer effect of chloroquine on proliferation of mouse colon cancer cell line CT26 in vivo and in vitro and the possible mechanism. We found that chloroquine inhibited CT26 proliferation by concentration- and time-dependent manner. This effect was associated with apoptosis induction and decreased level of phosphorylated p42/44 mitogen-activated protein kinase and phosphorylated Akt. The in vivo study showed chloroquine-reduced tumor volume and prolonged survival time in CT26-bearing mice. These observations indicated chloroquine could inhibit CT26 proliferation by inducing apoptosis both in vitro and in vivo, providing its chemotherapeutic potential of human cancers. PMID:19194831

  13. Different pH requirements are associated with divergent inhibitory effects of chloroquine on human and avian influenza A viruses

    PubMed Central

    Di Trani, Livia; Savarino, Andrea; Campitelli, Laura; Norelli, Sandro; Puzelli, Simona; D'Ostilio, Daniela; Vignolo, Edoardo; Donatelli, Isabella; Cassone, Antonio

    2007-01-01

    Chloroquine is a 4-aminoquinoline previously used in malaria therapy and now becoming an emerging investigational antiviral drug due to its broad spectrum of antiviral activities. To explore whether the low pH-dependency of influenza A viruses might affect the antiviral effects of chloroquine at clinically achievable concentrations, we tested the antiviral effects of this drug on selected human and avian viruses belonging to different subtypes and displaying different pH requirements. Results showed a correlation between the responses to chloroquine and NH4Cl, a lysosomotropic agent known to increase the pH of intracellular vesicles. Time-of-addition experiments showed that the inhibitory effect of chloroquine was maximal when the drug had been added at the time of infection and was lost after 2 h post-infection. This timing approximately corresponds to that of virus/cell fusion. Moreover, there was a clear correlation between the EC50 of chloroquine in vitro and the electrostatic potential of the HA subunit (HA2) mediating the virus/cell fusion process. Overall, the present study highlights the critical importance of a host cell factor such as intravesicular pH in determining the anti-influenza activity of chloroquine and other lysosomotropic agents. PMID:17477867

  14. 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

  15. 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. PMID:25866016

  16. 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.

  17. 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)

  18. Chloroquine-containing organoruthenium complexes are fast-acting multistage antimalarial agents.

    PubMed

    Macedo, Taís S; Colina-Vegas, Legna; DA Paixão, Marcelo; Navarro, Maribel; Barreto, Breno C; Oliveira, Poliana C M; Macambira, Simone G; Machado, Marta; Prudêncio, Miguel; D'Alessandro, Sarah; Basilico, Nicoletta; Moreira, Diogo R M; Batista, Alzir A; Soares, Milena B P

    2016-10-01

    We report the pharmacological activity of organoruthenium complexes containing chloroquine (CQ) as a chelating ligand. The complexes displayed intraerythrocytic activity against CQ-sensitive 3D7 and CQ-resistant W2 strains of Plasmodium falciparum, with potency and selectivity indexes similar to those of CQ. Complexes displayed activity against all intraerythrocytic stages, but moderate activity against Plasmodium berghei liver stages. However, unlike CQ, organoruthenium complexes impaired gametocyte viability and exhibited fast parasiticidal activity against trophozoites for P. falciparum. This functional property results from the ability of complexes to quickly induce oxidative stress. The parasitaemia of P. berghei-infected mice was reduced by treatment with the complex. Our findings demonstrated that using chloroquine for the synthesis of organoruthenium complexes retains potency and selectivity while leading to an increase in the spectrum of action and parasite killing rate relative to CQ.

  19. Active case detection, treatment of falciparum malaria with combined chloroquine and sulphadoxine/pyrimethamine and vivax malaria with chloroquine and molecular markers of anti-malarial resistance in the Republic of Vanuatu

    PubMed Central

    2010-01-01

    Background Chloroquine-resistant Plasmodium falciparum was first described in the Republic of Vanuatu in the early 1980s. In 1991, the Vanuatu Ministry of Health instituted new treatment guidelines for uncomplicated P. falciparum infection consisting of chloroquine/sulphadoxine-pyrimethamine combination therapy. Chloroquine remains the recommended treatment for Plasmodium vivax. Methods In 2005, cross-sectional blood surveys at 45 sites on Malo Island were conducted and 4,060 adults and children screened for malaria. Of those screened, 203 volunteer study subjects without malaria at the time of screening were followed for 13 weeks to observe peak seasonal incidence of infection. Another 54 subjects with malaria were followed over a 28-day period to determine efficacy of anti-malarial therapy; chloroquine alone for P. vivax and chloroquine/sulphadoxine-pyrimethamine for P. falciparum infections. Results The overall prevalence of parasitaemia by mass blood screening was 6%, equally divided between P. falciparum and P. vivax. Twenty percent and 23% of participants with patent P. vivax and P. falciparum parasitaemia, respectively, were febrile at the time of screening. In the incidence study cohort, after 2,303 person-weeks of follow-up, the incidence density of malaria was 1.3 cases per person-year with P. vivax predominating. Among individuals participating in the clinical trial, the 28-day chloroquine P. vivax cure rate was 100%. The 28-day chloroquine/sulphadoxine-pyrimethamine P. falciparum cure rate was 97%. The single treatment failure, confirmed by merozoite surface protein-2 genotyping, was classified as a day 28 late parasitological treatment failure. All P. falciparum isolates carried the Thr-76 pfcrt mutant allele and the double Asn-108 + Arg-59 dhfr mutant alleles. Dhps mutant alleles were not detected in the study sample. Conclusion Peak seasonal malaria prevalence on Malo Island reached hypoendemic levels during the study observation period. The only in

  20. Bisbenzylisoquinolines as modulators of chloroquine resistance in Plasmodium falciparum and multidrug resistance in tumor cells.

    PubMed

    Frappier, F; Jossang, A; Soudon, J; Calvo, F; Rasoanaivo, P; Ratsimamanga-Urverg, S; Saez, J; Schrevel, J; Grellier, P

    1996-06-01

    Ten naturally occurring bisbenzylisoquinolines (BBIQ) and two dihydro derivatives belonging to five BBIQ subgroups were evaluated in vitro for their ability to inhibit Plasmodium falciparum growth and, in drug combination, to reverse the resistance to chloroquine of strain FcB1. The same alkaloids were also assessed in vitro for their potentiating activity against vinblastine with the multidrug-resistant clone CCRF-CEM/VLB, established from lymphoblastic acute leukemia. Three of the BBIQ tested had 50% inhibitory concentrations of less than 1 microM. The most potent antimalarial agent was cocsoline (50% inhibitory concentration, 0.22 microM). Regarding the chloroquine-potentiating effect, fangchinoline exhibited the highest biological activity whereas the remaining compounds displayed either antagonistic or slight synergistic effects. Against the multidrug-resistant cancer cell line, fangchinoline was also by far the most active compound. Although there were clear differences between the activities of tested alkaloids, no relevant structure-activity relationship could be established. Nevertheless, fangchinoline appears to be a new biochemical tool able to help in the comprehension of the mechanism of both chloroquine resistance in P. falciparum and multidrug resistance in tumor cells. PMID:8726022

  1. Bisbenzylisoquinolines as modulators of chloroquine resistance in Plasmodium falciparum and multidrug resistance in tumor cells.

    PubMed Central

    Frappier, F; Jossang, A; Soudon, J; Calvo, F; Rasoanaivo, P; Ratsimamanga-Urverg, S; Saez, J; Schrevel, J; Grellier, P

    1996-01-01

    Ten naturally occurring bisbenzylisoquinolines (BBIQ) and two dihydro derivatives belonging to five BBIQ subgroups were evaluated in vitro for their ability to inhibit Plasmodium falciparum growth and, in drug combination, to reverse the resistance to chloroquine of strain FcB1. The same alkaloids were also assessed in vitro for their potentiating activity against vinblastine with the multidrug-resistant clone CCRF-CEM/VLB, established from lymphoblastic acute leukemia. Three of the BBIQ tested had 50% inhibitory concentrations of less than 1 microM. The most potent antimalarial agent was cocsoline (50% inhibitory concentration, 0.22 microM). Regarding the chloroquine-potentiating effect, fangchinoline exhibited the highest biological activity whereas the remaining compounds displayed either antagonistic or slight synergistic effects. Against the multidrug-resistant cancer cell line, fangchinoline was also by far the most active compound. Although there were clear differences between the activities of tested alkaloids, no relevant structure-activity relationship could be established. Nevertheless, fangchinoline appears to be a new biochemical tool able to help in the comprehension of the mechanism of both chloroquine resistance in P. falciparum and multidrug resistance in tumor cells. PMID:8726022

  2. 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

  3. 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.

  4. The anticancer activity of chloroquine-gold nanoparticles against MCF-7 breast cancer cells.

    PubMed

    Joshi, Prachi; Chakraborti, Soumyananda; Ramirez-Vick, Jaime E; Ansari, Z A; Shanker, Virendra; Chakrabarti, Pinak; Singh, Surinder P

    2012-06-15

    In the present study, 11-mercaptoundecanoic acid-modified gold nanoparticles (∼7 nm) were conjugated with chloroquine to explore their potential application in cancer therapeutics. The anticancer activity of chloroquine-gold nanoparticle conjugates (GNP-Chl) was demonstrated in MCF-7 breast cancer cells. The MCF-7 cells were treated with different concentrations of GNP-Chl conjugates, and the cell viability was assayed using trypan blue, resulting in an IC(50) value of 30 ± 5 μg/mL. Flow cytometry analysis revealed that the major pathway of cell death was necrosis, which was mediated by autophagy. The drug release kinetics of GNP-Chl conjugates revealed the release of chloroquine at an acidic pH, which was quantitatively estimated using optical absorbance spectroscopy. The nature of stimuli-responsive drug release and the inhibition of cancer cell growth by GNP-Chl conjugates could pave the way for the design of combinatorial therapeutic agents, particularly nanomedicine, for the treatment of cancer. PMID:22445746

  5. 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. PMID:27575269

  6. Synthesis and Antiplasmodial Evaluation of Analogues Based on the Tricyclic Core of Thiaplakortones A–D

    PubMed Central

    Schwartz, Brett D.; Coster, Mark J.; Skinner-Adams, Tina S.; Andrews, Katherine T.; White, Jonathan M.; Davis, Rohan A.

    2015-01-01

    Six regioisomers associated with the tricyclic core of thiaplakortones A–D have been synthesized. Reaction of 1H-indole-4,7-dione and 1-tosyl-1H-indole-4,7-dione with 2-aminoethanesulfinic acid afforded a regioisomeric series, which was subsequently deprotected and oxidized to yield the tricyclic core scaffolds present in the thiaplakortones. All compounds were fully characterized using NMR and MS data. A single crystal X-ray structure was obtained on one of the N-tosyl derivatives. All compounds were screened for in vitro antiplasmodial activity against chloroquine-sensitive (3D7) and multidrug-resistant (Dd2) Plasmodium falciparum parasite lines. Several analogues displayed potent inhibition of P. falciparum growth (IC50 < 500 nM) but only moderate selectivity for P. falciparum versus human neonatal foreskin fibroblast cells. PMID:26389920

  7. Synthesis and Antiplasmodial Evaluation of Analogues Based on the Tricyclic Core of Thiaplakortones A-D.

    PubMed

    Schwartz, Brett D; Coster, Mark J; Skinner-Adams, Tina S; Andrews, Katherine T; White, Jonathan M; Davis, Rohan A

    2015-09-01

    Six regioisomers associated with the tricyclic core of thiaplakortones A-D have been synthesized. Reaction of 1H-indole-4,7-dione and 1-tosyl-1H-indole-4,7-dione with 2-aminoethanesulfinic acid afforded a regioisomeric series, which was subsequently deprotected and oxidized to yield the tricyclic core scaffolds present in the thiaplakortones. All compounds were fully characterized using NMR and MS data. A single crystal X-ray structure was obtained on one of the N-tosyl derivatives. All compounds were screened for in vitro antiplasmodial activity against chloroquine-sensitive (3D7) and multidrug-resistant (Dd2) Plasmodium falciparum parasite lines. Several analogues displayed potent inhibition of P. falciparum growth (IC50 < 500 nM) but only moderate selectivity for P. falciparum versus human neonatal foreskin fibroblast cells. PMID:26389920

  8. Chloroquine resistance in Plasmodium falciparum is not reversed by BIBW-22, a compound reversing the multidrug resistance phenotype in mammalian cancer cells.

    PubMed

    Dieckmann-Schuppert, A; Bamberger, U; Schwarz, R T

    1993-10-19

    The pteridine derivative BIBW-22 (4-[N-(2-hydroxy-2-methyl-propyl)-ethanolamino]-2,7-bis(cis-2,6-di methyl-morpholino)-6-phenylpteridine), which had been developed for the treatment of multidrug-resistant cancer and binds to P-glycoprotein, was tested against chloroquine resistant Plasmodium falciparum strains in culture. Based on the result that BIBW-22 enhanced rather than lowered chloroquine resistance in vitro, it is concluded that chloroquine resistance in malaria parasites may not be mechanistically linked to the multidrug-resistant phenotype of chloroquine resistant P. falciparum. PMID:8240391

  9. [The ERG contribution in early diagnosis of chloroquine and hydroxychloroquine maculopathy].

    PubMed

    Karkanová, Michala; Matusková, V; Vlková, E; Dosková, H; Uhmannová, R

    2010-04-01

    Derivates of chloroquine (Plaquenil, Delagil), used for long-term treatment of rheumatic diseases, may cause clinically proven irreversible maculopathy, which may progress even after the discontinuation of their application. The optimal early diagnosis of ocular toxicity of chloroquine or hydroxychloroquine drug remains controversial up to now. The aim of this review paper was to evaluate how appropriate is the indication of the electroretinographic (ERG) examination due to the early diagnosis of cumulative drug-related maculopathy. Photopic, pattern, and multifocal ERG (Retiscan, according to the ISCEV methodology) were examined in 10 patients (20 eyes) treated by means of antimalarics, 9 due to the rheumatoid arthritis (RA) and 1 due to the systemic lupus erythremathodes (SLE). The average age of the patients was 60 +/- 15 years, the treatment period was 10 +/- 11 years; the median of the treatment period was 5 years. The control group consisted of 12 healthy, age matched patients (20 eyes) without any obvious ocular pathology. In all of them, the complete ophthalmologic examination was performed: the best corrected visual acuity (BCVA) for far using the Snellen charts, intraocular pressure (IOP) measured by means of the non contact tonometer NIDEK NT-2000, the Amsler grid test, examination of the anterior segment and the posterior segment with the slit lamp. The entry criteria in both groups were BCVA 5/7,5 (0.67) and better, the IOP in the normal range, negative Amsler grid test, anterior segment without significant decrease of the transparency, and physiological posterior segment or with subtle granular pigment dysgrupancies in the macula only. The significant difference between the group treated with chloroquine or hydrochloroquine and the control group at the 1% level of significance was found in following parameters: in the photopic ERG the value of the b wave latency [ms], in pattern ERG, the values of the waves N35 - P50 [microV] and P50 - N95 [micro

  10. Clinical and parasitological response to oral chloroquine and primaquine in uncomplicated human Plasmodium knowlesi infections

    PubMed Central

    2010-01-01

    Background Plasmodium knowlesi is a cause of symptomatic and potentially fatal infections in humans. There are no studies assessing the detailed parasitological response to treatment of knowlesi malaria infections in man and whether antimalarial resistance occurs. Methods A prospective observational study of oral chloroquine and primaquine therapy was conducted in consecutive patients admitted to Kapit Hospital, Sarawak, Malaysian Borneo with PCR-confirmed single P. knowlesi infections. These patients were given oral chloroquine for three days, and at 24 hours oral primaquine was administered for two consecutive days, primarily as a gametocidal agent. Clinical and parasitological responses were recorded at 6-hourly intervals during the first 24 hours, daily until discharge and then weekly to day 28. Vivax malaria patients were studied as a comparator group. Results Of 96 knowlesi malaria patients who met the study criteria, 73 were recruited to an assessment of the acute response to treatment and 60 completed follow-up over 28 days. On admission, the mean parasite stage distributions were 49.5%, 41.5%, 4.0% and 5.6% for early trophozoites, late trophozoites, schizonts and gametocytes respectively. The median fever clearance time was 26.5 [inter-quartile range 16-34] hours. The mean times to 50% (PCT50) and 90% (PCT90) parasite clearance were 3.1 (95% confidence intervals [CI] 2.8-3.4) hours and 10.3 (9.4-11.4) hours. These were more rapid than in a group of 23 patients with vivax malaria 6.3 (5.3-7.8) hours and 20.9 (17.6-25.9) hours; P = 0.02). It was difficult to assess the effect of primaquine on P. knowlesi parasites, due to the rapid anti-malarial properties of chloroquine and since primaquine was administered 24 hours after chloroquine. No P. knowlesi recrudescences or re-infections were detected by PCR. Conclusions Chloroquine plus primaqine is an inexpensive and highly effective treatment for uncomplicated knowlesi malaria infections in humans and there is

  11. 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.

  12. Aberrant Apoptotic Response of Colorectal Cancer Cells to Novel Nucleoside Analogues

    PubMed Central

    Harmse, Leonie; Dahan-Farkas, Nurit; Panayides, Jenny-Lee; van Otterlo, Willem; Penny, Clement

    2015-01-01

    Despite the increased understanding of colorectal cancer and the introduction of targeted drug therapy, the metastatic phase of the disease remains refractory to treatment. Since the deregulation of normal apoptosis contributes to the pathogenesis of colorectal cancer, novel nucleoside analogues were synthesized here and evaluated for their ability to induce apoptosis and cause cell death in two colorectal adeno-carcinoma cell lines, Caco-2 and HT-29. Three novel nucleoside analogues assessed here showed cytotoxic activity, as measured by the MTT assay against both cell lines: the IC50 values ranged between 3 and 37 μM, with Caco-2 cells being more sensitive than HT-29 cells. Compared to camptothecin, the positive control, the nucleoside analogues were significantly less toxic to normal unstimulated leukocytes (p>0.05). Moreover, the nucleosides were able to induce apoptosis as measured by an increase in caspase 8 and caspase 3 activity above that of the control. This was additionally supported by data derived from Annexin V-FITC assays. Despite marginal changes to the mitochondrial membrane potential, all three nucleosides caused a significant increase in cytosolic cytochrome c (p>0.05), with a corresponding decrease in mitochondrial cytochrome c. Morphological analysis of both cell lines showed the rapid appearance of vacuoles following exposure to two of the nucleosides, while a third caused cellular detachment, delayed cytoplasmic vacuolisation and nuclear abnormalities. Preliminary investigations, using the autophagic indicator monodansylcadaverine and chloroquine as positive control, showed that two of the nucleosides induced the formation of autophagic vacuoles. In summary, the novel nucleoside analogues showed selective cytotoxicity towards both cancer cell lines and are effective initiators of an unusual apoptotic response, demonstrating their potential to serve as structural scaffolds for more potent analogues. PMID:26390405

  13. Comparison of protein expression pattern between the Plasmodium falciparum chloroquine-resistant RKL9 and chloroquine-sensitive MRC2 strains

    PubMed Central

    Antony, Hiasindh Ashmi; Pathak, Vrushali; Ghosh, Kanjaksha; Parija, Subhash Chandra

    2016-01-01

    Objective: The objective of this study was to compare the protein expression patterns of Plasmodium falciparum extracellular and intracellular proteins separated by two-dimensional electrophoresis (2-DE) from the chloroquine-sensitive (CQS) MRC2 strain and chloroquine-resistant (CQR) RKL9 strain. Materials and Methods: Both the extracellular protein (ECP) and intracellular protein (ICP) were extracted and solubilized. The proteins were separated by 2-DE, first based on their charges using isoelectric focusing and then their sizes by electrophoresis. The separated protein spots were detected by silver staining, and further, the protein spot density was analyzed by an image analysis software. Results: 2-DE separated the proteins extracted from the CQS and CQR strains based on their differentially expressed protein patterns. Extracellular Protein Analysis: A total of 109 and 77 protein spots were detected by image analysis of ECP extracted from MRC2 and RKL9 strains, respectively. There was a marked reduction in protein expression pattern in the CQR strain when compared with the CQS strain. Interestingly, 50 and 18 protein spots were uniquely expressed in MRC2 and RKL9 strains, respectively. When MRC2 strain-expressed proteins were taken as the control, 12 upregulated and 14 downregulated protein spots were observed in the RKL9 strain-extracted proteins. Intracellular Protein Analysis: ICP extracted from MRC2 and RKL9 strains showed 187 and 199 protein spots by an image analysis software, and a small enhancement of protein expression was measured when comparing the CQR strain with CQS strain. There were 67 and 79 unique protein spots detected in MRC2 and RKL9 strains, respectively. A total of 120 protein spots were similar when MRC2 proteins were taken as the control; among these protein spots, 40 upregulated and 22 downregulated protein spots were detected in RKL9 strain-expressed protein. Conclusions: Both these unique and matched protein spots might be molecularly

  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. 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.

  16. 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.

  17. 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

  18. A Randomized Comparison of Chloroquine Versus Dihydroartemisinin-Piperaquine for the Treatment of Plasmodium vivax Infection in Vietnam.

    PubMed

    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; Thai, Le Hong; Hoa, Nhu Thi; Dong, Le Thanh; 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

    2016-04-01

    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

  19. Investigation of the Plasmodium falciparum food vacuole through inducible expression of the chloroquine resistance transporter (PfCRT).

    PubMed

    Ehlgen, Florian; Pham, James S; de Koning-Ward, Tania; Cowman, Alan F; Ralph, Stuart A

    2012-01-01

    Haemoglobin degradation during the erythrocytic life stages is the major function of the food vacuole (FV) of Plasmodium falciparum and the target of several anti-malarial drugs that interfere with this metabolic pathway, killing the parasite. Two multi-spanning food vacuole membrane proteins are known, the multidrug resistance protein 1 (PfMDR1) and Chloroquine Resistance Transporter (PfCRT). Both modulate resistance to drugs that act in the food vacuole. To investigate the formation and behaviour of the food vacuole membrane we have generated inducible GFP fusions of chloroquine sensitive and resistant forms of the PfCRT protein. The inducible expression system allowed us to follow newly-induced fusion proteins, and corroborated a previous report of a direct trafficking route from the ER/Golgi to the food vacuole membrane. These parasites also allowed the definition of a food vacuole compartment in ring stage parasites well before haemozoin crystals were apparent, as well as the elucidation of secondary PfCRT-labelled compartments adjacent to the food vacuole in late stage parasites. We demonstrated that in addition to previously demonstrated Brefeldin A sensitivity, the trafficking of PfCRT is disrupted by Dynasore, a non competitive inhibitor of dynamin-mediated vesicle formation. Chloroquine sensitivity was not altered in parasites over-expressing chloroquine resistant or sensitive forms of the PfCRT fused to GFP, suggesting that the PfCRT does not mediate chloroquine transport as a GFP fusion protein.

  20. Bisphenol A and Its Analogues Activate Human Pregnane X Receptor

    PubMed Central

    Sui, Yipeng; Ai, Ni; Park, Se-Hyung; Rios-Pilier, Jennifer; Perkins, Jordan T.; Welsh, William J.

    2012-01-01

    Background: Bisphenol A (BPA) is a base chemical used extensively in many consumer products. BPA and its analogues are present in environmental and human samples. Many endocrine-disrupting chemicals, including BPA, have been shown to activate the pregnane X receptor (PXR), a nuclear receptor that functions as a master regulator of xenobiotic metabolism. However, the detailed mechanism by which these chemicals activate PXR remains unknown. Objective: We investigated the mechanism by which BPA interacts with and activates PXR and examined selected BPA analogues to determine whether they bind to and activate PXR. Methods: Cell-based reporter assays, in silico ligand–PXR docking studies, and site-directed mutagenesis were combined to study the interaction between BPA and PXR. We also investigated the influence of BPA and its analogues on the regulation of PXR target genes in human LS180 cells. Results: We found that BPA and several of its analogues are potent agonists for human PXR (hPXR) but do not affect mouse PXR activity. We identified key residues within hPXR’s ligand-binding pocket that constitute points of interaction with BPA. We also deduced the structural requirements of BPA analogues that activate hPXR. BPA and its analogues can also induce PXR target gene expression in human LS180 cells. Conclusions: The present study advances our understanding of the mechanism by which BPA interacts with and activates human PXR. Activation of PXR by BPA may explain some of the adverse effects of BPA in humans. PMID:22214767

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

    PubMed

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

    2015-04-21

    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 ∼10(4)× 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

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

    PubMed

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

    2015-04-21

    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 ∼10(4)× 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.

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

    PubMed

    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

  4. 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

  5. The Association of K76T Mutation in Pfcrt Gene and Chloroquine Treatment Failure in Uncomplicated Plasmodium falciparum Malaria in a Cohort of Nigerian Children

    NASA Astrophysics Data System (ADS)

    Umar, R. A.; Hassan, S. W.; Ladan, M. J.; Nma Jiya, M.; Abubakar, M. K.; Nata`Ala, U.

    The aim of this study was to evaluate the association of K76T mutation in Pfcrt gene and chloroquine treatment failure following reports that the efficacy of chloroquine in the treatment of uncomplicated falciparum malaria in Africa is seriously compromised by high levels of drug resistance. The occurrence of mutation on codon 76 of Plasmodium falciparum chloroquine resistance transporter (Pfcrt) gene has been associated with development of resistance to chloroquine. We investigated the association of K76T mutation in Pfcrt gene in malaria-infected blood samples from a cohort of Nigerian children with uncomplicated falciparum malaria treated with chloroquine and its association with clinical (in vivo) resistance. The Pfcrt T76 allele was very significantly associated with resistance to chloroquine (Fischer exact test: p = 0.0001). We conclude that K76T mutation in Pfcrt gene is significantly associated with chloroquine resistance and that it could be used as a population marker for chloroquine resistance in this part of the country

  6. A clinical trial of malaria prophylaxis using a single dose of chloroquine at different intervals in an endemic malarious area.

    PubMed

    Karunakaran, C S

    1980-10-01

    A controlled trial of chloroquine prophylaxis was carried out to find whether this drug could be administered at intervals longer than the conventional ones recommended, in endemic malarious areas. Statistically significant results obtained show that chloroquine at suitable doses could be used successfully at intervals of 3 months. The possibility of chloroquine and acquired immunity acting together synergistically is discussed. The author is of the opinion that with this dose regime, the community would still be able to build up substantial immunity, so that in the event of the drug being discontinued, the community would not be faced with the problem of overwhelming malarial infections. The various advantages in using this regime are also considered.

  7. 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.

  8. 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

  9. 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

  10. 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

  11. Influence of turn (or fold) and local charge in fragmentation of the peptide analogue molecule CH3CO-Gly-NH2 following single-photon VUV (118.22 nm) ionization.

    PubMed

    Bhattacharya, Atanu; Bernstein, Elliot R

    2011-10-01

    The radical cationic reactivity of the peptide analogue molecule CH(3)CO-Gly-NH(2) is addressed both experimentally and theoretically. The radical cation intermediate of CH(3)CO-Gly-NH(2) is created by single-photon ionization of this molecule at 118.22 nm (~10.5 eV). The two most stable conformers (C(7) and C(5)) of this molecule exhibit different folds along the backbone: the C(7) conformer has a γ-turn structure, and the C(5) conformer has a β-strand structure. The experimental results show that the radical cation intermediate of CH(3)CO-Gly-NH(2) dissociates and generates a fragment-ion signal at 73 amu that is observed through TOFMS. Theoretical results show how the fragment-ion signal at 73 amu is generated by only one conformer of CH(3)CO-Gly-NH(2) (C(7)) and how local charge and specific hydrogen bonding in the molecule influence fragmentation of the radical cation intermediate of CH(3)CO-Gly-NH(2). The specific fold of the molecule controls fragmentation of this reactive radical cation intermediate. Whereas the radical cation of the C(7) conformer dissociates through a hydrogen-transfer mechanism followed by HNCO elimination, the radical cation of the C(5) conformer does not dissociate at all. CASSCF calculations show that positive charge in the radical cationic C(7) conformer is localized at the NH(2)CO moiety of the molecular ion. This site-specific localization of the positive charge enhances the acidity of the terminal NH(2) group, facilitating hydrogen transfer from the NH(2) to the COCH(3) end of the molecular ion. Positive charge in the C(5) conformer of the CH(3)CO-Gly-NH(2) radical cation is, however, localized at the COCH(3) end of the molecular ion, and this conformer does not have enough energy to surmount the energy barrier to dissociation on the ion potential energy surface. CASSCF results show that conformation-specific localization of charge in the CH(3)CO-Gly-NH(2) molecular ion occurs as a result of the different hydrogen

  12. Similarity in drugs: reflections on analogue design.

    PubMed

    Wermuth, Camille G

    2006-04-01

    A survey of novel small-molecule therapeutics reveals that the majority of them result from analogue design and that their market value represents two-thirds of all small-molecule sales. In natural science, the term analogue, derived from the Latin and Greek analogia, has always been used to describe structural and functional similarity. Extended to drugs, this definition implies that the analogue of an existing drug molecule shares structural and pharmacological similarities with the original compound. Formally, this definition allows the establishment of three categories of drug analogues: analogues possessing chemical and pharmacological similarities (direct analogues); analogues possessing structural similarities only (structural analogues); and chemically different compounds displaying similar pharmacological properties (functional analogues). PMID:16580977

  13. 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.

  14. Chloroquine eliminates cancer stem cells through deregulation of Jak2 and DNMT1

    PubMed Central

    Choi, Dong Soon; Blanco, Elvin; Kim, Yoo-Shin; Rodriguez, Angel A.; Zhao, Hong; Huang, Tim Hui-Ming; Chen, Chun-Liang; Jin, Guangxu; Landis, Melissa D.; Burey, Lacey A.; Qian, Wei; Granados, Sergio M.; Dave, Bhuvanesh; Wong, Helen H.; Ferrari, Mauro; Wong, Stephen TC; Chang, Jenny C.

    2014-01-01

    Triple negative breast cancer (TNBC) is known to contain a high percentage of CD44+/CD24−/low cancer stem cells (CSC), corresponding with a poor prognosis despite systemic chemotherapy. Chloroquine (CQ), an anti-malarial drug, is a lysotropic reagent which inhibits autophagy. CQ was identified as a potential CSC inhibitor through in silico gene expression signature analysis of the CD44+/CD24−/low CSC population. Autophagy plays a critical role in adaptation to stress conditions in cancer cells, and is related with drug resistance and CSC maintenance. Thus the objectives of this study were to examine the potential enhanced efficacy arising from addition of chloroquine (CQ) to standard chemotherapy (paclitaxel) in TNBC and to identify the mechanism by which CQ eliminates CSCs in TNBCs. Herein, we report that CQ sensitizes TNBC cells to paclitaxel through inhibition of autophagy and reduces the CD44+/CD24−/low CSC population in both preclinical and clinical settings. Also, we are the first to report a mechanism by which CQ regulates the CSCs in TNBC through inhibition of the Janus-activated kinase 2 (Jak2) - Signal transducer and activator of transcription 3 (STAT3) signaling pathway by reducing the expression of Jak2 and DNA methyltransferase 1 (DNMT1). PMID:24809620

  15. Repositioning chloroquine and metformin to eliminate cancer stem cell traits in pre-malignant lesions

    PubMed Central

    Vazquez-Martin, Alejandro; López-Bonetc, Eugeni; Cufí, Sílvia; Oliveras-Ferraros, Cristina; Del Barco, Sonia; Martin-Castillo, Begoña; Menendez, Javier A.

    2013-01-01

    Ideal oncology drugs would be curative after a short treatment course if they could eliminate epithelium-originated carcinomas at their non-invasive, pre-malignant stages. Such ideal molecules, which are expected to molecularly abrogate all the instrumental mechanisms acquired by migrating cancer stem cells (CSCs) to by-pass tumour suppressor barriers, might already exist. We here illustrate how system biology strategies for repositioning existing FDA-approved drugs may accelerate our therapeutic capacity to eliminate CSC traits in pre-invasive intraepithelial neoplasias. First, we describe a signalling network signature that overrides bioenergetics stress- and oncogene-induced senescence (OIS) phenomena in CSCs residing at pre-invasive lesions. Second, we functionally map the anti-malarial chloroquine and the anti-diabetic metformin (“old drugs”) to their recently recognized CSC targets (“new uses”) within the network. By discussing the preclinical efficacy of chloroquine and metformin to inhibiting the genesis and self-renewal of CSCs we finally underscore the expected translational impact of the “old drugs–new uses” repurposing strategy to open a new CSC-targeted chemoprevention era. PMID:21600837

  16. Repositioning chloroquine and metformin to eliminate cancer stem cell traits in pre-malignant lesions.

    PubMed

    Vazquez-Martin, Alejandro; López-Bonetc, Eugeni; Cufí, Sílvia; Oliveras-Ferraros, Cristina; Del Barco, Sonia; Martin-Castillo, Begoña; Menendez, Javier A

    2011-01-01

    Ideal oncology drugs would be curative after a short treatment course if they could eliminate epithelium-originated carcinomas at their non-invasive, pre-malignant stages. Such ideal molecules, which are expected to molecularly abrogate all the instrumental mechanisms acquired by migrating cancer stem cells (CSCs) to by-pass tumour suppressor barriers, might already exist. We here illustrate how system biology strategies for repositioning existing FDA-approved drugs may accelerate our therapeutic capacity to eliminate CSC traits in pre-invasive intraepithelial neoplasias. First, we describe a signalling network signature that overrides bioenergetics stress- and oncogene-induced senescence (OIS) phenomena in CSCs residing at pre-invasive lesions. Second, we functionally map the anti-malarial chloroquine and the anti-diabetic metformin ("old drugs") to their recently recognized CSC targets ("new uses") within the network. By discussing the preclinical efficacy of chloroquine and metformin to inhibiting the genesis and self-renewal of CSCs we finally underscore the expected translational impact of the "old drugs-new uses" repurposing strategy to open a new CSC-targeted chemoprevention era. PMID:21600837

  17. Hydroxychloroquine, chloroquine, and all-trans retinoic acid regulate growth, survival, and histone acetylation in breast cancer cells.

    PubMed

    Rahim, Rayhana; Strobl, Jeannine S

    2009-09-01

    The antimalarial drugs chloroquine (CQ) and hydroxychloroquine (HCQ) have potential applications in cancer treatment. The growth of MCF-7 and MDA-MB-231 human breast cancer cells in vitro was inhibited by CQ and HCQ and these cells were more sensitive than nontumorigenic MCF-10A breast epithelial cells. Furthermore, all-trans retinoic acid (ATRA) augmented the anticancer effects of CQ and HCQ as evidenced by significant reductions in Ki67-positive cancer cells and clonogenicity compared with cells treated with CQ or HCQ in the absence of ATRA. As an earlier study suggested that CQ, HCQ, and ATRA are breast cancer cell differentiation agents, these agents were screened in cell-free histone deacetylase (HDAC) and histone acetyltransferase (HAT) assays. ATRA, but not CQ or HCQ, inhibited HDAC activity in HeLa nuclear extracts. Growth inhibitory concentrations of HCQ and ATRA stimulated purified p300/CBP-associated factor, where CBP is the cAMP-response element binding protein, HAT activity. To investigate whether growth inhibitory concentrations of these agents influenced protein acetylation in cells, gel-purified histone H3 and histone H4 were analyzed using mass spectrometry. HCQ alone and HCQ+ATRA treatments altered the acetylation status in the N-terminal lysines of histones H3 and H4 compared with dimethyl sulfoxide (DMSO) controls. The results indicated that HCQ and ATRA regulate protein acetylation events in MCF-7 breast cancer cells, and identify a potential mechanism for their effects on breast cancer cell growth and differentiation. PMID:19584707

  18. Transcriptomic Analysis of Chloroquine-Sensitive and Chloroquine-Resistant Strains of Plasmodium falciparum: Toward Malaria Diagnostics and Therapeutics for Global Health.

    PubMed

    Antony, Hiasindh Ashmi; Pathak, Vrushali; Parija, Subhash Chandra; Ghosh, Kanjaksha; Bhattacherjee, Amrita

    2016-07-01

    Increasing drug resistance in Plasmodium falciparum is an important global health burden because it reverses the malarial control achieved so far. Hence, understanding the molecular mechanisms of drug resistance is the epicenter of the development agenda for novel diagnostic and therapeutic (drugs/vaccines) targets for malaria. In this study, we report global comparative transcriptome profiling (RNA-Seq) to characterize the difference in the transcriptome between 48-h intraerythrocytic stage of chloroquine-sensitive and chloroquine-resistant P. falciparum (3D7 and Dd2) strains. The two P. falciparum 3D7 and Dd2 strains have distant geographical origin, the Netherlands and Indochina, respectively. The strains were cultured by an in vitro method and harvested at the 48-h intraerythrocytic stage having 5% parasitemia. The whole transcriptome sequencing was performed using Illumina HiSeq 2500 platform with paired-end reads. The reads were aligned with the reference P. falciparum genome. The alignment percentages for 3D7, Dd2, and Dd2 w/CQ strains were 85.40%, 89.13%, and 84%, respectively. Nearly 40% of the transcripts had known gene function, whereas the remaining genes (about 60%) had unknown function. The genes involved in immune evasion showed a significant difference between the strains. The differential gene expression between the sensitive and resistant strains was measured using the cuffdiff program with the p-value cutoff ≤0.05. Collectively, this study identified differentially expressed genes between 3D7 and Dd2 strains, where we found 89 genes to be upregulated and 227 to be downregulated. On the contrary, for 3D7 and Dd2 w/CQ strains, 45 genes were upregulated and 409 were downregulated. These differentially regulated genes code, by and large, for surface antigens involved in invasion, pathogenesis, and host-parasite interactions, among others. The exhibition of transcriptional differences between these strains of P. falciparum contributes to our

  19. Transcriptomic Analysis of Chloroquine-Sensitive and Chloroquine-Resistant Strains of Plasmodium falciparum: Toward Malaria Diagnostics and Therapeutics for Global Health.

    PubMed

    Antony, Hiasindh Ashmi; Pathak, Vrushali; Parija, Subhash Chandra; Ghosh, Kanjaksha; Bhattacherjee, Amrita

    2016-07-01

    Increasing drug resistance in Plasmodium falciparum is an important global health burden because it reverses the malarial control achieved so far. Hence, understanding the molecular mechanisms of drug resistance is the epicenter of the development agenda for novel diagnostic and therapeutic (drugs/vaccines) targets for malaria. In this study, we report global comparative transcriptome profiling (RNA-Seq) to characterize the difference in the transcriptome between 48-h intraerythrocytic stage of chloroquine-sensitive and chloroquine-resistant P. falciparum (3D7 and Dd2) strains. The two P. falciparum 3D7 and Dd2 strains have distant geographical origin, the Netherlands and Indochina, respectively. The strains were cultured by an in vitro method and harvested at the 48-h intraerythrocytic stage having 5% parasitemia. The whole transcriptome sequencing was performed using Illumina HiSeq 2500 platform with paired-end reads. The reads were aligned with the reference P. falciparum genome. The alignment percentages for 3D7, Dd2, and Dd2 w/CQ strains were 85.40%, 89.13%, and 84%, respectively. Nearly 40% of the transcripts had known gene function, whereas the remaining genes (about 60%) had unknown function. The genes involved in immune evasion showed a significant difference between the strains. The differential gene expression between the sensitive and resistant strains was measured using the cuffdiff program with the p-value cutoff ≤0.05. Collectively, this study identified differentially expressed genes between 3D7 and Dd2 strains, where we found 89 genes to be upregulated and 227 to be downregulated. On the contrary, for 3D7 and Dd2 w/CQ strains, 45 genes were upregulated and 409 were downregulated. These differentially regulated genes code, by and large, for surface antigens involved in invasion, pathogenesis, and host-parasite interactions, among others. The exhibition of transcriptional differences between these strains of P. falciparum contributes to our

  20. Full-length sequence analysis of chloroquine resistance transporter gene in Plasmodium falciparum isolates from Sabah, Malaysia.

    PubMed

    Tan, Lii Lian; Lau, Tiek Ying; Timothy, William; Prabakaran, Dhanaraj

    2014-01-01

    Chloroquine resistance (CQR) in falciparum malaria was identified to be associated with several mutations in the chloroquine resistance transporter gene (pfcrt) that encodes the transmembrane transporter in digestive vacuole membrane of the parasite. This study aimed to investigate the point mutations across the full-length pfcrt in Plasmodium falciparum isolates in Sabah, Malaysia. A total of 31 P. falciparum positive samples collected from Keningau, Kota Kinabalu, and Kudat, Sabah, were analyzed. pfcrt was PCR amplified and cloned prior to sequence analysis. This study showed that all the previously described 10 point mutations associated with CQR at codons 72, 74, 75, 76, 97, 220, 271, 326, 356, and 371 were found with different prevalence. Besides, two novel point mutations, I166V and H273N, were identified with 22.5% and 19.3%, respectively. Three haplotypes, namely, CVMNK (29%), CVIET (3.2%), and SVMNT (67.7%), were identified. High prevalence of SVMNT among P. falciparum isolates from Sabah showed that these isolates are closer to the P. falciparum isolates from Papua New Guinea rather than to the more proximal Southeast Asian CVIET haplotype. Full-length analysis of pfcrt showed that chloroquine resistant P. falciparum in Sabah is still prevalent despite the withdrawal of chloroquine usage since 1979. PMID:25574497

  1. Central effects of angiotensin II, its fragment and analogues.

    PubMed

    Georgiev, V P; Klousha, V E; Petkov, V D; Markovska, V L; Svirskis, S V; Mountsinietse, R K; Anouans, Z E

    1984-01-01

    The effects of the octapeptide angiotensin II (AT II), its fragment Ile8 AT3-8 and the analogues Sar1 Ala8 AT II, Ala8 AT II and Ile8 AT II were studied with respect to: the level of biogenic amines (DA, 5-HT and their metabolites HVA and 5-HIAA) in the forebrain; the behaviour of the animals--haloperidol catalepsy, apomorphine stereotypy, unconditioned jumping reaction (UJR), convulsive threshold. Good correlation was found between the biochemical and behavioural effects. The fragment of AT II where phenylalanine is substituted at the C-terminal by Ile reduces the haloperidol-increased content of HVA, potentiates apomorphine stereotypy and reduces catalepsy, whereas the AT II analogues (where the C-terminal phenylalanine is substituted by Ala, and the N-terminal--by Sar) potentiate the effect of haloperidol increasing the HVA content, reduce apomorphine stereotypy and potentiate catalepsy; saralasine independently applied induces brief catalepsy; AT II, its fragment and analogues inhibit UJR, in combination with amphetamine and PTZ this effect becomes deeper; the duration of hexobarbital sleep is increased. The peptides investigated increase the convulsive threshold. The results show that the hexapeptide fragment has preserved the effects of AT II, whereas in the analogues (with changed C- and N-terminals) they are changed. The results obtained may be explained with the modulating influence of AT II-receptors on the DA-ergic receptors in the brain structures with which AT II and its fragment and analogues enter in contact.

  2. Mutations in the Plasmodium falciparum chloroquine resistance transporter, PfCRT, enlarge the parasite’s food vacuole and alter drug sensitivities

    PubMed Central

    Pulcini, Serena; Staines, Henry M.; Lee, Andrew H.; Shafik, Sarah H.; Bouyer, Guillaume; Moore, Catherine M.; Daley, Daniel A.; Hoke, Matthew J.; Altenhofen, Lindsey M.; Painter, Heather J.; Mu, Jianbing; Ferguson, David J. P.; Llinás, Manuel; Martin, Rowena E.; Fidock, David A.; Cooper, Roland A.; Krishna, Sanjeev

    2015-01-01

    Mutations in the Plasmodium falciparum chloroquine resistance transporter, PfCRT, are the major determinant of chloroquine resistance in this lethal human malaria parasite. Here, we describe P. falciparum lines subjected to selection by amantadine or blasticidin that carry PfCRT mutations (C101F or L272F), causing the development of enlarged food vacuoles. These parasites also have increased sensitivity to chloroquine and some other quinoline antimalarials, but exhibit no or minimal change in sensitivity to artemisinins, when compared with parental strains. A transgenic parasite line expressing the L272F variant of PfCRT confirmed this increased chloroquine sensitivity and enlarged food vacuole phenotype. Furthermore, the introduction of the C101F or L272F mutation into a chloroquine-resistant variant of PfCRT reduced the ability of this protein to transport chloroquine by approximately 93 and 82%, respectively, when expressed in Xenopus oocytes. These data provide, at least in part, a mechanistic explanation for the increased sensitivity of the mutant parasite lines to chloroquine. Taken together, these findings provide new insights into PfCRT function and PfCRT-mediated drug resistance, as well as the food vacuole, which is an important target of many antimalarial drugs. PMID:26420308

  3. Cell growth inhibition, G2/M cell cycle arrest, and apoptosis induced by chloroquine in human breast cancer cell line Bcap-37.

    PubMed

    Jiang, Pei-du; Zhao, Ying-lan; Shi, Wei; Deng, Xiao-qiang; Xie, Gang; Mao, Yong-qiu; Li, Zheng-guang; Zheng, Yu-zhu; Yang, Sheng-yong; Wei, Yu-quan

    2008-01-01

    Chloroquine is an antimalarial drug that has been used in the treatment and prophylaxis of malaria since the 1950s. The present study was undertaken to examine the effects of chloroquine on Bcap-37 human breast cancer cells' growth, cell cycle modulation, apoptosis induction, and associated molecular alterations in vitro. The chloroquine treatment decreased the viability of Bcap-37 cells in a concentration- and time-dependent manner, which correlated with G(2)/M phase cell cycle arrest. The chloroquine-mediated cell cycle arrest was associated with a decrease in protein levels/activity of polo-like kinase 1 (Plk1), phosphorylated cell division cycle 25C (Cdc25C), phosphorylated extracellular signal-regulated kinase 1/2 (ERK1/2), phosphorylated Akt. The chloroquine-treated Bcap-37 cells exhibited a marked decrease in the level of mitochondrial transmembrane potential (DeltaPsim), which was accompanied by the activation of caspase-3 and cleaved poly(ADP-ribose) polymerase (PARP). Exposure of Bcap-37 cells to chloroquine also resulted in the induction of spindle abnormalities. In conclusion, the findings in this study suggested that chloroquine might have potential anticancer efficacy, which could be attributed, in part, to its proliferation inhibition and apoptosis induction of cancer cells through modulation of apoptosis and cell cycle-related proteins expressions, down-regulation of mitochondrial transmembrane potential (DeltaPsim), and induction of spindle abnormalities. PMID:19088425

  4. Chloroquine or Chloroquine-PI3K/Akt Pathway Inhibitor Combinations Strongly Promote γ-Irradiation-Induced Cell Death in Primary Stem-Like Glioma Cells

    PubMed Central

    Firat, Elke; Weyerbrock, Astrid; Gaedicke, Simone; Grosu, Anca-Ligia; Niedermann, Gabriele

    2012-01-01

    We asked whether inhibitors of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway, which is highly active in cancer stem cells (CSCs) and upregulated in response to genotoxic treatments, promote γ-irradiationγIR)-induced cell death in highly radioresistant, patient-derived stem-like glioma cells (SLGCs). Surprisingly, in most cases the inhibitors did not promote γIR-induced cell death. In contrast, the strongly cytostatic Ly294002 and PI-103 even tended to reduce it. Since autophagy was induced we examined whether addition of the clinically applicable autophagy inhibitor chloroquine (CQ) would trigger cell death in SLGCs. Triple therapy with CQ at doses as low as 5 to 10 µM indeed caused strong apoptosis. At slightly higher doses, CQ alone strongly promoted γIR-induced apoptosis in all SLGC lines examined. The strong apoptosis in combinations with CQ was invariably associated with strong accumulation of the autophagosomal marker LC3-II, indicating inhibition of late autophagy. Thus, autophagy-promoting effects of PI3K/Akt pathway inhibitors apparently hinder cell death induction in γ-irradiated SLGCs. However, as we show here for the first time, the late autophagy inhibitor CQ strongly promotes γIR-induced cell death in highly radioresistant CSCs, and triple combinations of CQ, γIR and a PI3K/Akt pathway inhibitor permit reduction of the CQ dose required to trigger cell death. PMID:23091617

  5. Simulation of kinetic data on the influx and efflux of chloroquine by erythrocytes infected with Plasmodium falciparum. Evidence for a drug-importer in chloroquine-sensitive strains.

    PubMed

    Ferrari, V; Cutler, D J

    1991-12-11

    Literature data on influx and efflux kinetics of chloroquine (CQ) with erythrocytes infected with the malaria parasite Plasmodium falciparum were simulated using a four-compartment model with first-order exchange between the compartments. The four compartments represent (1) the buffer surrounding the infected erythrocyte; (2) the cytosol of the host erythrocyte; (3) the parasite cytosol; and (4) the food vacuole. Simulations showed that basal membrane transport of CQ, estimated from data on influx of CQ into uninfected red cells, largely accounts for uptake and release of CQ by erythrocytes infected with two different CQ-resistant (CQ-R) parasite strains. In contrast, the rate of uptake of CQ by erythrocytes infected with a CQ-sensitive (CQ-S) strain is substantially higher than predicted by uptake with membrane transfer by basal diffusion of CQ. Simulations also indicate that the difference in kinetics of CQ uptake by erythrocytes infected with the CQ-S and CQ-R strains can be explained by a net increase in the inward permeability coefficient at the host erythrocyte membrane, the composite membrane surrounding the parasite or the food vacuole membrane. The results are consistent with the presence of a drug-importer for CQ in erythrocytes infected with sensitive strains, which is absent in those infected with resistant strains. They are not consistent with the hypothesis that CQ resistance is attributable to a drug-exporter in resistant cells which is lacking in sensitive cells.

  6. Quality of casein based Mozzarella cheese analogue as affected by stabilizer blends.

    PubMed

    Jana, A H; Patel, H G; Suneeta, Pinto; Prajapati, J P

    2010-03-01

    Suitability of xanthan gum (XG)-locust bean gum (LBG), carrageenan (CAR)-LBG, and XG-CAR in 1:1 proportion at 0.42% in the formulation was assessed in the manufacture of Mozzarella cheese analogue. The stabilizer blends did not significantly influence the composition, texture profile, organoleptic, baking qualities and pizza-related characteristics of cheese analogues. Considering the influence of stabilizer blend on the sensory quality of analogue and sensory rating of pizza pie, XG-LBG blend (1:1) was preferred over XG-CAR and CAR-LBG.

  7. 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. PMID:26606142

  8. A focus of high degree chloroquine resistant P. falciparum in Mandla district (M.P.).

    PubMed

    Singh, N; Shukla, M M; Sharma, V P; Saxena, B N

    1989-03-01

    A study on the bioenvironmental control of malaria was launched in Bizadandi block (Mandla district, M.P.) in May 1986. Besides intervention, using environmental management methods and larvivorous fishes, weekly surveillance and chloroquine administration at 25 mg/kg body weight was practiced. Studies during 1987 revealed that a large number of P. falciparum cases did not respond to the standard anti-malarial treatment. Therefore, systematic 28 day in vivo studies were taken up on the follow-up of P. falciparum cases after administration of 3 day course of 25 mg/kg body weight as per the WHO procedure. Results revealed a high proportion of drug resistant cases belonging to RI (237), RII and RIII (182) category. In vivo studies on the sensitivity to metakelfin showed that some cases were resistant to this drug. There is an urgent need to eradicate this focus before it starts spreading to other areas. PMID:2680635

  9. 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.

  10. 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

  11. Doxorubicin and chloroquine coencapsulated liposomes: preparation and improved cytotoxicity on human breast cancer cells.

    PubMed

    Qiu, Liyan; Yao, Mingfei; Gao, Menghua; Zhao, Qinghe

    2012-09-01

    Doxorubicin, as a widely used chemotherapeutic, always causes multidrug resistance in human cancer cells. To circumvent drug resistance, we developed a novel formulation where doxorubicin hydrochloride (DOX) and chloroquine phosphate (CQ) were simultaneously loaded into liposomes by a pH-gradient method where CQ played the role of a chemical sensitizer. The various factors were investigated to optimize the formulation and manufacturing conditions of DOX and CQ coencapsulated liposomes (DCL). The resultant DCLs achieved the high encapsulation efficiency of both drugs over 90%. Further, DCLs significantly displayed resistance reversal action on a doxorubicin-resistant human breast cancer cell line (MCF-7/ADR) through the cooperation of CQ with DOX. The reversal fold of DCL with the DOX/CQ/soybean phosphatidylcholine weight ratio of 0.5:1:50 was 5.7, compared to free DOX. These results demonstrate that DCL is a promising formulation for the treatment of DOX-resistant breast cancer. PMID:22607110

  12. Genetic diversity of chloroquine-resistant Plasmodium vivax parasites from the western Brazilian Amazon.

    PubMed

    Lizcano, Omaira Vera; Resende, Sarah Stela; Chehuan, Yonne F; Lacerda, Marcus V G; Brito, Cristiana F A; Zalis, Mariano G

    2014-11-01

    The molecular basis of Plasmodium vivax chloroquine (CQ) resistance is still unknown. Elucidating the molecular background of parasites that are sensitive or resistant to CQ will help to identify and monitor the spread of resistance. By genotyping a panel of molecular markers, we demonstrate a similar genetic variability between in vitro CQ-resistant and sensitive phenotypes of P. vivax parasites. However, our studies identified two loci (MS8 and MSP1-B10) that could be used to discriminate between both CQ-susceptible phenotypes among P. vivax isolates in vitro. These preliminary data suggest that microsatellites may be used to identify and to monitor the spread of P. vivax-resistance around the world. PMID:25411001

  13. 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)

  14. 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) PMID:8525414

  15. Therapeutic Responses of Plasmodium vivax Malaria to Chloroquine and Primaquine Treatment in Northeastern Myanmar

    PubMed Central

    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

    2014-01-01

    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. PMID:25512415

  16. 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.

  17. Phosphonate analogue substrates for enolase.

    PubMed

    Anderson, V E; Cleland, W W

    1990-11-20

    Phosphonate analogues in which the bridge between C-2 and phosphorus is a CH2 group are slow substrates for yeast enolase. The pH variation of the kinetic parameters for the methylene analogue of 2-phosphoglycerate suggests that the substrate binds as a dianion and that Mg2+ can bind subsequently only if a metal ligand and the catalytic base are unprotonated. Primary deuterium isotope effects of 4-8 on V/KMg, but ones of only 1.15-1.32 on V for dehydration, show that proton removal to give the carbanion intermediate largely limits V/KMg and that a slow step follows which largely limits V (presumably carbanion breakdown). Since there is a D2O solvent isotope effect on V for the reverse reaction of 5, but not an appreciable one on the forward reaction, it appears that the slow rates with phosphonate analogues result from the fact that the carbanion intermediate is more stable than that formed from the normal substrates, and its reaction in both directions limits V. Increased stability as a result of replacement of oxygen by carbon at C-2 of the carbanion is the expected chemical behavior. PMID:2271661

  18. 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.

  19. Policy issues in space analogues

    NASA Astrophysics Data System (ADS)

    Auger, Robin N.; Facktor, Debra D.

    Space mission planning is increasingly focusing on destinations beyond Earth orbit. Advancements in technology will inevitably be required to enable long-duration human spaceflight missions, and breakthroughs in the policy arena will also be needed to achieve success in such missions. By exploring how policy issues have been addressed in analogous extreme environments, policymakers can develop a framework for addressing these issues as they apply to long-term human spaceflight. Policy issues that need to be addressed include: crew selection, training, organization, and activities, medical testing, illness, injury, and death; communication; legal accountability and liability; mission safety and risk management; and environmental contamination. This paper outlines the approach of a study underway by The George Washington University and ANSER to examine how these policy issues have been addressed in several analogues and how the experiences of these analogues can help formulate policies for long-duration human spaceflight missions. Analogues being studied include Antarctic bases, submarine voyages, undersea stations, Biosphere 2, and the U.S. Skylab and Russian Mir space stations.

  20. The Efficacy of Artesunate, Chloroquine, Doxycycline, Primaquine and a Combination of Artesunate and Primaquine against Avian Malaria in Broilers

    PubMed Central

    SOHSUEBNGARM, Damnern; SASIPREEYAJAN, Jiroj; NITHIUTHAI, Suwannee; CHANSIRIPORNCHAI, Niwat

    2014-01-01

    ABSTRACT The efficacy of 5 antimalarial drugs was evaluated on P. gallinaceum infected broilers. One hundred and forty-seven 19-day-old broilers were divided into 7 groups of 21 chicks each. Group 1 was the unmedicated, uninfected control. Groups 2–6 were infected and medicated with artesunate, chloroquine, doxycycline, primaquine and an artesunate-primaquine combination, respectively. Group 7 was the unmedicated, infected control. Infectivity, mortality, parasitemia, schizonts in tissues and body weight gain were monitored. The results revealed that the two most effective drugs for treating P. gallinaceum at the asexual erythrocyte stage were chloroquine and doxycycline. Tissue schizonts of P. gallinaceum in all the medicated groups were significantly fewer than the unmedicated, infected control (P<0.05). The mortality rate of all the medicated groups was significantly lower than the unmedicated, infected control (P<0.05). PMID:24531829

  1. 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

  2. Some histological effects of chronic administration of chloroquine on the medial geniculate body of adult wistar rat.

    PubMed

    Adjene, J O; Caxton-Martins, A E

    2006-06-01

    Some histological effects of chronic administration of chloroquine commonly used for prophylaxis or treatment of malaria. rheumatoid arthritis and lupus erythematosus on the medial geniculate body (MGB) of adult wistar rats was carefully studied. The rats of both sexes (n= 18), average weight of 184g were randomly assigned into treatment (n= 10) and control (n=7) groups. The rats in the treatment group received 2mg/kg body weight of chloroquine base dissolved in distilled water daily for fourteen days through the orogastric tube administration while the control rats received equal volume of distilled water daily through the same route. The rats were fed with rat pellets purchased from Topfeed Ltd. Sapele. Delta State. Nigeria and given water liberally and were then sacrificed on day fifteen of the experiment. The MGB were carefully dissected out and quickly fixed in 10% formal saline for routine histological study after H & E and thionin methods. The histological findings after H & E methods indicated that the treated sections of the MGB showed faintly reduced nuclei size, with the presence of many autophagic vacuoles and degenerative neurons when compared to the control sections. On the other hand. the thionin method indicated that the treated sections showed sparsely distributed neurons, which stain less intensely when compared with the control. The nissl substance in some of the neurons appeared degenerative while some hypertrophied with some vacuolations. These findings indicated that chronic administration of chloroquine has a deleterious effect on the neurons and nissl substance of the MGB. Chloroquine may probably have adverse effects on auditory sensibilities by its deleterious effects on the nerve cells and nissl substances of the MGB of the adult wistar rats. It is recommended that further studies aimed at corroborating these observations be carried out. PMID:17209307

  3. Effect of chloroquine phosphate treatment on serum MMP-9 and TIMP-1 levels in patients with systemic lupus erythematosus.

    PubMed

    Lesiak, A; Narbutt, J; Sysa-Jedrzejowska, A; Lukamowicz, J; McCauliffe, D P; Wózniacka, A

    2010-05-01

    Antimalarials are widely used for the treatment of systemic lupus erythematosus. However, their mechanisms of action have not been fully elucidated. Literature data indicate that matrix metalloproteinases may play a role in the immune response and tissue damage that occur in autoimmune skin diseases. The aim of this study was to determine the effect of 3 months of chloroquine treatment on serum levels of MMP-9 and TIMP-1 in patients with systemic lupus erythematosus. The study group consisted of 25 patients with systemic lupus erythematosus and 25 sex- and age-matched healthy volunteers. Before drug administration, serum levels of MMP-9 and TIMP-1 were determined by enzyme-linked immunosorbent assay. The same procedure was performed after chloroquine treatment. We found significantly higher median serum levels of MMP-9 in patients with systemic lupus erythematosus before therapy (57.20 ng/ml) when compared with controls (44.50 ng/ml) (p < 0.001). After chloroquine therapy the median MMP-9 serum level of systemic lupus erythematosus patients decreased significantly (43 ng/ml; p < 0.001). Before treatment the median TIMP-1 serum level in the patients with systemic lupus erythematosus was significantly higher than in the control group (500 vs. 200 ng/ml; p < 0.001), and after therapy it increased significantly (750 ng/ml TIMP-1; p < 0.001). The results suggest that chloroquine treatment may affect the matrix metalloproteinase network, and this effect may contribute to the immunoregulatory and anti-inflammatory properties of antimalarials.

  4. Arguments against Chemoprophylaxis in Areas at Low Risk for Chloroquine-Resistant Plasmodium falciparum.

    PubMed

    Armengaud

    1995-03-01

    Chemoprophylaxis of malaria prevents the disease not the infection (suppressive chemoprophylaxis) with "high levels of confusion and low levels of compliance." The magnitude of danger of contracting malaria for travelers varies in several endemic zones. In West Africa, without prophylaxis, malaria is estimated to have an incidence of 1.4% per person per month. In South and Central America, the incidence is 0.05 and 0.01% per month, respectively. In Asia, the transmission and percentage of infection due to Plasmodium falciparum is much lower. The dangers of chemoprophylaxis in an area at low risk for chloroquine resistant P. falciparum are a reality. Incompletely active drugs change clinical manifestations, and changes in clinical manifestations delay the establishment of a correct diagnosis. The rate of adverse events is 15-20%, and hospitalization due to side effects of prophylaxis occurs in one in 10,000 travelers. Neuropsychiatric side effects have been reported with both mefloquine and chloroquine. A false sense of security can hinder a physician practicing in a nonendemic area from thinking of malaria when a traveler returns with fever. To complicate the picture, in many countries, there is an emerging drug resistance in P. falciparum as well as an emerging chloroquine resistance in P. vivax strains (20% in New Guinea and Irian Jaya). In short, no available chemoprophylaxis is free from toxicity, and its efficacy is never 100%. Alternatives to conventional chemoprophylaxis are encouraged in areas of low morbidity of malaria. In areas where P. vivax occurs primarily, and when the risk of serious side effects from chemoprophylaxis outweighs the risk of life threatening P. falciparum infection, there are four alternative strategies.2,3 The first strategy is that the traveler avoid mosquito bites. With a compulsive attitude, a high degree of protection can be realized with the proper use of pyrethrum-impregnated mosquito netting, topical DEET-containing insect

  5. 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

  6. Gene encoding a deubiquitinating enzyme is mutated in artesunate- and chloroquine-resistant rodent malaria parasites§

    PubMed Central

    Hunt, Paul; Afonso, Ana; Creasey, Alison; Culleton, Richard; Sidhu, Amar Bir Singh; Logan, John; Valderramos, Stephanie G; McNae, Iain; Cheesman, Sandra; do Rosario, Virgilio; Carter, Richard; Fidock, David A; Cravo, Pedro

    2007-01-01

    Artemisinin- and artesunate-resistant Plasmodium chabaudi mutants, AS-ART and AS-ATN, were previously selected from chloroquine-resistant clones AS-30CQ and AS-15CQ respectively. Now, a genetic cross between AS-ART and the artemisinin-sensitive clone AJ has been analysed by Linkage Group Selection. A genetic linkage group on chromosome 2 was selected under artemisinin treatment. Within this locus, we identified two different mutations in a gene encoding a deubiquitinating enzyme. A distinct mutation occurred in each of the clones AS-30CQ and AS-ATN, relative to their respective progenitors in the AS lineage. The mutations occurred independently in different clones under drug selection with chloroquine (high concentration) or artesunate. Each mutation maps to a critical residue in a homologous human deubiquitinating protein structure. Although one mutation could theoretically account for the resistance of AS-ATN to artemisinin derivates, the other cannot account solely for the resistance of AS-ART, relative to the responses of its sensitive progenitor AS-30CQ. Two lines of Plasmodium falciparum with decreased susceptibility to artemisinin were also selected. Their drug-response phenotype was not genetically stable. No mutations in the UBP-1 gene encoding the P. falciparum orthologue of the deubiquitinating enzyme were observed. The possible significance of these mutations in parasite responses to chloroquine or artemisinin is discussed. PMID:17581118

  7. The anti-malarial chloroquine overcomes Primary resistance and restores sensitivity to Trastuzumab in HER2-positive breast cancer

    PubMed Central

    Cufí, Sílvia; Vazquez-Martin, Alejandro; Oliveras-Ferraros, Cristina; Corominas-Faja, Bruna; Cuyàs, Elisabet; López-Bonet, Eugeni; Martin-Castillo, Begoña; Joven, Jorge; Menendez, Javier A.

    2013-01-01

    Autophagy may control the de novo refractoriness of HER2 gene-amplified breast carcinomas to the monoclonal antibody trastuzumab (Herceptin). Tumor cells originally obtained from a patient who rapidly progressed on trastuzumab ab initio display increased cellular levels of the LC3-II protein—a finding that correlates with increased numbers of autophagosomes—and decreased levels of the autophagy receptor p62/SQSTM1, a protein selectively degraded by autophagy. Trastuzumab-refractory cells are in a state of “autophagy addiction” because genetic ablation of autophagy-specific genes (ATG8, ATG5, ATG12) notably reduces intrinsic refractoriness to trastuzumab. When the anti-malarial lysosomotropic drug chloroquine impedes autophagic resolution of the accumulation of autophagolysosomes formed in the presence of trastuzumab, cells commit to die by apoptosis. Accordingly, combination treatment with trastuzumab and chloroquine radically suppresses tumor growth by > 90% in a tumor xenograft completely refractory to trastuzumab. Adding chloroquine to trastuzumab-based regimens may therefore improve outcomes among women with autophagy-addicted HER2-positive breast cancer. PMID:23965851

  8. Genotyping of chloroquine resistant Plasmodium falciparum in wild caught Anopheles minimus mosquitoes in a malaria endemic area of Assam, India.

    PubMed

    Sarma, D K; Mohapatra, P K; Bhattacharyya, D R; Mahanta, J; Prakash, A

    2014-09-01

    We validated the feasibility of using Plasmodium falciparum, the human malaria parasite, DNA present in wild caught vector mosquitoes for the characterization of chloroquine resistance status. House frequenting mosquitoes belonging to Anopheles minimus complex were collected from human dwellings in a malaria endemic area of Assam, Northeast India and DNA was extracted from the head-thorax region of individual mosquitoes. Anopheles minimus complex mosquitoes were identified to species level and screened for the presence of Plasmodium sp. using molecular tools. Nested PCR-RFLP method was used for genotyping of P. falciparum based on K76T mutation in the chloroquine resistance transporter (pfcrt) gene. Three of the 27 wild caught An. minimus mosquitoes were harbouring P. falciparum sporozoites (positivity 11.1%) and all 3 were had 76T mutation in the pfcrt gene, indicating chloroquine resistance. The approach of characterizing antimalarial resistance of malaria parasite in vector mosquitoes can potentially be used as a surveillance tool for monitoring transmission of antimalarial drug resistant parasite strains in the community.

  9. The anti-malarial chloroquine overcomes primary resistance and restores sensitivity to trastuzumab in HER2-positive breast cancer.

    PubMed

    Cufí, Sílvia; Vazquez-Martin, Alejandro; Oliveras-Ferraros, Cristina; Corominas-Faja, Bruna; Cuyàs, Elisabet; López-Bonet, Eugeni; Martin-Castillo, Begoña; Joven, Jorge; Menendez, Javier A

    2013-01-01

    Autophagy may control the de novo refractoriness of HER2 gene-amplified breast carcinomas to the monoclonal antibody trastuzumab (Herceptin). Tumor cells originally obtained from a patient who rapidly progressed on trastuzumab ab initio display increased cellular levels of the LC3-II protein--a finding that correlates with increased numbers of autophagosomes--and decreased levels of the autophagy receptor p62/SQSTM1, a protein selectively degraded by autophagy. Trastuzumab-refractory cells are in a state of "autophagy addiction" because genetic ablation of autophagy-specific genes (ATG8, ATG5, ATG12) notably reduces intrinsic refractoriness to trastuzumab. When the anti-malarial lysosomotropic drug chloroquine impedes autophagic resolution of the accumulation of autophagolysosomes formed in the presence of trastuzumab, cells commit to die by apoptosis. Accordingly, combination treatment with trastuzumab and chloroquine radically suppresses tumor growth by > 90% in a tumor xenograft completely refractory to trastuzumab. Adding chloroquine to trastuzumab-based regimens may therefore improve outcomes among women with autophagy-addicted HER2-positive breast cancer. PMID:23965851

  10. Current european regulatory perspectives on insulin analogues.

    PubMed

    Enzmann, Harald G; Weise, Martina

    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

  11. 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

  12. Strain-Specific Protective Effect of the Immunity Induced by Live Malarial Sporozoites under Chloroquine Cover

    PubMed Central

    Wijayalath, Wathsala; Cheesman, Sandra; Tanabe, Kazuyuki; Handunnetti, Shiroma; Carter, Richard; Pathirana, Sisira

    2012-01-01

    The efficacy of a whole-sporozoite malaria vaccine would partly be determined by the strain-specificity of the protective responses against malarial sporozoites and liver-stage parasites. Evidence from previous reports were inconsistent, where some studies have shown that the protective immunity induced by irradiated or live sporozoites in rodents or humans were cross-protective and in others strain-specific. In the present work, we have studied the strain-specificity of live sporozoite-induced immunity using two genetically and immunologically different strains of Plasmodium cynomolgi, Pc746 and PcCeylon, in toque monkeys. Two groups of monkeys were immunized against live sporozoites of either the Pc746 (n = 5), or the PcCeylon (n = 4) strain, by the bites of 2–4 sporozoite-infected Anopheles tessellates mosquitoes per monkey under concurrent treatments with chloroquine and primaquine to abrogate detectable blood infections. Subsequently, a group of non-immunized monkeys (n = 4), and the two groups of immunized monkeys were challenged with a mixture of sporozoites of the two strains by the bites of 2–5 infective mosquitoes from each strain per monkey. In order to determine the strain-specificity of the protective immunity, the proportions of parasites of the two strains in the challenge infections were quantified using an allele quantification assay, Pyrosequencing™, based on a single nucleotide polymorphism (SNP) in the parasites’ circumsporozoite protein gene. The Pyrosequencing™ data showed that a significant reduction of parasites of the immunizing strain in each group of strain-specifically immunized monkeys had occurred, indicating a stronger killing effect on parasites of the immunizing strain. Thus, the protective immunity developed following a single, live sporozoite/chloroquine immunization, acted specifically against the immunizing strain and was, therefore, strain-specific. As our experiment does not allow us to determine the

  13. 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)

  14. The Canadian Analogue Research Network (CARN): Opportunities for Terrestrial Analogue Studies in Canada and Abroad

    NASA Astrophysics Data System (ADS)

    Hipkin, V.; Osinski, G. R.; Berinstain, A.; Léveillé, R.

    2007-03-01

    We will present an overview of the Canadian Analogue Research Network (CARN), including a description of the various analogue sites in CARN, potential new sites, and a discussion regarding how CARN is applicable to the global exploration strategy.

  15. 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.

  16. Chloroquine improves left ventricle diastolic function in streptozotocin-induced diabetic mice

    PubMed Central

    Yuan, Xun; Xiao, Yi-Chuan; Zhang, Gui-Ping; Hou, Ning; Wu, Xiao-Qian; Chen, Wen-Liang; Luo, Jian-Dong; Zhang, Gen-Shui

    2016-01-01

    Diabetes is a potent risk factor for heart failure with preserved ejection fraction (HFpEF). Autophagy can be activated under pathological conditions, including diabetic cardiomyopathy. The therapeutic effects of chloroquine (CQ), an autophagy inhibitor, on left ventricle function in streptozotocin (STZ)-induced diabetic mice were investigated. The cardiac function, light chain 3 (LC3)-II/LC3-I ratio, p62, beclin 1, reactive oxygen species, apoptosis, and fibrosis were measured 14 days after CQ (ip 60 mg/kg/d) administration. In STZ-induced mice, cardiac diastolic function was decreased significantly with normal ejection fraction. CQ significantly ameliorated cardiac diastolic function in diabetic mice with HFpEF. In addition, CQ decreased the autophagolysosomes, cardiomyocyte apoptosis, and cardiac fibrosis but increased LC3-II and p62 expressions. These results suggested that CQ improved the cardiac diastolic function by inhibiting autophagy in STZ-induced HFpEF mice. Autophagic inhibitor CQ might be a potential therapeutic agent for HFpEF. PMID:27621594

  17. Harmine Is a Potent Antimalarial Targeting Hsp90 and Synergizes with Chloroquine and Artemisinin

    PubMed Central

    Shahinas, Dea; MacMullin, Gregory; Benedict, Christan; Crandall, Ian

    2012-01-01

    Previous studies have shown an antimalarial effect of total alkaloids extracted from leaves of Guiera senegalensis from Mali in West Africa. We independently observed that the beta-carboline alkaloid harmine obtained from a natural product library screen inhibited Plasmodium falciparum heat shock protein 90 (PfHsp90) ATP-binding domain. In this study, we confirmed harmine-PfHsp90-specific affinity using surface plasmon resonance analysis (dissociation constant [Kd] of 40 μM). In contrast, the related compound harmalol bound human Hsp90 (HsHsp90) (Kd of 224 μM) more tightly than PfHsp90 (Kd of 7,010 μM). Site-directed mutagenesis revealed that Arg98 in PfHsp90 is essential for harmine selectivity. In keeping with our model indicating that Hsp90 inhibition affords synergistic combinations with existing antimalarials, we demonstrated that harmine potentiates the effect of chloroquine and artemisinin in vitro and in the Plasmodium berghei mouse model. These findings have implications for the development of novel therapeutic combinations that are synergistic with existing antimalarials. PMID:22615284

  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. Suppression of autophagy by chloroquine sensitizes 5-fluorouracil-mediated cell death in gallbladder carcinoma cells

    PubMed Central

    2014-01-01

    Autophagy1 is a complex of adaptive cellular response that enhances cancer cell survival in the face of cellular stresses such as chemothery. Here we show that in human gallbladder carcinoma (GBC) cells lines, SGC-996 and GBC-SD, autophagy is induced by the DNA damaging agent 5-fluorouracil (5-FU). While in combination with the pre-treatment of chloroquine (CQ), a inhibitor of autophagy, the inhibition of 5-FU to the proliferation and viability of GBC cells was potentiated. Furthermore, 5-FU treatment resulted in a general increase of the apoptotic rate and G0/G1 arrest of GBC cells, and the effect was potentiated by CQ pre-treatment. Since 5-FU induced autophagy in GBC cells, and CQ inhibited autophagy, our findings suggest a possible mechanism that CQ inhibited 5-FU-induced autophagy, which modified the cytotoxicity of 5-FU. The combination therapy of CQ and 5-FU should be considered as an effective strategy for the treatment of gallbladder carcinoma. PMID:24581180

  20. Chloroquine improves left ventricle diastolic function in streptozotocin-induced diabetic mice.

    PubMed

    Yuan, Xun; Xiao, Yi-Chuan; Zhang, Gui-Ping; Hou, Ning; Wu, Xiao-Qian; Chen, Wen-Liang; Luo, Jian-Dong; Zhang, Gen-Shui

    2016-01-01

    Diabetes is a potent risk factor for heart failure with preserved ejection fraction (HFpEF). Autophagy can be activated under pathological conditions, including diabetic cardiomyopathy. The therapeutic effects of chloroquine (CQ), an autophagy inhibitor, on left ventricle function in streptozotocin (STZ)-induced diabetic mice were investigated. The cardiac function, light chain 3 (LC3)-II/LC3-I ratio, p62, beclin 1, reactive oxygen species, apoptosis, and fibrosis were measured 14 days after CQ (ip 60 mg/kg/d) administration. In STZ-induced mice, cardiac diastolic function was decreased significantly with normal ejection fraction. CQ significantly ameliorated cardiac diastolic function in diabetic mice with HFpEF. In addition, CQ decreased the autophagolysosomes, cardiomyocyte apoptosis, and cardiac fibrosis but increased LC3-II and p62 expressions. These results suggested that CQ improved the cardiac diastolic function by inhibiting autophagy in STZ-induced HFpEF mice. Autophagic inhibitor CQ might be a potential therapeutic agent for HFpEF. PMID:27621594

  1. Low level genotypic chloroquine resistance near Malawi's northern border with Tanzania.

    PubMed

    Bridges, Daniel J; Molyneux, Malcolm; Nkhoma, Standwell

    2009-09-01

    We conducted a prevalence study of mutations in Plasmodium falciparum that are associated with antimalarial drug resistance at a rural site in Karonga near Malawi's northern border with Tanzania. We found a higher prevalence of the key chloroquine resistance-conferring mutation in the pfcrt gene (K76T) at this site in comparison with the prevalence in Blantyre, a city in the south of Malawi, far from an international border (9%vs. 0%; P < 0.0005). In contrast we found a lower prevalence of the quintuple dhfr/dhps mutation, which is highly predictive of SP treatment failure, at the Karonga site compared to Blantyre (76%vs. 88%; P < 0.005). The prevalence of the K76T pfcrt mutation at two Tanzanian sites close to the border with Malawi was recently reported to be over 50%. Our findings suggest a considerable 'leakage' of parasite antimalarial drug resistance across the border between two countries with different national malaria control policies and with different levels of resistance. Neighbouring countries should consider implementing common regional rather than national malaria treatment policies to prevent the spread of antimalarial drug resistance alleles across their borders.

  2. Chloroquine improves left ventricle diastolic function in streptozotocin-induced diabetic mice

    PubMed Central

    Yuan, Xun; Xiao, Yi-Chuan; Zhang, Gui-Ping; Hou, Ning; Wu, Xiao-Qian; Chen, Wen-Liang; Luo, Jian-Dong; Zhang, Gen-Shui

    2016-01-01

    Diabetes is a potent risk factor for heart failure with preserved ejection fraction (HFpEF). Autophagy can be activated under pathological conditions, including diabetic cardiomyopathy. The therapeutic effects of chloroquine (CQ), an autophagy inhibitor, on left ventricle function in streptozotocin (STZ)-induced diabetic mice were investigated. The cardiac function, light chain 3 (LC3)-II/LC3-I ratio, p62, beclin 1, reactive oxygen species, apoptosis, and fibrosis were measured 14 days after CQ (ip 60 mg/kg/d) administration. In STZ-induced mice, cardiac diastolic function was decreased significantly with normal ejection fraction. CQ significantly ameliorated cardiac diastolic function in diabetic mice with HFpEF. In addition, CQ decreased the autophagolysosomes, cardiomyocyte apoptosis, and cardiac fibrosis but increased LC3-II and p62 expressions. These results suggested that CQ improved the cardiac diastolic function by inhibiting autophagy in STZ-induced HFpEF mice. Autophagic inhibitor CQ might be a potential therapeutic agent for HFpEF.

  3. Design and synthesis of chloroquine analogs with anti-breast cancer property.

    PubMed

    Solomon, V R; Hu, Changkun; Lee, Hoyun

    2010-09-01

    A series of chloroquine (CQ) analogs were designed and synthesized in a repositioning approach to develop compounds with high anti-breast cancer property. The compounds were then examined for their antiproliferative effects on two human breast tumor cell lines and a matching non-cancer cell line. Although many of them showed substantial antiproliferative effects on breast cancer cells examined, two compounds, 7-chloro-N-(3-(4-(7-(trifluoromethyl)quinolin-4-yl)piperazin-1-yl)propyl)quinolin-4-amine (14) and {3-[4-(7-chloro-quinolin-4-yl)-piperazin-1-yl]-propyl}-(7-trifluoromethyl-quinolin-4-yl)-amine (26), emerged as the most active among this series. They were particularly potent against MCF7 cells when compared to CQ and cisplatin, a widely prescribed anti-cancer drug. The results suggest that these CQ analogs could serve as bases for the development of a new group of effective cancer chemotherapeutics. PMID:20561720

  4. Chloroquine eliminates cancer stem cells through deregulation of Jak2 and DNMT1.

    PubMed

    Choi, Dong Soon; Blanco, Elvin; Kim, Yoo-Shin; Rodriguez, Angel A; Zhao, Hong; Huang, Tim Hui-Ming; Chen, Chun-Liang; Jin, Guangxu; Landis, Melissa D; Burey, Lacey A; Qian, Wei; Granados, Sergio M; Dave, Bhuvanesh; Wong, Helen H; Ferrari, Mauro; Wong, Stephen T C; Chang, Jenny C

    2014-09-01

    Triple negative breast cancer (TNBC) is known to contain a high percentage of CD44(+) /CD24(-/low) cancer stem cells (CSCs), corresponding with a poor prognosis despite systemic chemotherapy. Chloroquine (CQ), an antimalarial drug, is a lysotropic reagent which inhibits autophagy. CQ was identified as a potential CSC inhibitor through in silico gene expression signature analysis of the CD44(+) /CD24(-/low) CSC population. Autophagy plays a critical role in adaptation to stress conditions in cancer cells, and is related with drug resistance and CSC maintenance. Thus, the objectives of this study were to examine the potential enhanced efficacy arising from addition of CQ to standard chemotherapy (paclitaxel) in TNBC and to identify the mechanism by which CQ eliminates CSCs in TNBCs. Herein, we report that CQ sensitizes TNBC cells to paclitaxel through inhibition of autophagy and reduces the CD44(+) /CD24(-/low) CSC population in both preclinical and clinical settings. Also, we are the first to report a mechanism by which CQ regulates the CSCs in TNBC through inhibition of the Janus-activated kinase 2 (Jak2)-signal transducer and activator of transcription 3 signaling pathway by reducing the expression of Jak2 and DNA methyltransferase 1. PMID:24809620

  5. Chloroquine enhances the cytotoxicity of topotecan by inhibiting autophagy in lung cancer cells.

    PubMed

    Wang, Yao; Peng, Rui-Qing; Li, Dan-Dan; Ding, Ya; Wu, Xiao-Qi; Zeng, Yi-Xin; Zhu, Xiao-Feng; Zhang, Xiao-Shi

    2011-10-01

    Although the anti-malaria drug chloroquine (CQ) has been shown to enhance chemotherapy and radiation sensitivity in clinical trials, the potential mechanisms underlying this enhancement are still unclear. Here, we examined the relevant mechanisms by which the multipotent CQ enhanced the cytotoxicity of topotecan (TPT). The lung cancer cell line A549 was treated with TPT alone or TPT combined with CQ at non-cytotoxic concentrations. Cell viability was assessed using the MTT assay. The percentage of apoptotic cells and the presence of a side population of cells were both determined by flow cytometry. Autophagy and the expression of Bcl-2 family proteins were examined by Western blotting. The accumulation of YFP-LC3 dots and the formation of acidic vesicular organelles were examined by confocal microscopy. CQ sensitized A549 cells to TPT and enhanced TPT-induced apoptosis in a Bcl-2 family protein-independent fashion. CQ inhibited TPT-induced autophagy, which modified the cytotoxicity of TPT. However, CQ failed to modify the transfer of TPT across the cytoplasmic membrane and did not increase lysosomal permeability. This study showed that CQ at non-cytotoxic concentrations potentiated the cytotoxicity of TPT by interfering with autophagy, implying that CQ has significant potential as a chemotherapeutic enhancer. PMID:21959046

  6. Chloroquine enhances the cytotoxicity of topotecan by inhibiting autophagy in lung cancer cells

    PubMed Central

    Wang, Yao; Peng, Rui-Qing; Li, Dan-Dan; Ding, Ya; Wu, Xiao-Qi; Zeng, Yi-Xin; Zhu, Xiao-Feng; Zhang, Xiao-Shi

    2011-01-01

    Although the anti-malaria drug chloroquine (CQ) has been shown to enhance chemotherapy and radiation sensitivity in clinical trials, the potential mechanisms underlying this enhancement are still unclear. Here, we examined the relevant mechanisms by which the multipotent CQ enhanced the cytotoxicity of topotecan (TPT). The lung cancer cell line A549 was treated with TPT alone or TPT combined with CQ at non-cytotoxic concentrations. Cell viability was assessed using the MTT assay. The percentage of apoptotic cells and the presence of a side population of cells were both determined by flow Cytometry. Autophagy and the expression of Bcl-2 family proteins were examined by Western blotting. The accumulation of YFP-LC3 dots and the formation of acidic vesicular organelles were examined by confocal microscopy. CQ sensitized A549 cells to TPT and enhanced TPT-induced apoptosis in a Bcl-2 family protein-independent fashion. CQ inhibited TPT-induced autophagy, which modified the cytotoxicity of TPT. However, CQ failed to modify the transfer of TPT across the cytoplasmic membrane and did not increase lysosomal permeability. This study showed that CQ at non-cytotoxic concentrations potentiated the cytotoxicity of TPT by interfering with autophagy, implying that CQ has significant potential as a chemotherapeutic enhancer. PMID:21959046

  7. Reemergence of chloroquine (CQ) analogs as multi-targeting antimalarial agents: a review.

    PubMed

    Mushtaque, Md; Shahjahan

    2015-01-27

    Amongst several communicable diseases (CDs), malaria is one of the deadliest parasitic disease all over the world, particularly in African and Asian countries. To curb this menace, numbers of antimalarial agents are being sold as over the counter (OTC) drugs. Chloroquine (CQ) is one of them and is one of the oldest, cheapest, and easily available synthetic agents used to curb malaria. Unfortunately, after the reports of CQ-resistance against different strains of malarial parasite strains worldwide, scientist are continuously modifying the core structure of CQ to get an efficient drug. Interestingly, several new drugs have been emerged in due course having unique and enhanced properties (like dual stage inhibitors, resistance reversing ability etc.) and are ready to enter into the clinical trial. In this course, some new agents have also been discovered which are; though inactive against CQS strain, highly active against CQR strains. The present article describes the role of modification of the core structure of CQ and its effects on the biological activities. Moreover, the attempt has also been made to predict the future prospects of such drugs to reemerge as antimalarial agents. PMID:25461328

  8. Replication of Plasmodium in reticulocytes can occur without hemozoin formation, resulting in chloroquine resistance

    PubMed Central

    Lin, Jing-wen; Spaccapelo, Roberta; Schwarzer, Evelin; Sajid, Mohammed; Annoura, Takeshi; Deroost, Katrien; Ravelli, Raimond B.G.; Aime, Elena; Capuccini, Barbara; Mommaas-Kienhuis, Anna M.; O’Toole, Tom; Prins, Frans; Franke-Fayard, Blandine M.D.; Ramesar, Jai; Chevalley-Maurel, Séverine; Kroeze, Hans; Koster, Abraham J.; Tanke, Hans J.; Crisanti, Andrea; Langhorne, Jean; Arese, Paolo; Van den Steen, Philippe E.; Janse, Chris J.

    2015-01-01

    Most studies on malaria-parasite digestion of hemoglobin (Hb) have been performed using P. falciparum maintained in mature erythrocytes, in vitro. In this study, we examine Plasmodium Hb degradation in vivo in mice, using the parasite P. berghei, and show that it is possible to create mutant parasites lacking enzymes involved in the initial steps of Hb proteolysis. These mutants only complete development in reticulocytes and mature into both schizonts and gametocytes. Hb degradation is severely impaired and large amounts of undigested Hb remains in the reticulocyte cytoplasm and in vesicles in the parasite. The mutants produce little or no hemozoin (Hz), the detoxification by-product of Hb degradation. Further, they are resistant to chloroquine, an antimalarial drug that interferes with Hz formation, but their sensitivity to artesunate, also thought to be dependent on Hb degradation, is retained. Survival in reticulocytes with reduced or absent Hb digestion may imply a novel mechanism of drug resistance. These findings have implications for drug development against human-malaria parasites, such as P. vivax and P. ovale, which develop inside reticulocytes. PMID:25941254

  9. Double mutation in the pfmdr1 gene is associated with emergence of chloroquine-resistant Plasmodium falciparum malaria in Eastern India.

    PubMed

    Das, Sabyasachi; Mahapatra, Santanu Kar; Tripathy, Satyajit; Chattopadhyay, Sourav; Dash, Sandeep Kumar; Mandal, Debasis; Das, Balaram; Hati, Amiya Kumar; Roy, Somenath

    2014-10-01

    Malaria is a major public health problem in tropical and subtropical countries, including India. This study elucidates the cause of chloroquine treatment failure (for Plasmodium falciparum infection) before the introduction of artemisinin combination therapy. One hundred twenty-six patients were randomized to chloroquine treatment, and the therapeutic efficacy was monitored from days 1 to 28. An in vitro susceptibility test was performed with all isolates. Parasitic DNA was isolated, followed by PCR and restriction digestion of different codons of the pfcrt gene (codons 72 to 76) and the pfmdr1 gene (N86Y, Y184F, S1034C, N1042D, and D1246Y). Finally, sequencing was done to confirm the mutations. Forty-three (34.13%) early treatment failure cases and 16 (12.69%) late treatment failure cases were observed after chloroquine treatment. In vitro chloroquine resistance was found in 103 isolates (81.75%). Twenty-six (60.47%) early treatment failure cases and 6 (37.5%) late treatment failure cases were associated with the CVMNK-YYSNY allele (the underlined amino acids are those that were mutated). Moreover, the CVIEK-YYSNY allele was found in 8 early treatment failure (18.60%) and 2 late treatment failure (12.5%) cases. The presence of the wild-type pfcrt (CVMNK) and pfmdr1 (YYSNY) double mutant allele in chloroquine-nonresponsive cases was quite uncommon. In vivo chloroquine treatment failure and in vitro chloroquine resistance were strongly correlated with the CVMNK-YYSNY and CVIEK-YYSNY haplotypes (P < 0.01).

  10. 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

  11. 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.

  12. 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.

  13. Synthesis and antiplasmodial activity of betulinic acid and ursolic acid analogues.

    PubMed

    Innocente, Adrine M; Silva, Gloria N S; Cruz, Laura Nogueira; Moraes, Miriam S; Nakabashi, Myna; Sonnet, Pascal; Gosmann, Grace; Garcia, Célia R S; Gnoatto, Simone C B

    2012-10-12

    More than 40% of the World population is at risk of contracting malaria, which affects primarily poor populations in tropical and subtropical areas. Antimalarial pharmacotherapy has utilised plant-derived products such as quinine and artemisinin as well as their derivatives. However, worldwide use of these antimalarials has caused the spread of resistant parasites, resulting in increased malaria morbidity and mortality. Considering that the literature has demonstrated the antimalarial potential of triterpenes, specially betulinic acid (1) and ursolic acid (2), this study investigated the antimalarial activity against P. falciparum chloroquine-sensitive 3D7 strain of some new derivatives of 1 and 2 with modifications at C-3 and C-28. The antiplasmodial study employed flow cytometry and spectrofluorimetric analyses using YOYO-1, dihydroethidium and Fluo4/AM for staining. Among the six analogues obtained, compounds 1c and 2c showed excellent activity (IC₅₀ = 220 and 175 nM, respectively) while 1a and b demonstrated good activity (IC₅₀ = 4 and 5 μM, respectively). After cytotoxicity evaluation against HEK293T cells, 1a was not toxic, while 1c and 2c showed IC₅₀ of 4 μM and a selectivity index (SI) value of 18 and 23, respectively. Moreover, compound 2c, which presents the best antiplasmodial activity, is involved in the calcium-regulated pathway(s).

  14. 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

  15. 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.

  16. 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

  17. Plasmodium vivax drug resistance genes; Pvmdr1 and Pvcrt-o polymorphisms in relation to chloroquine sensitivity from a malaria endemic area of Thailand.

    PubMed

    Rungsihirunrat, Kanchana; Muhamad, Poonuch; Chaijaroenkul, Wanna; Kuesap, Jiraporn; Na-Bangchang, Kesara

    2015-02-01

    The aim of the study was to explore the possible molecular markers of chloroquine resistance in Plasmodium vivax isolates in Thailand. A total of 30 P. vivax isolates were collected from a malaria endemic area along the Thai-Myanmar border in Mae Sot district of Thailand. Dried blood spot samples were collected for analysis of Pvmdr1 and Pvcrt-o polymorphisms. Blood samples (100 μl) were collected by finger-prick for in vitro chloroquine susceptibility testing by schizont maturation inhibition assay. Based on the cut-off IC50 of 100 nM, 19 (63.3%) isolates were classified as chloroquine resistant P. vivax isolates. Seven non-synonymous mutations and 2 synonymous were identified in Pvmdr1 gene. Y976F and F1076L mutations were detected in 7 (23.3%) and 16 isolates (53.3%), respectively. Analysis of Pvcrt-o gene revealed that all isolates were wild-type. Our results suggest that chloroquine resistance gene is now spreading in this area. Monitoring of chloroquine resistant molecular markers provide a useful tool for future control of P. vivax malaria.

  18. Identification of a Mutant PfCRT-Mediated Chloroquine Tolerance Phenotype in Plasmodium falciparum

    PubMed Central

    Valderramos, Stephanie G.; Valderramos, Juan-Carlos; Musset, Lise; Purcell, Lisa A.; Mercereau-Puijalon, Odile; Legrand, Eric; Fidock, David A.

    2010-01-01

    Mutant forms of the Plasmodium falciparum transporter PfCRT constitute the key determinant of parasite resistance to chloroquine (CQ), the former first-line antimalarial, and are ubiquitous to infections that fail CQ treatment. However, treatment can often be successful in individuals harboring mutant pfcrt alleles, raising questions about the role of host immunity or pharmacokinetics vs. the parasite genetic background in contributing to treatment outcomes. To examine whether the parasite genetic background dictates the degree of mutant pfcrt-mediated CQ resistance, we replaced the wild type pfcrt allele in three CQ-sensitive strains with mutant pfcrt of the 7G8 allelic type prevalent in South America, the Oceanic region and India. Recombinant clones exhibited strain-dependent CQ responses that ranged from high-level resistance to an incremental shift that did not meet CQ resistance criteria. Nonetheless, even in the most susceptible clones, 7G8 mutant pfcrt enabled parasites to tolerate CQ pressure and recrudesce in vitro after treatment with high concentrations of CQ. 7G8 mutant pfcrt was found to significantly impact parasite responses to other antimalarials used in artemisinin-based combination therapies, in a strain-dependent manner. We also report clinical isolates from French Guiana that harbor mutant pfcrt, identical or related to the 7G8 haplotype, and manifest a CQ tolerance phenotype. One isolate, H209, harbored a novel PfCRT C350R mutation and demonstrated reduced quinine and artemisinin susceptibility. Our data: 1) suggest that high-level CQR is a complex biological process dependent on the presence of mutant pfcrt; 2) implicate a role for variant pfcrt alleles in modulating parasite susceptibility to other clinically important antimalarials; and 3) uncover the existence of a phenotype of CQ tolerance in some strains harboring mutant pfcrt. PMID:20485514

  19. 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

  20. Discovering thiamine transporters as targets of chloroquine using a novel functional genomics strategy.

    PubMed

    Huang, Zhiwei; Srinivasan, Sankaranarayanan; Zhang, Jianhuai; Chen, Kaifu; Li, Yongxiang; Li, Wei; Quiocho, Florante A; Pan, Xuewen

    2012-01-01

    Chloroquine (CQ) and other quinoline-containing antimalarials are important drugs with many therapeutic benefits as well as adverse effects. However, the molecular targets underlying most such effects are largely unknown. By taking a novel functional genomics strategy, which employs a unique combination of genome-wide drug-gene synthetic lethality (DGSL), gene-gene synthetic lethality (GGSL), and dosage suppression (DS) screens in the model organism Saccharomyces cerevisiae and is thus termed SL/DS for simplicity, we found that CQ inhibits the thiamine transporters Thi7, Nrt1, and Thi72 in yeast. We first discovered a thi3Δ mutant as hypersensitive to CQ using a genome-wide DGSL analysis. Using genome-wide GGSL and DS screens, we then found that a thi7Δ mutation confers severe growth defect in the thi3Δ mutant and that THI7 overexpression suppresses CQ-hypersensitivity of this mutant. We subsequently showed that CQ inhibits the functions of Thi7 and its homologues Nrt1 and Thi72. In particular, the transporter activity of wild-type Thi7 but not a CQ-resistant mutant (Thi7(T287N)) was completely inhibited by the drug. Similar effects were also observed with other quinoline-containing antimalarials. In addition, CQ completely inhibited a human thiamine transporter (SLC19A3) expressed in yeast and significantly inhibited thiamine uptake in cultured human cell lines. Therefore, inhibition of thiamine uptake is a conserved mechanism of action of CQ. This study also demonstrated SL/DS as a uniquely effective methodology for discovering drug targets.

  1. Effect of Khat (Catha edulis) Use on the Bioavailability, Plasma Levels and Antimalarial Activity of Chloroquine

    PubMed Central

    Issa, Faiza H.; Al-Habori, Molhem; Chance, Michael L.

    2016-01-01

    Objectives: This study aimed to evaluate the effect of khat (Catha edulis) on chloroquine (CQ) bioavailability in healthy Yemeni adults and its effect on CQ plasma levels and parasite clearance among malaria patients. Methods: This study took place between January and April 2007 in Bajil and Sana’a, Yemen. Two CQ doses (600 mg each) were given to 15 healthy males on separate occasions; the first dose was followed by a khat-chewing session (phase one) while controls abstained from khat-chewing for the second (phase two). Additionally, 103 patients with Plasmodium falciparum-induced malaria, including both regular khat chewers (n = 57) and non-khat chewers (n = 46), were treated with CQ (25 mg/kg) over three days. Pharmacokinetic parameters were analysed among both controls and malaria patients. Parasite clearance was also investigated for the latter group. Results: The mean area under the concentration-time curve (AUC) was 2,108.9 versus 2,797.4 ng/hour/mL, mean peak plasma concentration (Cmax) was 415.6 versus 508.7 ng/mL and mean time to reach Cmax was 3.8 versus 3.6 hours for controls in phase one versus phase two, respectively; both AUC and Cmax levels were significantly reduced by khat-chewing (P <0.050). For khat- versus non-khat-chewing malaria patients, mean plasma CQ concentrations were 266.4 ng/mL versus 427.5 ng/mL (P <0.001). Furthermore, CQ was effective in 71.7% and 75.4% of non-khat and khat-chewing malaria patients, respectively (P = 0.823). Conclusion: Khat-chewing was found to significantly reduce plasma CQ levels among healthy volunteers and malaria patients. While receiving CQ treatment, patients should be advised not to chew khat. PMID:27226909

  2. pfmdr1 amplification and fixation of pfcrt chloroquine resistance alleles in Plasmodium falciparum in Venezuela.

    PubMed

    Griffing, Sean; Syphard, Luke; Sridaran, Sankar; McCollum, Andrea M; Mixson-Hayden, Tonya; Vinayak, Sumiti; Villegas, Leopoldo; Barnwell, John W; Escalante, Ananias A; Udhayakumar, Venkatachalam

    2010-04-01

    Molecular tools are valuable for determining evolutionary history and the prevalence of drug-resistant malaria parasites. These tools have helped to predict decreased sensitivity to antimalarials and fixation of multidrug resistance genotypes in some regions. In order to assess how historical drug policies impacted Plasmodium falciparum in Venezuela, we examined molecular changes in genes associated with drug resistance. We examined pfmdr1 and pfcrt in samples from Sifontes, Venezuela, and integrated our findings with earlier work describing dhfr and dhps in these samples. We characterized pfmdr1 genotypes and copy number variation, pfcrt genotypes, and proximal microsatellites in 93 samples originating from surveillance from 2003 to 2004. Multicopy pfmdr1 was found in 12% of the samples. Two pfmdr1 alleles, Y184F/N1042D/D1246Y (37%) and Y184F/S1034C/N1042D/D1246Y (63%), were found. These alleles share ancestry, and no evidence of strong selective pressure on mutations was found. pfcrt chloroquine resistance alleles are fixed with two alleles: S(tct)VMNT (91%) and S(agt)VMNT (9%). These alleles are associated with strong selection. There was also an association between pfcrt, pfmdr1, dhfr, and dhps genotypes/haplotypes. Duplication of pfmdr1 suggests a potential shift in mefloquine sensitivity in this region, which warrants further study. A bottleneck occurred in P. falciparum in Sifontes, Venezuela, and multidrug resistance genotypes are present. This population could be targeted for malaria elimination programs to prevent the possible spread of multidrug-resistant parasites.

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

    PubMed

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

    2010-05-01

    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.

  4. Detection of chloroquine and artemisinin resistance molecular markers in Plasmodium falciparum: A hospital based study

    PubMed Central

    Ramani, S; Parija, Subhash Chandra; Mandal, Jharna; Hamide, Abdoul; Bhat, Vishnu

    2016-01-01

    Introduction: Emergence of chloroquine (CQ) resistance in Plasmodium falciparum has increased the morbidity and mortality of falciparum malaria worldwide. Artemisinin-based combination therapies are now recommended by the World Health Organization as the first line treatment for falciparum malaria. Numerous molecular markers have been implicated in the CQ and artemisinin resistance. Materials and Methods: A total of 26 confirmed cases of falciparum malaria (by giemsa stained thick and thin smear, quantitative buffy coat, immunochromatographic test, or polymerase chain reaction [PCR]) were included in the study. About 5 ml of ethylenediaminetetraacetic acid blood sample was collected and stored at −20°C till use. Plasmodium DNA was extracted using QIAamp whole blood DNA extraction kit. PCR was done to amplify pfcrt, pfmdr1, pfserca, and pfmrp1 genes and the amplicons obtained were sequenced by Macrogen, Inc., Korea. Single nucleotide polymorphism (SNP) analysis was done using Bio-Edit Sequence Alignment Editor. Results: Out of the four genes targeted, we noted a SNP in the pfcrt gene alone. This SNP (G > T) was noted in the 658th position of the gene, which was seen in 13 patients. The pfmdr1 and pfserca genes were present in 9 and 14 patients respectively. But we could not find any SNPs in these genes. This SNP in pfcrt gene was not significantly associated with any adverse outcome and neither altered disease progression. Conclusion: Presence of a single SNP may not be associated with any adverse clinical outcome. As the sample size was small, we may have not been able to detect any other known or unknown polymorphisms. PMID:26998436

  5. Discovering Thiamine Transporters as Targets of Chloroquine Using a Novel Functional Genomics Strategy

    PubMed Central

    Huang, Zhiwei; Srinivasan, Sankaranarayanan; Zhang, Jianhuai; Chen, Kaifu; Li, Yongxiang; Li, Wei; Quiocho, Florante A.; Pan, Xuewen

    2012-01-01

    Chloroquine (CQ) and other quinoline-containing antimalarials are important drugs with many therapeutic benefits as well as adverse effects. However, the molecular targets underlying most such effects are largely unknown. By taking a novel functional genomics strategy, which employs a unique combination of genome-wide drug-gene synthetic lethality (DGSL), gene-gene synthetic lethality (GGSL), and dosage suppression (DS) screens in the model organism Saccharomyces cerevisiae and is thus termed SL/DS for simplicity, we found that CQ inhibits the thiamine transporters Thi7, Nrt1, and Thi72 in yeast. We first discovered a thi3Δ mutant as hypersensitive to CQ using a genome-wide DGSL analysis. Using genome-wide GGSL and DS screens, we then found that a thi7Δ mutation confers severe growth defect in the thi3Δ mutant and that THI7 overexpression suppresses CQ-hypersensitivity of this mutant. We subsequently showed that CQ inhibits the functions of Thi7 and its homologues Nrt1 and Thi72. In particular, the transporter activity of wild-type Thi7 but not a CQ-resistant mutant (Thi7T287N) was completely inhibited by the drug. Similar effects were also observed with other quinoline-containing antimalarials. In addition, CQ completely inhibited a human thiamine transporter (SLC19A3) expressed in yeast and significantly inhibited thiamine uptake in cultured human cell lines. Therefore, inhibition of thiamine uptake is a conserved mechanism of action of CQ. This study also demonstrated SL/DS as a uniquely effective methodology for discovering drug targets. PMID:23209439

  6. Acidic extracellular pH neutralizes the autophagy-inhibiting activity of chloroquine

    PubMed Central

    Pellegrini, Paola; Strambi, Angela; Zipoli, Chiara; Hägg-Olofsson, Maria; Buoncervello, Maria; Linder, Stig; De Milito, Angelo

    2014-01-01

    Acidic pH is an important feature of tumor microenvironment and a major determinant of tumor progression. We reported that cancer cells upregulate autophagy as a survival mechanism to acidic stress. Inhibition of autophagy by administration of chloroquine (CQ) in combination anticancer therapies is currently evaluated in clinical trials. We observed in 3 different human cancer cell lines cultured at acidic pH that autophagic flux is not blocked by CQ. This was consistent with a complete resistance to CQ toxicity in cells cultured in acidic conditions. Conversely, the autophagy-inhibiting activity of Lys-01, a novel CQ derivative, was still detectable at low pH. The lack of CQ activity was likely dependent on a dramatically reduced cellular uptake at acidic pH. Using cell lines stably adapted to chronic acidosis we could confirm that CQ lack of activity was merely caused by acidic pH. Moreover, unlike CQ, Lys-01 was able to kill low pH-adapted cell lines, although higher concentrations were required as compared with cells cultured at normal pH conditions. Notably, buffering medium pH in low pH-adapted cell lines reverted CQ resistance. In vivo analysis of tumors treated with CQ showed that accumulation of strong LC3 signals was observed only in normoxic areas but not in hypoxic/acidic regions. Our observations suggest that targeting autophagy in the tumor environment by CQ may be limited to well-perfused regions but not achieved in acidic regions, predicting possible limitations in efficacy of CQ in antitumor therapies. PMID:24492472

  7. Chloroquine inhibits cell growth and induces cell death in A549 lung cancer cells.

    PubMed

    Fan, Chuandong; Wang, Weiwei; Zhao, Baoxiang; Zhang, Shangli; Miao, Junying

    2006-05-01

    To investigate the effects of chloroquine diphosphate (CQ) on lung cancer cell growth, we treated A549 cells, a lung cancer cell line, with the drug at various concentrations (0.25-128 microM) for 24-72 h. The results showed that, at lower concentrations (from 0.25 to 32 microM), CQ inhibited the growth of A549 cells and, at the same time, it induced vacuolation with increased volume of acidic compartments (VAC). On the other hand, at higher concentrations (64-128 microM), CQ induced apoptosis at 24 h, while its effect of inducing vacuolation declined. The lactate dehydrogenase (LDH) assay showed that with the treatment of CQ 32-64 microM for 72 h or 128 microM for 48 h, CQ induced necrosis of A549 cells. To understand the possible mechanism by which CQ acts in A549 cells, we further incubated the cells with this drug at the concentrations of 32 or 128 microM in the presence of D609, a specific inhibitor of phosphatidylcholine-specific phospholipase C (PC-PLC). The results showed that D609 (50 microM) could inhibit the effects of CQ 32 microM on the viability and VAC, but it could not change the effects of CQ 128 microM on the same. Our data suggested that CQ inhibited A549 lung cancer cell growth at lower concentrations by increasing the volume of lysosomes and that PC-PLC might be involved in this process. The data also indicated that, at higher concentrations, CQ induced apoptosis and necrosis, but at this time its ability to increase the volume of lysosome gradually declined, and PC-PLC might not be implicated in the process. PMID:16413786

  8. Characterization of chloroquine-hematin mu-oxo dimer binding by isothermal titration calorimetry.

    PubMed

    Vippagunta, S R; Dorn, A; Ridley, R G; Vennerstrom, J L

    2000-07-01

    Numerous studies indicate that a key feature of chloroquine's (CQ) antimalarial activity is its interaction with hematin. We now characterize this CQ-hematin interaction in detail using isothermal titration calorimetry (ITC). Between pH 5.6 and 9.0, association constants (K(a) values) for enthalpy-driven CQ-hematin mu-oxo dimer binding fell in the narrow range of 2.3-4.4 x 10(5) M(-1). It is therefore probable that CQ-hematin mu-oxo dimer binding affinity does not diminish at the pH range (4.8-5.4) of the parasite food vacuole. The binding affinity was unaffected by high salt concentrations, suggesting that ionic interactions do not contribute significantly to this complexation. With increasing ionic strength, the entropic penalty of CQ-hematin mu-oxo dimer binding decreased accompanied by increased hematin mu-oxo dimer aggregation. A stoichiometry (n) of 1:4 in the pH range 6.5-9.0 indicates that CQ binds to two hematin mu-oxo dimers. At pH 5.6, a stoichiometry of 1:8 suggests that CQ binds to an aggregate of four hematin mu-oxo dimers. This work adds further evidence supporting the hypothesis that CQ impedes hematin monomer incorporation into hemozoin by producing a forward shift in the hematin monomer-hematin mu-oxo dimer equilibrium, contributing to a destructive accumulation of soluble forms of hematin in the parasite and leading to its death by hematin poisoning.

  9. 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.

  10. Evaluation of pharmacokinetics of single-dose chloroquine in malnourished children with malaria- a comparative study with normally nourished children

    PubMed Central

    Kadam, Prashant P.; Gogtay, Nithya Jaideep; Karande, Sunil; Shah, V.; Thatte, Urmila M.

    2016-01-01

    Objectives: Studies on antimalarial kinetics in children or adults who are undernourished or malnourished are both limited and have yielded conflicting results. The present study was carried out with the objectives of evaluating the pharmacokinetics of single dose chloroquine and its metabolite desethylchloroquine in children who were undernourished and compare them with children who were normally nourished. Methods: Children of either gender between the ages of 5 and 12 years, smear positive for P. vivax malaria and classified either as well nourished or undernourished were included. Undernourishment was adjudged based on the Indian Academy of Pediatrics (IAP) classification of protein energy malnutrition [PEM] which in turn was based on Khadilkar's growth charts. All participants received 10 mg/kg on the first day followed by 10 mg/kg on Day 2 and 5 mg/kg on Day 3 along with supportive treatment. Blood samples for the levels of chloroquine [CQ] and desethylchloroquine [DECQ] were collected at 0, 0.5, 1, 2 4, 8, 12, 24, 48, 72 hours and 14 days after the first dose and levels assessed by High Performance Liquid Chromatography. Results: A total of 12 children who were normally nourished and 13 who were undernourished were studied. Wide inter-individual variability was seen in the levels of both drug and metabolite in both groups of patients. However, the differences in Cmax, AUC 0-inf, Clearance, half life and Vd between the two groups were not significantly different. Discussion: Our results indicate that dosage requirement is unlikely to be needed for chloroquine in undernourished children with uncomplicated P. vivax malaria. PMID:27721533

  11. Association of Plasmodium falciparum isolates encoding the p. Falciparum chloroquine resistance transporter gene K76T polymorphism with anemia and splenomegaly, but not with multiple infections.

    PubMed

    Abdel-Aziz, Inas Z; Oster, Nadja; Stich, August; Coulibaly, Boubacar; Guigemdé, Wendyam A; Wickert, Hannes; Andrews, Kathy T; Kouyaté, Bocar; Lanzer, Michael

    2005-03-01

    The aim of the study was to assess whether infections with Plasmodium falciparum isolates encoding the P. falciparum chloroquine resistance transporter (pfcrt) gene K76T polymorphism, a molecular marker for chloroquine resistance, are associated with multiple infections, age, or clinical signs of malaria in a semi-immune population in a holoendemic area of Burkina Faso. The parameters of interest were investigated in 210 P. falciparum-positive inhabitants. Logistic regression analysis showed that pfcrt K76T-carrying isolates are significantly more likely to cause anemia and splenomegaly. Furthermore, we found that infections with P. falciparum isolates encoding pfcrt K76T are dependent on age rather than multiple infections. Our findings suggest that pfcrt K76T might serve as a valuable marker for assessing the long-term clinical effect of chronic infections with chloroquine-resistant P. falciparum isolates in populations, without the need of drug efficacy trials.

  12. 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.

  13. 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

  14. In Vivo and In Vitro Antimalarial Properties of Azithromycin-Chloroquine Combinations That Include the Resistance Reversal Agent Amlodipine ▿ †

    PubMed Central

    Pereira, Marcus R.; Henrich, Philipp P.; Sidhu, Amar bir Singh; Johnson, David; Hardink, Joel; Van Deusen, Jeffrey; Lin, Jian; Gore, Katrina; O'Brien, Connor; Wele, Mamadou; Djimde, Abdoulaye; Chandra, Richa; Fidock, David A.

    2011-01-01

    Evidence of emerging Plasmodium falciparum resistance to artemisinin-based combination therapies, documented in western Cambodia, underscores the continuing need to identify new antimalarial combinations. Given recent reports of the resurgence of chloroquine-sensitive P. falciparum parasites in Malawi, after the enforced and prolonged withdrawal of this drug, and indications of a possible synergistic interaction with the macrolide azithromycin, we sought to further characterize chloroquine-azithromycin combinations for their in vitro and in vivo antimalarial properties. In vitro 96-h susceptibility testing of chloroquine-azithromycin combinations showed mostly additive interactions against freshly cultured P. falciparum field isolates obtained from Mali. Some evidence of synergy, however, was apparent at the fractional 90% inhibitory concentration level. Additional in vitro testing highlighted the resistance reversal properties of amlodipine for both chloroquine and quinine. In vivo experiments, using the Peters 4-day suppressive test in a P. yoelii mouse model, revealed up to 99.9% suppression of parasitemia following treatment with chloroquine-azithromycin plus the R enantiomer of amlodipine. This enantiomer was chosen because it does not manifest the cardiac toxicities observed with the racemic mixture. Pharmacokinetic/pharmacodynamic analyses in this rodent model and subsequent extrapolation to a 65-kg adult led to the estimation that 1.8 g daily of R-amlodipine would be required to achieve similar efficacy in humans, for whom this is likely an unsafe dose. While these data discount amlodipine as an additional partner for chloroquine-based combination therapy, our studies continue to support azithromycin as a safe and effective addition to antimalarial combination therapies. PMID:21464242

  15. Synergistic anti-tumour effects of tetrandrine and chloroquine combination therapy in human cancer: a potential antagonistic role for p21

    PubMed Central

    Mei, Liufeng; Chen, Yicheng; Wang, Zhimeng; Wang, Jian; Wan, Jiali; Yu, Chunrong; Liu, Xin; Li, Wenhua

    2015-01-01

    Background and Purpose Tetrandrine, a bisbenzylisoquinoline alkaloid isolated from the Chinese medicinal herb Stephaniae tetrandrae, has a long history in Chinese clinical applications to treat diverse diseases. Tetrandrine induced apoptosis or, at low concentrations, autophagy of human hepatocellular carcinoma cells. Here we have tested the effects of inhibitors of autophagy such as chloroquine, on the response to low concentrations of tetrandrine in cancer cells. Experimental Approach Cultures of several cancer cell lines, including Huh7, U251, HCT116 and A549 cells, were exposed to tetrandrine, chloroquine or a combination of these compounds. Cell viability and content of reactive oxygen species (ROS) were measured and synergy assessed by calculation of the combination index. Western blot and RT-PCR assays were also used along with fluorescence microscopy and histochemical techniques. Key Results Combinations of tetrandrine and chloroquine were more cytotoxic than the same concentrations used separately and these effects showed synergy. Such effects involved increased ROS generation and were dependent on caspase-3 but independent of Akt activity. Blockade of tetrandrine-induced autophagy with 3-methyladenine or bafilomycin-A1 induced apoptosis in cancer cells. Lack of p21 protein (p21−/− HCT116 cells) increased sensitivity to the apoptotic effects of the combination of tetrandrine and chloroquine. In a tumour xenograft model in mice, combined treatment with tetrandrine and chloroquine induced ROS accumulation and cell apoptosis, and decreased tumour growth. Conclusions and Implications The combinations of tetrandrine and chloroquine exhibited synergistic anti-tumour activity, in vitro and in vivo. Our results suggest a novel therapeutic strategy for tumour treatment. PMID:25521075

  16. 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.

  17. 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].

  18. 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. PMID:27208626

  19. Antimicrobial activity of resveratrol analogues.

    PubMed

    Chalal, Malik; Klinguer, Agnès; Echairi, Abdelwahad; Meunier, Philippe; Vervandier-Fasseur, Dominique; Adrian, Marielle

    2014-01-01

    Stilbenes, especially resveratrol and its derivatives, have become famous for their positive effects on a wide range of medical disorders, as indicated by a huge number of published studies. A less investigated area of research is their antimicrobial properties. A series of 13 trans-resveratrol analogues was synthesized via Wittig or Heck reactions, and their antimicrobial activity assessed on two different grapevine pathogens responsible for severe diseases in the vineyard. The entire series, together with resveratrol, was first evaluated on the zoospore mobility and sporulation level of Plasmopara viticola (the oomycete responsible for downy mildew). Stilbenes displayed a spectrum of activity ranging from low to high. Six of them, including the most active ones, were subsequently tested on the development of Botrytis cinerea (fungus responsible for grey mold). The results obtained allowed us to identify the most active stilbenes against both grapevine pathogens, to compare the antimicrobial activity of the evaluated series of stilbenes, and to discuss the relationship between their chemical structure (number and position of methoxy and hydroxy groups) and antimicrobial activity. PMID:24918540

  20. 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.

  1. Antimicrobial activity of resveratrol analogues.

    PubMed

    Chalal, Malik; Klinguer, Agnès; Echairi, Abdelwahad; Meunier, Philippe; Vervandier-Fasseur, Dominique; Adrian, Marielle

    2014-06-10

    Stilbenes, especially resveratrol and its derivatives, have become famous for their positive effects on a wide range of medical disorders, as indicated by a huge number of published studies. A less investigated area of research is their antimicrobial properties. A series of 13 trans-resveratrol analogues was synthesized via Wittig or Heck reactions, and their antimicrobial activity assessed on two different grapevine pathogens responsible for severe diseases in the vineyard. The entire series, together with resveratrol, was first evaluated on the zoospore mobility and sporulation level of Plasmopara viticola (the oomycete responsible for downy mildew). Stilbenes displayed a spectrum of activity ranging from low to high. Six of them, including the most active ones, were subsequently tested on the development of Botrytis cinerea (fungus responsible for grey mold). The results obtained allowed us to identify the most active stilbenes against both grapevine pathogens, to compare the antimicrobial activity of the evaluated series of stilbenes, and to discuss the relationship between their chemical structure (number and position of methoxy and hydroxy groups) and antimicrobial activity.

  2. 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.

  3. 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.

  4. 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

  5. Sulfur analogues of psychotomimetic agents. Monothio analogues of mescaline and isomescaline.

    PubMed

    Jacob, P; Shulgin, A T

    1981-11-01

    Two monothio analogues of mescaline and three monothio analogues of 2,3,4-trimethoxyphenethylamine (isomescaline) have been synthesized and characterized. Only the two mescaline analogues (3-and 4-thiomescaline) were found to be psychotomimetics in man, being 6 and 12 times more potent than mescaline, respectively. All five compounds can serve as substrates for bovine plasma monoamine oxidase in vitro, but no positive correlation is apparent between the extent of enzymatic degradation and human psychotomimetic potency.

  6. The structure activity relationship of discodermolide analogues.

    PubMed

    Shaw, Simon J

    2008-03-01

    The marine polyketide discodermolide is a member of a class of natural products that stabilize microtubules. Many analogues have been synthesized suggesting that few changes can be made to the internal carbon backbone. Both ends of the molecule, however, can be modified. The majority of analogues have been generated via modification of the lactone region. This suggests that significant simplifications can be made in this region provided that the lactone moiety is maintained.

  7. Phosphorous-containing analogues of aspartame.

    PubMed

    Nelson, V; Mastalerz, P

    1984-12-01

    Four analogues of aspartame (aspartylphenylalanine methyl ester) were prepared in which one of the carboxylate groups was replaced by a phosphonate group. None of the peptides so obtained was sweet, in contrast with the parent compound which is over 100 times sweeter than sucrose. These results contrast with several published reports of phosphonate analogues of amino acids and peptides which are potent inhibitors of enzymes containing acceptor sites for the parent compound.

  8. 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.

  9. Molecular interaction of selected phytochemicals under the charged environment of Plasmodium falciparum chloroquine resistance transporter (PfCRT) model.

    PubMed

    Patel, Saumya K; Khedkar, Vijay M; Jha, Prakash C; Jasrai, Yogesh T; Pandya, Himanshu A; George, Linz-Buoy; Highland, Hyacinth N; Skelton, Adam A

    2016-01-01

    Phytochemicals of Catharanthus roseus Linn. and Tylophora indica have been known for their inhibition of malarial parasite, Plasmodium falciparum in cell culture. Resistance to chloroquine (CQ), a widely used antimalarial drug, is due to the CQ resistance transporter (CRT) system. The present study deals with computational modeling of Plasmodium falciparum chloroquine resistance transporter (PfCRT) protein and development of charged environment to mimic a condition of resistance. The model of PfCRT was developed using Protein homology/analogy engine (PHYRE ver 0.2) and was validated based on the results obtained using PSI-PRED. Subsequently, molecular interactions of selected phytochemicals extracted from C. roseus Linn. and T. indica were studied using multiple-iterated genetic algorithm-based docking protocol in order to investigate the translocation of these legends across the PfCRT protein. Further, molecular dynamics studies exhibiting interaction energy estimates of these compounds within the active site of the protein showed that compounds are more selective toward PfCRT. Clusters of conformations with the free energy of binding were estimated which clearly demonstrated the potential channel and by this means the translocation across the PfCRT is anticipated.

  10. 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

  11. Are Long-Term Chloroquine or Hydroxychloroquine Users Being Checked Regularly for Toxic Maculopathy?

    PubMed Central

    Nika, Melisa; Blachley, Taylor S.; Edwards, Paul; Lee, Paul P.; Stein, Joshua D.

    2014-01-01

    Importance According to evidence-based, expert recommendations, long-term users of chloroquine (CQ) or hydroxychloroquine (HCQ) should undergo regular visits to eye-care providers and diagnostic testing to check for maculopathy. Objective To determine whether patients with rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE) taking CQ or HCQ are regularly visiting eye-care providers and being screened for maculopathy. Setting, Design and Participants Patients with RA or SLE who were continuously enrolled in a particular managed-care network for ≥5 years during 2001-2011 were studied. Patients' amount of CQ/HCQ use in the 5 years since initial RA/SLE diagnosis was calculated, along with their number of eye-care visits and diagnostic tests for maculopathy. Those at high risk for maculopathy were identified. Visits to eye providers and diagnostic testing for maculopathy were assessed for each enrollee over the study period. Logistic regression was performed to assess potential factors associated with regular eye-care-provider visits (≥3 in 5 years) among CQ/HCQ users, including those at greatest risk for maculopathy. Main Outcome Measures Among CQ/HCQ users and those at high risk for toxic maculopathy, the proportions with regular eye-care visits and diagnostic testing, and the likelihood of regular eye-care visits (odds ratios [ORs] with 95% confidence intervals [CI]). Results Among 18,051 beneficiaries with RA or SLE, 6,339 (35.1%) had ≥1 record of HCQ/CQ use and 1,409 (7.8%) used HCQ/CQ for ≥4 years. Among those at high risk for maculopathy, 27.9% lacked regular eye-provider visits, 6.1% had no visits to eye providers, and 34.5% had no diagnostic testing for maculopathy during the 5-year period. Among high-risk patients, each additional month of HCQ/CQ use was associated with a 2.0%-increased likelihood of regular eye care (adjusted OR=1.02, CI=1.01-1.03). High-risk patients whose SLE/RA were managed by rheumatologists had a 77%-increased

  12. 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

  13. Autophagy inhibition by chloroquine sensitizes HT-29 colorectal cancer cells to concurrent chemoradiation

    PubMed Central

    Schonewolf, Caitlin A; Mehta, Monal; Schiff, Devora; Wu, Hao; Haffty, Bruce G; Karantza, Vassiliki; Jabbour, Salma K

    2014-01-01

    AIM: To investigate whether the inhibition of autophagy by chloroquine (CQ) sensitizes rectal tumors to radiation therapy (RT) or concurrent chemoradiation (chemoRT). METHODS: In vitro, HCT-116 and HT-29 colorectal cancer (CRC) cell lines were treated as following: (1) PBS; (2) CQ; (3) 5-fluorouracil (5-FU); (4) RT; (5) CQ and RT; (6) 5-FU and RT; (7) CQ and 5-FU; and (8) 5-FU and CQ and RT. Each group was then exposed to various doses of radiation (0-8 Gy) depending on the experiment. Cell viability and proliferative capacity were measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and clonogenic assays. Clonogenic survival curves were constructed and compared across treatment groups. Autophagy status was determined by assessing the LC3-II to LC3-I ratio on western blot analysis, autophagosome formation on electron microscopy and identification of a perinuclear punctate pattern with GFP-labeled LC3 on fluorescence microscopy. Cell cycle arrest and cell death were evaluated by FACS and Annexin V analysis. All experiments were performed in triplicate and statistical analysis was performed by the student’s t test to compare means between treatment groups. RESULTS: RT (2-8 Gy) induced autophagy in HCT-116 and HT-29 CRC cell lines at 4 and 6 h post-radiation, respectively, as measured by increasing LC3-II to LC3-I ratio on western blot. Additionally, electron microscopy demonstrated autophagy induction in HT-29 cells 24 h following irradiation at a dose of 8 Gy. Drug treatment with 5-FU (25 μmol/L) induced autophagy and the combination of 5-FU and RT demonstrated synergism in autophagy induction. CQ (10 μmol/L) alone and in combination with RT effectively inhibited autophagy and sensitized both HCT-116 and HT-29 cells to treatment with radiation (8 Gy; P < 0.001 and 0.00001, respectively). Significant decrease in clonogenic survival was seen only in the HT-29 cell line, when CQ was combined with RT at doses of 2 and 8 Gy (P < 0.5 and

  14. Chloroquine Enhances Gefitinib Cytotoxicity in Gefitinib-Resistant Nonsmall Cell Lung Cancer Cells

    PubMed Central

    Tang, Mei-Chuan; Wu, Mei-Yi; Hwang, Ming-Hung; Chang, Ya-Ting; Huang, Hui-Ju; Lin, Anya Maan-Yuh; Yang, James Chih-Hsin

    2015-01-01

    Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), including gefitinib, are effective for non-small cell lung cancer (NSCLC) patients with EGFR mutations. However, these patients eventually develop resistance to EGFR-TKI. The goal of the present study was to investigate the involvement of autophagy in gefitinib resistance. We developed gefitinib-resistant cells (PC-9/gef) from PC-9 cells (containing exon 19 deletion EGFR) after long-term exposure in gefitinib. PC-9/gef cells (B4 and E3) were 200-fold more resistant to gefitinib than PC-9/wt cells. Compared with PC-9/wt cells, both PC-9/gefB4 and PC-9/gefE3 cells demonstrated higher basal LC3-II levels which were inhibited by 3-methyladenine (3-MA, an autophagy inhibitor) and potentiated by chloroquine (CQ, an inhibitor of autophagolysosomes formation), indicating elevated autophagy in PC-9/gef cells. 3-MA and CQ concentration-dependently inhibited cell survival of both PC-9wt and PC-9/gef cells, suggesting that autophagy may be pro-survival. Furthermore, gefitinib increased LC3-II levels and autolysosome formation in both PC-9/wt cells and PC-9/gef cells. In PC-9/wt cells, CQ potentiated the cytotoxicity by low gefitinib (3nM). Moreover, CQ overcame the acquired gefitinib resistance in PC-9/gef cells by enhancing gefitinib-induced cytotoxicity, activation of caspase 3 and poly (ADP-ribose) polymerase cleavage. Using an in vivo model xenografting with PC-9/wt and PC-9/gefB4 cells, oral administration of gefitinib (50 mg/kg) completely inhibited the tumor growth of PC-9/wt but not PC-9/gefB4cells. Combination of CQ (75 mg/kg, i.p.) and gefitinib was more effective than gefitinib alone in reducing the tumor growth of PC-9/gefB4. Our data suggest that inhibition of autophagy may be a therapeutic strategy to overcome acquired resistance of gefitinib in EGFR mutation NSCLC patients. PMID:25807554

  15. Chloroquine enhances gefitinib cytotoxicity in gefitinib-resistant nonsmall cell lung cancer cells.

    PubMed

    Tang, Mei-Chuan; Wu, Mei-Yi; Hwang, Ming-Hung; Chang, Ya-Ting; Huang, Hui-Ju; Lin, Anya Maan-Yuh; Yang, James Chih-Hsin

    2015-01-01

    Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), including gefitinib, are effective for non-small cell lung cancer (NSCLC) patients with EGFR mutations. However, these patients eventually develop resistance to EGFR-TKI. The goal of the present study was to investigate the involvement of autophagy in gefitinib resistance. We developed gefitinib-resistant cells (PC-9/gef) from PC-9 cells (containing exon 19 deletion EGFR) after long-term exposure in gefitinib. PC-9/gef cells (B4 and E3) were 200-fold more resistant to gefitinib than PC-9/wt cells. Compared with PC-9/wt cells, both PC-9/gefB4 and PC-9/gefE3 cells demonstrated higher basal LC3-II levels which were inhibited by 3-methyladenine (3-MA, an autophagy inhibitor) and potentiated by chloroquine (CQ, an inhibitor of autophagolysosomes formation), indicating elevated autophagy in PC-9/gef cells. 3-MA and CQ concentration-dependently inhibited cell survival of both PC-9wt and PC-9/gef cells, suggesting that autophagy may be pro-survival. Furthermore, gefitinib increased LC3-II levels and autolysosome formation in both PC-9/wt cells and PC-9/gef cells. In PC-9/wt cells, CQ potentiated the cytotoxicity by low gefitinib (3 nM). Moreover, CQ overcame the acquired gefitinib resistance in PC-9/gef cells by enhancing gefitinib-induced cytotoxicity, activation of caspase 3 and poly (ADP-ribose) polymerase cleavage. Using an in vivo model xenografting with PC-9/wt and PC-9/gefB4 cells, oral administration of gefitinib (50 mg/kg) completely inhibited the tumor growth of PC-9/wt but not PC-9/gefB4cells. Combination of CQ (75 mg/kg, i.p.) and gefitinib was more effective than gefitinib alone in reducing the tumor growth of PC-9/gefB4. Our data suggest that inhibition of autophagy may be a therapeutic strategy to overcome acquired resistance of gefitinib in EGFR mutation NSCLC patients. PMID:25807554

  16. Planetary habitability: lessons learned from terrestrial analogues

    NASA Astrophysics Data System (ADS)

    Preston, Louisa J.; Dartnell, Lewis R.

    2014-01-01

    Terrestrial analogue studies underpin almost all planetary missions and their use is essential in the exploration of our Solar system and in assessing the habitability of other worlds. Their value relies on the similarity of the analogue to its target, either in terms of their mineralogical or geochemical context, or current physical or chemical environmental conditions. Such analogue sites offer critical ground-truthing for astrobiological studies on the habitability of different environmental parameter sets, the biological mechanisms for survival in extreme environments and the preservation potential and detectability of biosignatures. The 33 analogue sites discussed in this review have been selected on the basis of their congruence to particular extraterrestrial locations. Terrestrial field sites that have been used most often in the literature, as well as some lesser known ones which require greater study, are incorporated to inform on the astrobiological potential of Venus, Mars, Europa, Enceladus and Titan. For example, the possibility of an aerial habitable zone on Venus has been hypothesized based on studies of life at high-altitudes in the terrestrial atmosphere. We also demonstrate why many different terrestrial analogue sites are required to satisfactorily assess the habitability of the changing environmental conditions throughout Martian history, and recommend particular sites for different epochs or potential niches. Finally, habitable zones within the aqueous environments of the icy moons of Europa and Enceladus and potentially in the hydrocarbon lakes of Titan are discussed and suitable analogue sites proposed. It is clear from this review that a number of terrestrial analogue sites can be applied to multiple planetary bodies, thereby increasing their value for astrobiological exploration. For each analogue site considered here, we summarize the pertinent physiochemical environmental features they offer and critically assess the fidelity with which

  17. 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

  18. Chloroquine improved carbon tetrachloride-induced liver fibrosis through its inhibition of the activation of hepatic stellate cells: role of autophagy.

    PubMed

    He, Wei; Wang, Bin; Yang, Jing; Zhuang, Yun; Wang, Liangzhi; Huang, Xiaodan; Chen, Jianping

    2014-01-01

    Autophagy is involved in the activation of hepatic stellate cells (HSCs), which is the key process of liver fibrosis. We reasoned that chloroquine, based on its ability to inhibit autophagy, might exert beneficial effects in liver fibrosis. Liver fibrosis in rats was induced by carbon tetrachloride (CCl4). Rats were divided into three groups, a normal control group (N group), model group (M group), and chloroquine group (CQ group). Liver fibrosis in the rats was evaluated by hematoxyline-eosin (H&E) and Masson staining. The activities of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin (TB) were determined using an automated biochemistry analyzer. Total hepatic hydroxyproline levels were determined with a kit. The expressions of α-smooth muscle actin (α-SMA) and transforming growth factor-β1 (TGF-β1) were detected by immunofluorescence staining, and the expressions of LC3-II and p62 were determined by Western blotting. Compared with N group, M group showed impaired liver function, liver fibrosis, increased hydroxyproline content, up-regulated expressions of α-SMA and TGF-β1, which have been reported to be pro-fibrogenic genes in vivo, and increased autophagy flux as indicated by the accumulation of LC3-II and degradation of p62. These changes were attenuated by chloroquine treatment. Chloroquine exerts beneficial effects in CCl4-induced liver fibrosis. The mechanism of action includes inhibition of autophagy pathways and inhibition of activation of HSCs. PMID:25177034

  19. Presence of cobalamin analogues in animal tissues

    PubMed Central

    Kondo, Haruki; Kolhouse, Fred; Allen, Robert H.

    1980-01-01

    Cobalamin (Cbl, vitamin B-12) has been extracted and isolated from a number of animal tissues by using (i) reverse-affinity chromatography on R protein-Sepharose followed by adsorption to and elution from charcoal-coated agarose and (ii) paper chromatography. Radioisotope dilution assays showed that only 75-97% of the Cbl chromatographed in the position of crystalline Cbl. The remaining 3-25% was present in a number of slower and faster moving fractions. This suggested that Cbl analogues are present in animal tissues because appropriate controls ruled out the possibility that this material was artifactually derived from Cbl during the extraction and purification procedures. With a large-scale isolation from rabbit kidney, the material in five such fractions contained cobalt and had absorption spectra that were similar to but different from the spectrum of Cbl, indicating that they were Cbl analogues. Compared to Cbl, these Cbl analogues had decreased but definite affinities for Cbl-binding proteins with the following order of strength of binding: R protein > transcobalamin II > intrinsic factor. Compared to Cbl, they also had decreased but definite growth-promoting activity for two microorganisms, Euglena gracilis and Lactobacillus leichmannii, which require Cbl for growth. These Cbl analogues differed from each other and from 18 synthetic Cbl analogues, including the most common Cbl analogues synthesized by microorganisms, in at least one of the above features. These studies indicate that animal tissues contain a number of Cbl analogues whose origins, structures, and biologic activities remain to be determined. PMID:6928681

  20. About past interglacials as analogues to the Holocene and Anthropocene

    NASA Astrophysics Data System (ADS)

    Berger, Andre; Yin, Qiuzhen

    2014-05-01

    analogues of the whole Holocene and its future, it must be stressed that the next minimum of eccentricity at the 400-ka time scale is approaching. With this and a CO2 concentration at the interglacial level, and even larger under human influence, our interglacial was predicted to be exceptionally long. The same happened during MIS-11. According to the sensitivity experiments of Berger et al. (1999), moderate values of CO2 sustained for sufficiently long might have led to an interglacial MIS-19 even much longer than MIS-11 and MIS-1.

  1. The Canadian Analogue Research Network (CARN): Opportunities for Mars Analogue Studies in the Canadian Arctic

    NASA Astrophysics Data System (ADS)

    Osinski, G. R.; Berinstain, A.; Lebeuf, M.; Léveillé, R.

    2006-10-01

    The Canadian Analogue Research Network has been established by the Canadian Space Agency. This network of analogue sites, many of which are in the Arctic, provides a unique opportunity to further our understanding of the polar regions of Earth and Mars.

  2. 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

  3. Synthesis and anticancer evaluation of spermatinamine analogues.

    PubMed

    Moosa, Basem A; Sagar, Sunil; Li, Song; Esau, Luke; Kaur, Mandeep; Khashab, Niveen M

    2016-03-15

    Spermatinamine was isolated from an Australian marine sponge, Pseudoceratina sp. as an inhibitor of isoprenylcysteine carboxyl methyltransferase (Icmt), an attractive and novel anticancer target. Herein, we report the synthesis of spermatinamine analogues and their cytotoxic evaluation against three human cancer cell lines, that is, cervix adenocarcinoma (HeLa), breast adenocarcinoma (MCF-7), and prostate carcinoma (DU145). Analogues 12, 14 and 15 were found to be the most potent against one or more cell lines with the IC50 values in the range of 5-10 μM. The obtained results suggested that longer polyamine linker along with aromatic oxime substitution provided the most potent analogue compounds against cancer cell lines. PMID:26874403

  4. Dolastatin 11 conformations, analogues and pharmacophore.

    PubMed

    Ali, Md Ahad; Bates, Robert B; Crane, Zackary D; Dicus, Christopher W; Gramme, Michelle R; Hamel, Ernest; Marcischak, Jacob; Martinez, David S; McClure, Kelly J; Nakkiew, Pichaya; Pettit, George R; Stessman, Chad C; Sufi, Bilal A; Yarick, Gayle V

    2005-07-01

    Twenty analogues of the natural antitumor agent dolastatin 11, including majusculamide C, were synthesized and tested for cytotoxicity against human cancer cells and stimulation of actin polymerization. Only analogues containing the 30-membered ring were active. Molecular modeling and NMR evidence showed the low-energy conformations. The amide bonds are all trans except for the one between the Tyr and Val units, which is cis. Since an analogue restricted to negative 2-3-4-5 angles stimulated actin polymerization but was inactive in cells, the binding conformation (most likely the lowest-energy conformation in water) has a negative 2-3-4-5 angle, whereas a conformation with a positive 2-3-4-5 angle (most likely the lowest energy conformation in chloroform) goes through cell walls. The highly active R alcohol from borohydride reduction of dolastatin 11 is a candidate for conversion to prodrugs.

  5. Molecular Analysis of Chloroquine and Sulfadoxine-Pyrimethamine Resistance-Associated Alleles in Plasmodium falciparum Isolates from Nicaragua

    PubMed Central

    Sridaran, Sankar; Rodriguez, Betzabe; Mercedes Soto, Aida; Macedo De Oliveira, Alexandre; Udhayakumar, Venkatachalam

    2014-01-01

    Chloroquine (CQ) is used as a first-line therapy for the treatment of Plasmodium falciparum malaria in Nicaragua. We investigated the prevalence of molecular markers associated with CQ and sulfadoxine-pyrimethamine (SP) resistance in P. falciparum isolates obtained from the North Atlantic Autonomous Region of Nicaragua. Blood spots for this study were made available from a CQ and SP drug efficacy trial conducted in 2005 and also from a surveillance study performed in 2011. Polymorphisms in P. falciparum CQ resistance transporter, dihydrofolate reductase, and dihydropteroate synthase gene loci that are associated with resistance to CQ, pyrimethamine, and sulfadoxine, respectively, were detected by DNA sequencing. In the 2005 dataset, only 2 of 53 isolates had a CQ resistance allele (CVIET), 2 of 52 had a pyrimethamine resistance allele, and 1 of 49 had a sulfadoxine resistance allele. In the 2011 dataset, none of 45 isolates analyzed had CQ or SP resistance alleles. PMID:24615126

  6. Molecular analysis of chloroquine and sulfadoxine-pyrimethamine resistance-associated alleles in Plasmodium falciparum isolates from Nicaragua.

    PubMed

    Sridaran, Sankar; Rodriguez, Betzabe; Soto, Aida Mercedes; Macedo De Oliveira, Alexandre; Udhayakumar, Venkatachalam

    2014-05-01

    Chloroquine (CQ) is used as a first-line therapy for the treatment of Plasmodium falciparum malaria in Nicaragua. We investigated the prevalence of molecular markers associated with CQ and sulfadoxine-pyrimethamine (SP) resistance in P. falciparum isolates obtained from the North Atlantic Autonomous Region of Nicaragua. Blood spots for this study were made available from a CQ and SP drug efficacy trial conducted in 2005 and also from a surveillance study performed in 2011. Polymorphisms in P. falciparum CQ resistance transporter, dihydrofolate reductase, and dihydropteroate synthase gene loci that are associated with resistance to CQ, pyrimethamine, and sulfadoxine, respectively, were detected by DNA sequencing. In the 2005 dataset, only 2 of 53 isolates had a CQ resistance allele (CVIET), 2 of 52 had a pyrimethamine resistance allele, and 1 of 49 had a sulfadoxine resistance allele. In the 2011 dataset, none of 45 isolates analyzed had CQ or SP resistance alleles.

  7. Solution conformation of C-linked antifreeze glycoprotein analogues and modulation of ice recrystallization.

    PubMed

    Tam, Roger Y; Rowley, Christopher N; Petrov, Ivan; Zhang, Tianyi; Afagh, Nicholas A; Woo, Tom K; Ben, Robert N

    2009-11-01

    Antifreeze glycoproteins (AFGPs) are a unique class of proteins that are found in many organisms inhabiting subzero environments and ensure their survival by preventing ice growth in vivo. During the last several years, our laboratory has synthesized functional C-linked AFGP analogues (3 and 5) that possess custom-tailored antifreeze activity suitable for medical, commercial, and industrial applications. These compounds are potent inhibitors of ice recrystallization and do not exhibit thermal hysteresis. The current study explores how changes in the length of the amide-containing side chain between the carbohydrate moiety and the polypeptide backbone in 5 influences ice recrystallization inhibition (IRI) activity. Analogue 5 (n = 3, where n is the number of carbons in the side chain) was a potent inhibitor of ice recrystallization, while 4, 6, and 7 (n = 4, 2, and 1, respectively) exhibited no IRI activity. The solution conformation of the polypeptide backbone in C-linked AFGP analogues 4-7 was examined using circular dichroism (CD) spectroscopy. The results suggested that all of the analogues exhibit a random coil conformation in solution and that the dramatic increase in IRI activity observed with 5 is not due to a change in long-range solution conformation. Variable-temperature (1)H NMR studies on truncated analogues 26-28 failed to elucidate the presence of persistent intramolecular bonds between the amide in the side chain and the peptide backbone. Molecular dynamics simulations performed on these analogues also failed to show persistent intramolecular hydrogen bonds. However, the simulations did indicate that the side chain of IRI-active analogue 26 (n = 3) adopts a unique short-range solution conformation in which it is folded back onto the peptide backbone, orienting the more hydrophilic face of the carbohydrate moiety away from the bulk solvent. In contrast, the solution conformation of IRI-inactive analogues 25, 27, and 28 had fully extended side chains

  8. The detection of pfcrt and pfmdr1 point mutations as molecular markers of chloroquine drug resistance, Pahang, Malaysia

    PubMed Central

    2012-01-01

    Background Malaria is still a public health problem in Malaysia with chloroquine (CQ) being the first-line drug in the treatment policy of uncomplicated malaria. There is a scarcity in information about the magnitude of Plasmodium falciparum CQ resistance. This study aims to investigate the presence of single point mutations in the P. falciparum chloroquine-resistance transporter gene (pfcrt) at codons 76, 271, 326, 356 and 371 and in P. falciparum multi-drug resistance-1 gene (pfmdr1) at codons 86 and 1246, as molecular markers of CQ resistance. Methods A total of 75 P. falciparum blood samples were collected from different districts of Pahang state, Malaysia. Single nucleotide polymorphisms in pfcrt gene (codons 76, 271, 326, 356 and 371) and pfmdr1 gene (codons 86 and 1246) were analysed by using mutation-specific nested PCR and restriction fragment length polymorphism (PCR-RFLP) methods. Results Mutations of pfcrt K76T and pfcrt R371I were the most prevalent among pfcrt gene mutations reported by this study; 52% and 77%, respectively. Other codons of the pfcrt gene and the positions 86 and 1246 of the pfmdr1 gene were found mostly of wild type. Significant associations of pfcrt K76T, pfcrt N326S and pfcrt I356T mutations with parasitaemia were also reported. Conclusion The high existence of mutant pfcrt T76 may indicate the low susceptibility of P. falciparum isolates to CQ in Peninsular Malaysia. The findings of this study establish baseline data on the molecular markers of P. falciparum CQ resistance, which may help in the surveillance of drug resistance in Peninsular Malaysia. PMID:22853645

  9. A switch between cytoprotective and cytotoxic autophagy in the radio sensitization of breast tumor cells by chloroquine and vitamin D

    PubMed Central

    Wilson, Eden N.; Bristol, Molly L.; Di, Xu; Maltese, William A.; Koterba, Kristen; Beckman, Matthew J.; Gewirtz, David A.

    2012-01-01

    Calcitriol or 1,25 dihydroxy vitamin D3, the hormonally active form of vitamin D, as well as vitamin D analogs, have been shown to increase sensitivity to ionizing radiation in breast tumor cells. The current studies indicate that the combination of 1,25 dihydroxy vitamin D3 with radiation appears to kill p53 wild type, estrogen receptor positive ZR-75-1 breast tumor cells through autophagy. Minimal apoptosis was observed based on cell morphology by DAPI and TUNEL staining, Annexin/PI analysis, Caspase-3 and PARP cleavage as well as cell cycle analysis. Induction of autophagy was indicated by increased acridine orange staining, RFP-LC3 redistribution and detection of autophagic vesicles by electron microscopy, while autophagic flux was monitored based on p62 degradation. The autophagy inhibitors, chloroquine and Bafilomycin A1, as well as genetic suppression of the autophagic signaling proteins Atg5 or Atg 7 attenuated the impact of the combination treatment of 1,25 D3 with radiation. In contrast to autophagy mediating the effects of the combination treatment, the autophagy induced by radiation alone was apparently cytoprotective in that either pharmacological or genetic inhibition increased sensitivity to radiation. These studies support the potential utility of vitamin D for improving the impact of radiation for breast cancer therapy, support the feasibility of combining chloroquine with radiation for the treatment of breast cancer and demonstrate the existence of an “autophagic switch” from cytoprotective autophagy with radiation alone to cytotoxic autophagy with the 1, 25 D3 – radiation combination. PMID:21887591

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

    PubMed Central

    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

    2015-01-01

    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. PMID:26261345

  11. Importation of chloroquine-resistant Plasmodium falciparum by Guatemalan peacekeepers returning from the Democratic Republic of the Congo

    PubMed Central

    2013-01-01

    Background Malaria elimination is being pursued in five of seven Central American countries. Military personnel returning from peacekeeping missions in sub-Saharan Africa could import chloroquine-resistant Plasmodium falciparum, posing a threat to elimination and to the continued efficacy of first-line chloroquine (CQ) treatment in these countries. This report describes the importation of P. falciparum from among 150 Guatemalan army special forces and support staff who spent ten months on a United Nations’ peacekeeping mission in the Democratic Republic of the Congo (DRC) in 2010. Methods Investigators reviewed patients’ medical charts and interviewed members of the contingent to identify malaria cases and risk factors for malaria acquisition. Clinical specimens were tested for malaria; isolated parasites were characterized molecularly for CQ resistance. Results Investigators identified 12 cases (8%) of laboratory-confirmed P. falciparum infection within the contingent; one case was from a soldier infected with a CQ-resistant pfcrt genotype resulting in his death. None of the contingent used an insecticide-treated bed net (ITN) or completely adhered to malaria chemoprophylaxis while in the DRC. Conclusion This report highlights the need to promote use of malaria prevention measures, in particular ITNs and chemoprophylaxis, among peacekeepers stationed in malaria-endemic areas. Countries attempting to eliminate malaria should consider appropriate methods to screen peacekeepers returning from endemic areas for malaria infections. Cases of malaria in travellers, immigrants and soldiers returning to Central America from countries with CQ-resistant malaria should be assumed to be carry resistant parasites and receive appropriate anti-malarial therapy to prevent severe disease and death. PMID:24060234

  12. 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. PMID:26261345

  13. 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.

  14. 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.

  15. A fluorescent cholesterol analogue for observation of free cholesterol in the plasma membrane of live cells.

    PubMed

    Ogawa, Yoshikatsu; Tanaka, Mutsuo

    2016-01-01

    Free cholesterol in mammalian cells resides mostly in the plasma membrane, where it plays an important role in cellular homeostasis. We synthesized a new fluorescent cholesterol analogue that retained an intact alkyl chain and the sterane backbone of cholesterol. The hydroxyl group of cholesterol was converted into an amino group that was covalently linked to the fluorophore tetramethylrhodamine to retain the ability to form hydrogen bonds with adjacent molecules. Incubating live MDCK (Madin-Darby canine kidney) cells with our fluorescent cholesterol analogue resulted in the generation of intense signals that were detected by microscopy at the plasma membrane. Incubation with the analogue exerted minimal, if any, influence on cell growth, indicating that it could serve as a useful tool for analyzing free cholesterol at the plasma membrane.

  16. The runout of granular material: from analogue to numerical modelling

    NASA Astrophysics Data System (ADS)

    Longchamp, Celine; Caspar, Olivier; Gygax, Remo; Podladchikov, Yury; Jaboyedoff, Michel

    2014-05-01

    Rock avalanches are catastrophic events in which important granular rock masses (>106 m3) travel at velocities up to ten meters per second. The mobilized rock mass travel long distances, which in exceptional cases can reach up to tens of kilometers. Those highly destructive and uncontrollable events, give important insight to understand the interactions between the displaced masses and landscape conditions. However, as those events are not frequent, analogue and numerical modelling plays a fundamental role to better understand their behaviour. The objective of the research is to explore the propagation of rock avalanches and to compare a simple numerical model with analogue modelling. The laboratory experiments investigate the fluidlike flow of a granular mass down a slope. The flow is unconfined, following a 45° slope and spreading freely on a horizontal depositional surface. Different grainsize of calibrate material (115, 545 and 2605 μm) and substratum roughness (simulate by aluminium and sandpapers with grainsize from 16 to 425 μm) were used in order to understand their influence on the motion of a granular mass. High speed movies are recorded to analyse the behaviour of the mass during the whole experiment. The numerical model is based on the continuum mechanics approach and solving the shallow water equations. The avalanche is described from an eulerian point of view within a continuum framework as single phase of incompressible granular material following Mohr-Coulomb friction law. The combination of the fluid dynamic equation with the frictional law enables the self-channelization of the mass without any topographic constraints or special border conditions. The results obtained with the numerical model are similar to those observed with the analogue. In both cases, based on similar initial condition (slope, volume, basal friction, height of fall and initial velocity), the runout of the mass is of comparable size and the shape of the deposit matches well

  17. 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.

  18. GLP-1 analogue improves hepatic lipid accumulation by inducing autophagy via AMPK/mTOR pathway.

    PubMed

    He, Qin; Sha, Sha; Sun, Lei; Zhang, Jing; Dong, Ming

    2016-08-01

    The incidence of nonalcoholic fatty liver disease (NAFLD) keeps rising year by year, and NAFLD is rapidly becoming the most common liver disease worldwide. Clinical studies have found that glucagon-like peptide-1 (GLP-1) analogue, liraglutide (LRG), cannot only reduce glucose levels, but also improve hepatic lipase, especially in patients also with type 2 diabetes mellitus (T2DM). In addition, enhancing autophagy decreases lipid accumulation in hepatocytes. The aim of the present study is to explore the effect of LRG on hepatocyte steatosis and the possible role of autophagy. We set up an obesity mouse model with a high-fat diet (HFD) and induced hepatocyte steatosis with free fatty acids (FFA) in human L-O2 cells. LRG and two inhibitors of autophagy, Chloroquine (CQ) and bafilomycin A1 (Baf), were added into each group, respectively. The lipid profiles and morphological modifications of each group were tested. Immunohistochemistry, immunofluorescence staining and transmission electron microscopy (TEM) were used to measure autophagy in this study. The autophagy protein expression of SQSTM1 (P62), and LC3B, along with the signaling pathway proteins of mTOR, phosphorylated mTOR (p-mTOR), AMPK, phosphorylated AMPK (p-AMPK) and Beclin1, were evaluated by western blot. Our results showed that LRG improved hepatocyte steatosis by inducing autophagy, and the AMPK/mTOR pathway is involved. These findings suggest an important mechanism for the positive effects of LRG on hepatic steatosis, and provide new evidence for clinical use of LRG in NAFLD. PMID:27208776

  19. Structure Activity Relationship and Mechanism of Action Studies of Manzamine Analogues for the Control of Neuroinflammation and Cerebral Infections

    PubMed Central

    Peng, Jiangnan; Kudrimoti, Sucheta; Prasanna, Sivaprakasam; Odde, Srinivas; Doerksen, Robert J.; Pennaka, Hari K; Choo, Yeun-Mun; Rao, Karumanchi V.; Tekwani, Babu L.; Madgula, Vamsi; Khan, Shabana I.; Wang, Bin; Mayer, Alejandro M. S.; Jacob, Melissa R.; Tu, Lan Chun; Gertsch, Jürg; Hamann, Mark T.

    2010-01-01

    Structure-activity relationship studies were carried out by chemical modification of manzamine A (1), 8-hydroxymanzamine A (2), manzamine F (14), and ircinol isolated from the sponge Acanthostrongylophora. The derived analogues were evaluated for antimalarial, antimicrobial, and antineuroinflammatory activities. Several modified products exhibited potent and improved in vitro antineuroinflammatory, antimicrobial, and antimalarial activity. 1 showed improved activity against malaria compared to chloroquine in both multi- and single-dose in vivo experiments. The significant antimalarial potential was revealed by a 100% cure rate of malaria in mice with one administration of 100 mg/kg of 1. The potent antineuroinflammatory activity of the manzamines will provide great benefit for the prevention and treatment of cerebral infections (e.g. Cryptococcus and Plasmodium). In addition, 1 was shown to permeate across the blood-brain barrier (BBB) in an in vitro model using a MDR-MDCK monolayer. Docking studies support that 2 binds to the ATP-noncompetitive pocket of glycogen synthesis kinase-3β (GSK-3β), which is a putative target of manzamines. Based on the results presented here it will be possible to initiate rational drug design efforts around this natural product scaffold for the treatment of several different diseases. PMID:20017491

  20. Pyridopyrimidine analogues as novel adenosine kinase inhibitors.

    PubMed

    Zheng, G Z; Lee, C; Pratt, J K; Perner, R J; Jiang, M Q; Gomtsyan, A; Matulenko, M A; Mao, Y; Koenig, J R; Kim, K H; Muchmore, S; Yu, H; Kohlhaas, K; Alexander, K M; McGaraughty, S; Chu, K L; Wismer, C T; Mikusa, J; Jarvis, M F; Marsh, K; Kowaluk, E A; Bhagwat, S S; Stewart, A O

    2001-08-20

    A novel series of pyridopyrimidine analogues 9 was identified as potent adenosine kinase inhibitors based on the SAR and computational studies. Substitution of the C7 position of the pyridopyrimidino core with C2' substituted pyridino moiety increased the in vivo potency and enhanced oral bioavailability of these adenosine kinase inhibitors.

  1. Analogues of thiolactomycin as potential antimalarial agents.

    PubMed

    Jones, Simon M; Urch, Jonathan E; Kaiser, Marcel; Brun, Reto; Harwood, John L; Berry, Colin; Gilbert, Ian H

    2005-09-22

    Analogues of the natural antibiotic thiolactomycin (TLM), an inhibitor of the condensing reactions of type II fatty acid synthase, were synthesized and evaluated for their ability to inhibit the growth of the malaria parasite Plasmodium falciparum. Alkylation of the C4 hydroxyl group led to the most significant increase in growth inhibition (over a 100-fold increase in activity compared to TLM). To investigate the mode of action, the P. falciparum KASIII enzyme was produced for inhibitor assay. A number of TLM derivatives were identified that showed improved inhibition of this enzyme compared to TLM. Structure-activity relationships for enzyme inhibition were identified for some series of TLM analogues, and these also showed weak correlation with inhibition of parasite growth, but this did not hold for other series. On the basis of the lack of a clear correlation between inhibition of pfKASIII activity and parasite growth, we conclude that pfKASIII is not the primary target of TLM analogues. Some of the analogues also inhibited the growth of the parasitic protozoa Trypanosoma cruzi, T. brucei, and Leishmania donovani.

  2. 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.

  3. Stilbenophane analogues of deoxycombretastatin A-4.

    PubMed

    Mateo, Carmen; Pérez-Melero, Concepción; Peláez, Rafael; Medarde, Manuel

    2005-08-01

    A new family of polyoxygenated stilbenophanes has been synthesized as conformationally restricted analogues of antimitotic combretastatins. By means of the McMurry olefination process, compounds derived from diethyleneglycol and 1,6-hexanediol were obtained, whereas Grubbs' catalyst failed in producing the ring-closing metathesis to this kind of macrocyclic products.

  4. Analogue Representations of Spatial Objects and Tranformations.

    ERIC Educational Resources Information Center

    Cooper, Lynn A.

    Considerable discussion and debate have been devoted to the extent and nature of structural or functional correspondence between internal representations and their external visual counterparts. An analogue representation or process is one in which the relational structure of external events is preserved in the corresponding internal…

  5. 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.

  6. Synthesis and antimicrobial activity of squalamine analogue.

    PubMed

    Kim, H S; Choi, B S; Kwon, K C; Lee, S O; Kwak, H J; Lee, C H

    2000-08-01

    Synthesis and antimicrobial activity of squalamine analogue 2 are reported. The synthesis of 2 was accomplished from bisnoralcohol 3. The spermidine moiety was introduced via reductive amination of an appropriately functionalized 3beta-aminosterol with spermidinyl aldehyde 17 utilizing sodium triacetoxyborohydride as the reducing agent. Compound 2 shows weaker antimicrobial activity than squalamine. PMID:11003150

  7. Site-specific and regiospecific installation of methylarginine analogues into recombinant histones and insights into effector protein binding.

    PubMed

    Le, Daniel D; Cortesi, Arianna T; Myers, Samuel A; Burlingame, Alma L; Fujimori, Danica Galonić

    2013-02-27

    Arginine methylation has emerged as a widespread post-translational modification with influence over myriad cellular processes. However, the molecular mechanisms underlying such methylarginine-dependent phenomena remain unclear. To aid in this research, a facile method was developed to install methylarginine analogues on recombinant protein for use in biochemical, biophysical, and structural studies. Through chemical conjugation of novel α,β-unsaturated amidine precursors with proteins, methylarginine mimics can be displayed with control of methylation site, extent, and regiospecificity. Analogue installation into histones using this strategy produced modified proteins that were recognized by antibodies specific to endogenous methylarginine, and these histones retained the capacity to form mononucleosomes. Moreover, a native methylarginine-specific binding domain was shown to interact with methylarginine analogue-modified substrates. This chemical conjugation method for installing methylarginine analogues provides an efficient route to produce homogeneous modified proteins for subsequent investigations of methylarginine-dependent processes.

  8. [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.

  9. [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. PMID:27301366

  10. [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.

  11. 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].).

  12. 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 Central

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

    2014-01-01

    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].) PMID:25421474

  13. 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].). PMID:25421474

  14. Antiplasmodial properties of kaempferol-3-O-rhamnoside isolated from the leaves of Schima wallichii against chloroquine-resistant Plasmodium falciparum

    PubMed Central

    BARLIANA, MELISA I.; SURADJI, EKA W.; ABDULAH, RIZKY; DIANTINI, AJENG; HATABU, TOSHIMITSU; NAKAJIMA-SHIMADA, JUNKO; SUBARNAS, ANAS; KOYAMA, HIROSHI

    2014-01-01

    Previous intervention studies have shown that the most effective agents used in the treatment of malaria were isolated from natural sources. Plants consumed by non-human primates serve as potential drug sources for human disease management due to the similarities in anatomy, physiology and disease characteristics. The present study investigated the antiplasmodial properties of the primate-consumed plant, Schima wallichii (S. wallichii) Korth. (family Theaceae), which has already been reported to have several biological activities. The ethanol extract of S. wallichii was fractionated based on polarity using n-hexane, ethyl acetate and water. The antiplasmodial activity was tested in vitro against chloroquine-resistant Plasmodium falciparum (P. falciparum) at 100 μg/ml for 72 h. The major compound of the most active ethyl acetate fraction was subsequently isolated using column chromatography and identified by nuclear magnetic resonance. The characterized compound was also tested against chloroquine-resistant P. falciparum in culture to evaluate its antiplasmodial activity. The ethanol extract of S. wallichii at 100 μg/ml exhibited a significant parasite shrinkage after 24 h of treatment. The ethyl acetate fraction at 100 μg/ml was the most active fraction against chloroquine-resistant P. falciparum. Based on the structural characterization, the major compound isolated from the ethyl acetate fraction was kaempferol-3-O-rhamnoside, which showed promising antiplasmodial activity against chloroquine-resistant P. falciparum with an IC50 of 106 μM after 24 h of treatment. The present study has provided a basis for the further investigation of kaempferol-3-O-rhamnoside as an active compound for potential antimalarial therapeutics. PMID:24944812

  15. Distribution of chloroquine in ocular tissue of pigmented rat using matrix-assisted laser desorption/ionization imaging quadrupole time-of-flight tandem mass spectrometry.

    PubMed

    Yamada, Yasuhiro; Hidefumi, Kaji; Shion, Henry; Oshikata, Motoji; Haramaki, Yukari

    2011-06-15

    In pharmacology and toxicology, localization of the distribution of a drug molecule in its target tissue provides very important in vivo biological information. Traditionally, this has been examined using autoradiography (ARG). However, there are significant limitations in this application. One is the synthesis and use of radiolabeled compounds, the other is that the image generated expresses an undifferentiated mixture of the parent drug and/or its metabolites. The objective of the study was to define the specific distribution of the parent drug in rat ocular tissue containing melanin (e.g. the retina) using non-labeled chloroquine by MALDI Imaging tandem mass spectrometry (MS/MS). After single oral administration (at 20 mg/kg) of chloroquine, sections (10 µm) of rat eye tissue were prepared at 24 h. The MS system used was a quadrupole time-of flight (Q-TOF) tandem mass spectrometer (MALDI Synapt™, Waters, Milford, MA, USA). Tissue sections were sprayed with CHCA (α-cyano-4-hydroxycinnamic acid, 5 mg/mL) in 80% acetonitrile (ACN) containing 5% formic acid (FA) using either a manual sprayer (airbrush) or an automated sprayer (TM-Sprayer™, HTX Technologies, Carrboro, NC, USA). Chloroquine was readily detected in the MS/MS mode by monitoring one of its major fragment ions (m/z 247.10) and imaged through the rat eye tissue. The image of the specific distribution within the retina in the rat eye tissue was confirmed, and found to be similar to autoradiograms after oral administration of (14)C-chloroquine reported previously.

  16. Antiplasmodial activity-aided isolation and identification of quercetin-4'-methyl ether in Chromolaena odorata leaf fraction with high activity against chloroquine-resistant Plasmodium falciparum.

    PubMed

    Ezenyi, I C; Salawu, O A; Kulkarni, R; Emeje, M

    2014-12-01

    The present study was undertaken to evaluate the antiplasmodial activity of Chromolaena odorata leaf extract and gradient fractions through in vivo and in vitro tests, aimed at identifying its antiplasmodial constituents. Sub-fractions obtained from the most active gradient fraction were further tested for cytotoxicity against THP-1 cells, chloroquine-sensitive (HB3) and chloroquine-resistant (FCM29) Plasmodium falciparum. Our results showed the dichloromethane gradient fraction was most effective, significantly (P < 0.05) suppressing infection by 99.46% at 100 mg/kg body weight. Amongst its 13 sub-fractions (DF1-DF13), DF11 was highly active, with IC50 of 4.8 and 6.74 μg/ml against P. falciparum HB3 and FCM29, respectively. Cytotoxicity of DF11 was estimated to be above 50 μg/ml, and its separation by column chromatography yielded a flavonoid which was characterized as 3, 5, 7, 3' tetrahydroxy-4'-methoxyflavone from its spectroscopic data. It significantly suppressed infection (65.43-81.48%) in mice at 2.5-5 mg/kg doses and compared favourably with the effects of chloroquine and artemisinin. It may therefore serve as a useful phytochemical and antiplasmodial activity marker of C. odorata leaves, which exhibit potential for development as medicine against malaria.

  17. The effect of pH on the uptake and toxicity of the bivalent weak base chloroquine tested on Salix viminalis and Daphnia magna.

    PubMed

    Rendal, Cecilie; Kusk, Kresten Ole; Trapp, Stefan

    2011-02-01

    The uptake and accumulation of most electrolytes will change with pH because of the different speciation states of these compounds at various pH. Non-ionized compounds will partition into fatty and organic phases (such as cell membranes) more readily than the corresponding charged compounds, and therefore a higher toxicity can be expected. The current study examines the pH-dependent toxicity and bioaccumulation of the bivalent weak base chloroquine (pK(a): 10.47 and 6.33, log K(OW) 4.67) tested on Salix viminalis (basket willow) and Daphnia magna (water flea). The transpiration rates of hydroponically grown willow cuttings were used to determine the toxicity of chloroquine at pH levels of 6, 7, 8, and 9. Root concentration factors were calculated from solution measurements. Results showed more than 10-fold higher toxicity and four to seven times higher root concentration factor at pH 9 than at pH 6. The toxicity of chloroquine was tested on Daphnia magna using the standard Organisation for Economic Co-operation and Development acute toxicity test modified to accommodate testing at pH levels of 7, 8, and 9. Increasing toxicity was seen at higher pH. The results of the current study confirm that the toxicity of weak bases with intermediate pK(a) values is higher at high pH levels.

  18. Anti-HIV screening for cell-penetrating peptides using chloroquine and identification of anti-HIV peptides derived from matrix proteins.

    PubMed

    Mizuguchi, Takaaki; Ohashi, Nami; Nomura, Wataru; Komoriya, Mao; Hashimoto, Chie; Yamamoto, Naoki; Murakami, Tsutomu; Tamamura, Hirokazu

    2015-08-01

    Previously, compounds which inhibit the HIV-1 replication cycle were found in overlapping peptide libraries covering the whole sequence of an HIV-1 matrix (MA) protein constructed with the addition of an octa-arginyl group. The two top lead compounds are sequential fragments MA-8L and MA-9L. In the present study, the addition of chloroquine in cell-based anti-HIV assays was proven to be an efficient method with which to find anti-HIV compounds among several peptides conjugated by cell-penetrating signals such as an octa-arginyl group: the conjugation of an octa-arginyl group to individual peptides contained in whole proteins in combination with the addition of chloroquine in cells is a useful assay method to search active peptides. To find more potent fragment peptides, individual peptides between MA-8L and MA-9L, having the same peptide chain length but with sequences shifted by one amino acid residue, were synthesized in this paper and their anti-HIV activity was evaluated with an anti-HIV assay using chloroquine. As a result, the peptides in the C-terminal side of the series, which are relatively close to MA-9L, showed more potent inhibitory activity against both X4-HIV-1 and R5-HIV-1 than the peptides in the N-terminal side.

  19. Antiplasmodial activity of certain medicinal plants against chloroquine resistant Plasmodium berghei infected white albino BALB/c mice.

    PubMed

    Rajendran, C; Begam, M; Kumar, Dharmendra; Baruah, Indra; Gogoi, H K; Srivastava, R B; Veer, Vijay

    2014-06-01

    In the present study of antimalarial efficacy, aqueous extracts of leaves and unripe fruits of Psidium guajava, leaves of Ocimum sanctum and leaves of Murraya koenigii are evaluated against Plasmodium berghei (chloroquine resistant NK65 strain) infected white albino BALB/c mice. A 7 days oral administration was adopted with different dosage viz., 350 mg, 750 mg and 1,000 mg/kg body weight as treatment schedule along with parasite (Group I) and drug control with Chloroquine, 50 mg/kg body weight (Group II). All the parts were extracted based on the decoction method, which is commonly seen among the villagers/tribes as their usual method of preparation of decoction for most of the ailments. The antimalarial activities were evaluated from the giemsa stained blood smears collected from different treated groups of mice used in this experiment. The antiplasmodial effect that is percent parasitaemia and percent suppression (values in parenthesis) showed by the treated groups of mice at 350 mg/kg b. wt. by the aqueous extracts of P. guajava leaves (Group III) was 19.8 ± 1.22 (73.7 %), P. guajava unripe fruits (Group IV) was 52.7 ± 2.19 (30.0 %), leaves of O. sanctum (Group V) was 64.0 ± 0.73 (15.1 %) and leaves of M. koenigii (Group VI) was 28.9 ± 0.81 (61.6 %) whereas at 750 mg/kg b. wt., it all showed 10.3 ± 0.7 (80.2 %), 26.3 ± 0.52 (65.1 %), 42.0 ± 0.47 (44.2 %) and 14.9 ± 0.46 (71.5 %) whereas at 1,000 mg/kg b. wt. dose, it all showed 9.2 ± 0.39 (85.8 %), 25.6 ± 0.40 (62.0 %), 41.8 ± 0.29 (35.5 %) and 14.0 ± 0.42 (76.9 %) respectively.

  20. 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

  1. Antiplasmodial activity of certain medicinal plants against chloroquine resistant Plasmodium berghei infected white albino BALB/c mice.

    PubMed

    Rajendran, C; Begam, M; Kumar, Dharmendra; Baruah, Indra; Gogoi, H K; Srivastava, R B; Veer, Vijay

    2014-06-01

    In the present study of antimalarial efficacy, aqueous extracts of leaves and unripe fruits of Psidium guajava, leaves of Ocimum sanctum and leaves of Murraya koenigii are evaluated against Plasmodium berghei (chloroquine resistant NK65 strain) infected white albino BALB/c mice. A 7 days oral administration was adopted with different dosage viz., 350 mg, 750 mg and 1,000 mg/kg body weight as treatment schedule along with parasite (Group I) and drug control with Chloroquine, 50 mg/kg body weight (Group II). All the parts were extracted based on the decoction method, which is commonly seen among the villagers/tribes as their usual method of preparation of decoction for most of the ailments. The antimalarial activities were evaluated from the giemsa stained blood smears collected from different treated groups of mice used in this experiment. The antiplasmodial effect that is percent parasitaemia and percent suppression (values in parenthesis) showed by the treated groups of mice at 350 mg/kg b. wt. by the aqueous extracts of P. guajava leaves (Group III) was 19.8 ± 1.22 (73.7 %), P. guajava unripe fruits (Group IV) was 52.7 ± 2.19 (30.0 %), leaves of O. sanctum (Group V) was 64.0 ± 0.73 (15.1 %) and leaves of M. koenigii (Group VI) was 28.9 ± 0.81 (61.6 %) whereas at 750 mg/kg b. wt., it all showed 10.3 ± 0.7 (80.2 %), 26.3 ± 0.52 (65.1 %), 42.0 ± 0.47 (44.2 %) and 14.9 ± 0.46 (71.5 %) whereas at 1,000 mg/kg b. wt. dose, it all showed 9.2 ± 0.39 (85.8 %), 25.6 ± 0.40 (62.0 %), 41.8 ± 0.29 (35.5 %) and 14.0 ± 0.42 (76.9 %) respectively. PMID:24808642

  2. Synthesis and biological evaluation of hydrazidomycin analogues.

    PubMed

    Meyer, Florian; Ueberschaar, Nico; Dahse, Hans-Martin; Hertweck, Christian

    2013-11-15

    Hydrazidomycin A is an unusual secondary metabolite of Streptomyces atratus that features a rare enehydrazide core. To learn more about structure-activity relationships of the reported cytotoxic and antiproliferative agent several synthetic routes were explored to synthesize a variety of hydrazidomycin derivatives. Specifically, the size of the side chains, the nature of the double bond and the polar head group were altered. Overall, fourteen analogues were tested for their cytotoxic and antiproliferative effects. Re-examination of synthetic hydrazidomycin A suggests that the antiproliferative activity is attributed to a yet unknown compound that results from degradation or rearrangement. Several of the less complex analogues, however, show antiproliferative activities against individual cancer cell lines and turned out to be more potent than hydrazidomycin A.

  3. 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

  4. Platinum analogues in preclinical and clinical development.

    PubMed

    Hamilton, T C; O'Dwyer, P J; Ozols, R F

    1993-11-01

    The impact of cisplatin on chemotherapy for solid tumors has led to the synthesis of many molecules with platinum as their central building block. These so-called platinum analogues have been developed with the obvious goals of improving the antitumor activity of cisplatin and hopefully, at the same time, altering the dose-limiting side effects of the prototype drug. At least 10 such molecules are in clinical development, whereas several others are at various stages of preclinical testing. PMID:8305533

  5. 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.

  6. 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

  7. 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.

  8. Mutant pfcrt "SVMNT" haplotype and wild type pfmdr1 "N86" are endemic in Plasmodium vivax dominated areas of India under high chloroquine exposure

    PubMed Central

    2012-01-01

    Background Chloroquine resistance (CQR) phenotype in Plasmodium falciparum is associated with mutations in pfcrt and pfmdr-1 genes. Mutations at amino acid position 72-76 of pfcrt gene, here defined as pfcrt haplotype are associated with the geographic origin of chloroquine resistant parasite. Here, mutations at 72-76 and codon 220 of pfcrt gene and N86Y pfmdr-1 mutation were studied in blood samples collected across 11 field sites, inclusive of high and low P. falciparum prevalent areas in India. Any probable correlation between these mutations and clinical outcome of CQ treatment was also investigated. Methods Finger pricked blood spotted on Whatman No.3 papers were collected from falciparum malaria patients of high and low P. falciparum prevalent areas. For pfcrt haplotype investigation, the parasite DNA was extracted from blood samples and used for PCR amplification, followed by partial sequencing of the pfcrt gene. For pfmdr-1 N86Y mutation, the PCR product was subjected to restriction digestion with AflIII endonuclease enzyme. Results In 240 P. falciparum isolates with reported in vivo CQ therapeutic efficacy, the analysis of mutations in pfcrt gene shows that mutant SVMNT-S (67.50%) and CVIET-S (23.75%) occurred irrespective of clinical outcome and wild type CVMNK-A (7.91%) occurred only in adequate clinical and parasitological response samples. Of 287 P. falciparum isolates, SVMNTS 192 (66.89%) prevailed in all study sites and showed almost monomorphic existence (98.42% isolates) in low P. falciparum prevalent areas. However, CVIETS-S (19.51%) and CVMNK-A (11.84%) occurrence was limited to high P. falciparum prevalent areas. Investigation of pfmdr-1 N86Y mutation shows no correlation with clinical outcomes. The wild type N86 was prevalent in all the low P. falciparum prevalent areas (94.48%). However, mutant N86Y was comparably higher in numbers at the high P. falciparum prevalent areas (42.76%). Conclusions The wild type pfcrt gene is linked to chloroquine

  9. 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

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

    PubMed

    Zuluaga-Idárraga, Lina; Blair, Silvia; Akinyi Okoth, Sheila; Udhayakumar, Venkatachalam; Marcet, Paula L; Escalante, Ananias A; Alexander, Neal; Rojas, Carlos

    2016-08-01

    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

  11. Preparation and in vitro evaluation of liposomal chloroquine diphosphate loaded by a transmembrane pH-gradient method.

    PubMed

    Qiu, Liyan; Jing, Na; Jin, Yi

    2008-09-01

    This study developed an active loading method for encapsulating chloroquine diphosphate (CQ) into liposomes. The effects of different formulation factors on the encapsulation efficiency (EE) and the size of CQ liposomes were investigated. These factors included the internal phase of liposomes, the external phase of liposomes, the ratio of drug to soybean phosphatidylcholine (drug/SPC), the ratio of cholesterol to soybean phosphatidylcholine (Chol/SPC), and the incubation temperature and time. The EE (93%) was obtained when using drug/SPC (1:50 mass ratio), SPC/Chol (1:5 mass ratio) at 0.10 M citrate-sodium citrate buffer (pH 3.6). As 5 mol% methoxypoly(ethylene glycol)(2,000) cholesteryl succinate (CHS-PEG(2000)) or distearoyl phosphatidylethanolamine-poly (ethylene glycol)(2,000) (DSPE-PEG(2000)) was added, the size of particle was reduced and the EE was improved. Freeze-drying with 5% trehalose as a cryoprotectant was carried out to achieve long-term stability. The drug release studies were performed in vitro simulating the desired application conditions, such as physiological fluids (pH 7.4), tumor tissues (pH 6.5) and endosomal compartments (pH 5.5). The release of CQ from the liposomes prepared via remote loading showed the significant pH-sensitivity and retention properties, which favored the application of liposomal CQ at tumor tissues and endosomal compartments.

  12. [Comparison of efficacy of chloroquine versus sulfadoxine-pyrimethamine in malaria prevention in pregnant women in the Toamasina region (Madagascar)].

    PubMed

    Randriambelomanana, J A; Rakotoarisoa, H; Herinirina, S A; Zafindravola, B A; Andrianampanalinarivo, H R

    2011-10-01

    Malaria still represents a great cause of death in sub-Saharan African areas, mainly among pregnant women. We conducted this prospective study during two years in a malaria-endemic stable region in the east of Madagascar (Toamasina) with an aim to compare the efficacy of weekly chloroquine (CQ) and the use of intermittent presumptive treatment by sulfadoxine-pyrimethamine (SP). 519 pregnant women were included in this study (CQ = 285; SP = 256). Socio-demographical characteristics of each group were identical. We found more peripheral parasitemia (CQ = 8.07% vs SP = 2.73%; P = 0.0068) and severe malaria in the CQ group (CQ = 1.75% vs SP = 0%; P = 0.0332). Anemia was more frequent in the CQ group (CQ = 4.21% vs SP = 0.35%; P = 0.0038). Placental infestation rate was also higher in the CQ group (CQ = 7.01% vs SP = 0.39%; P = 0.00001). Low birth weight and fetal death were lower in the SP group respectively [(CQ = 4.21% vs SP = 0.78%; P = 0.0121) and (CQ = 1.75%vs SP = 0%; P = 0.0332)].

  13. Efficacy of Pyrimethamine/Sulfadoxine versus Chloroquine for the Treatment of Uncomplicated Falciparum Malaria in Children Aged Under 5 Years

    PubMed Central

    Zheng, W; Jiang, H; Xiong, Z; Jiang, Z; Chen, H

    2013-01-01

    The children aged under 5 years from vast African areas badly suffer from falciparum malaria and many of them die of this disease. Therapeutic efficacy of anti-malaria drugs, especially pyrimethamine-sulfadoxine (PS) and chloroquine (CQ) to falciparum malaria is frequently evaluated and reported in recent 10 years. Unfortunately, to date, these widespread materials and researches have not been systematically collected and analyzed. In our study, two investigators were employed to widely and independently gather researches on efficacy of PS vs. CQ mono-therapy of falciparum malaria in children aged below 5 years in unpublished and published databases. Meta-analyses were conducted in categories of PS group and CQ group respectively. Pooled OR of PS vs. CQ was 0.11 (95%CI, 0.05-0.24). PS showed higher therapeutic efficacy to falciparum malaria in less-than-5-year children than CQ. Random model was chosen to analyze for the heterogeneity existence between different studies. Subgroup analyses were performed, but heterogeneity was still presented. Heterogeneity might be caused by different resistance of falciparum malaria to PS and CQ in different settings. Malaria type associated with parasite species, basic information of PS and CQ, and PS & CQ resistant malaria control measures were demonstrated and discussed respectively in detail in this article. PMID:23682255

  14. Therapeutic efficacy of chloroquine for the treatment of uncomplicated Plasmodium falciparum in Haiti after many decades of its use.

    PubMed

    Okech, Bernard A; Existe, Alexandre; Romain, Jean R; Memnon, Gladys; Victor, Yves Saint; de Rochars, Madsen Beau; Fukuda, Mark

    2015-03-01

    Chloroquine (CQ) has been used for malaria treatment in Haiti for several decades, but reports of CQ resistance are scarce. The efficacy of CQ in patients with uncomplicated Plasmodium falciparum undergoing treatment in Haiti was evaluated. Malaria patients were enrolled, treated with CQ, and monitored over a 42-day period. The treatment outcomes were evaluated on day 28 by microscopy. The P. falciparum slide-confirmed rate was 9.5% (121 of 1,277). Malaria infection was seasonal, with peak observations between October and January; 88% (107 of 121) of patients consented to participate. Sixty patients successfully completed the 42-day follow-up, whereas 47 patients withdrew consent or were lost to follow-up. The mean parasite density declined rapidly within the first few days after treatment. Seven patients did not clear their malaria infections and were clinically asymptomatic; therefore, they were considered late parasitological failures. About 90% (95% confidence interval = 84.20-97.90) of patients had no detectable parasitemia by day 28 and remained malaria-free to day 42. Testing for recrudescence, reinfection, and CQ serum levels was not done in the seven patients, and therefore, their CQ resistance status is unresolved. CQ resistance surveillance by patient follow-up, in vitro drug sensitivity studies, and molecular markers is urgently needed in Haiti.

  15. Combination of chloroquine and GX15-070 (obatoclax) results in synergistic cytotoxicity against pancreatic cancer cells.

    PubMed

    Wang, Guan; Chen, Shaohua; Edwards, Holly; Cui, Xinming; Cui, Li; Ge, Yubin

    2014-12-01

    Pancreatic cancer is an aggressive disease with a poor prognosis. Therefore, new treatment is urgently required. GX15-070 is a pan-Bcl-2 inhibitor which has shown promising antitumor activity in different malignancies. We previously demonstrated that clinically achievable concentrations of GX15-070 caused growth arrest in pancreatic cancer cell lines. However, they only induced minimal levels of apoptosis. We hypothesized that GX15-070 induced autophagy in pancreatic cancer cells which blocked apoptosis. In this study, we investigated the effects of GX15-070 on autophagy and the antitumor activities of the combination of GX15-070 and chloroquine (CQ), an autophagy inhibitor, in six pancreatic cancer cell lines. We found that GX15-070 treatment indeed induced autophagy in 5 of the 6 pancreatic cancer cell lines, reflected by the conversion of LC3B-I to LC3B-II and detection of autophagosomes by transmission electron microscopy. Furthermore, we found additive to synergistic antitumor interactions in all six cell lines by MTT assays. CQ significantly enhanced GX15-070-induced apoptosis in the cell line models, possibly due to downregulation of Bcl-2, Bcl-xL and Mcl-1 in the cells by the two agents. These results provide compelling evidence for the further development of the combination of GX15-070 and CQ in pancreatic cancer. PMID:25333301

  16. Inhibition of autophagy by chloroquine potentiates synergistically anti-cancer property of artemisinin by promoting ROS dependent apoptosis.

    PubMed

    Ganguli, Arnab; Choudhury, Diptiman; Datta, Satabdi; Bhattacharya, Surela; Chakrabarti, Gopal

    2014-12-01

    Artemisinin (ART) is a well-known anti-malarial drug, and recently it is shown prospective to selectively kill cancer cells. But low potency makes it inappropriate for use as an anticancer drug. In this study, we modulated the ART-induced autophagy to increase Potency of ART as an anticancer agent. ART reduced the cell viability and colony forming ability of non-small lung carcinoma (A549) cells and it was non-toxic against normal lung (WI38) cells. ART induced autophagy at the early stage of treatment. Pre-treatment with chloroquine (CQ) and followed by ART treatment had synergistic combination index (CI) for cell death. Inhibition of autophagy by CQ pre-treatment led to accumulation of acidic vacuoles (AVOs) which acquainted with unprocessed damage mitochondria that subsequently promoted ROS generation, and resulted releases of Cyt C in cytosol that caused caspase-3 dependent apoptosis cell death in ART-treated A549 cells. Scavenging of ROS by antioxidant N-acetyl-cysteine (NAC) inhibited caspase-3 activity and rescued the cells from apoptosis. Similar effects were observed in other cancer cells SCC25 and MDA-MB-231. The appropriate manipulation of autophagy by using CQ provides a powerful strategy to increase the Potency of selective anticancer property of ART. PMID:25308836

  17. A Controlled Trial to Assess the Effect of Quinine, Chloroquine, Amodiaquine, and Artesunate on Loa loa Microfilaremia

    PubMed Central

    Kamgno, Joseph; Djomo, Patrick Nguipdop; Pion, Sébastien D.; Thylefors, Björn; Boussinesq, Michel

    2010-01-01

    Onchocerciasis control is currently based on mass ivermectin treatment. Unfortunately, this drug can induce serious adverse events (SAEs) in persons with high levels of Loa loa microfilaremia (> 30,000 microfilaria/mL). A means of preventing SAEs would be to treat at risk populations with a drug that would progressively reduce the microfilarial loads before administering ivermectin. Antimalarial drugs are a potential solution because they have shown some activity against various filarial species. A controlled trial was conducted to assess the effect of standard doses of quinine, chloroquine, amodiaquine, and artesunate on L. loa microfilaremia. Ninety-eight patients were randomly allocated into five groups (one for each drug and a control group) after stratification on microfilarial load. Loa loa microfilaremia was monitored on days 0, 3, 7, 15, 30, 60, and 90. No significant change in the loads was recorded in any of the treatment groups. A comprehensive review of the effects of antimalarial drugs against filariae is also provided. PMID:20207860

  18. A precision analogue integrator system for heavy current measurement in MFDC resistance spot welding

    NASA Astrophysics Data System (ADS)

    Xia, Yu-Jun; Zhang, Zhong-Dian; Xia, Zhen-Xin; Zhu, Shi-Liang; Zhang, Rui

    2016-02-01

    In order to control and monitor the quality of middle frequency direct current (MFDC) resistance spot welding (RSW), precision measurement of the welding current up to 100 kA is required, for which Rogowski coils are the only viable current transducers at present. Thus, a highly accurate analogue integrator is the key to restoring the converted signals collected from the Rogowski coils. Previous studies emphasised that the integration drift is a major factor that influences the performance of analogue integrators, but capacitive leakage error also has a significant impact on the result, especially in long-time pulse integration. In this article, new methods of measuring and compensating capacitive leakage error are proposed to fabricate a precision analogue integrator system for MFDC RSW. A voltage holding test is carried out to measure the integration error caused by capacitive leakage, and an original integrator with a feedback adder is designed to compensate capacitive leakage error in real time. The experimental results and statistical analysis show that the new analogue integrator system could constrain both drift and capacitive leakage error, of which the effect is robust to different voltage levels of output signals. The total integration error is limited within  ±0.09 mV s-1 0.005% s-1 or full scale at a 95% confidence level, which makes it possible to achieve the precision measurement of the welding current of MFDC RSW with Rogowski coils of 0.1% accuracy class.

  19. 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

  20. 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.

  1. Digitoxin Analogues with Improved Anticytomegalovirus Activity

    PubMed Central

    2014-01-01

    Cardiac glycosides are potent inhibitors of cancer cell growth and possess antiviral activities at nanomolar concentrations. In this study we evaluated the anticytomegalovirus (CMV) activity of digitoxin and several of its analogues. We show that sugar type and sugar length attached to the steroid core structure affects its anticytomegalovirus activity. Structure–activity relationship (SAR) studies identified the l-sugar containing cardiac glycosides as having improved anti-CMV activity and may lead to better understanding of how these compounds inhibit CMV replication. PMID:24900847

  2. Materials analogue of zero-stiffness structures

    NASA Astrophysics Data System (ADS)

    Kumar, Arun; Subramaniam, Anandh

    2011-04-01

    Anglepoise lamps and certain tensegrities are examples of zero-stiffness structures. These structures are in a state of neutral equilibrium with respect to changes in configuration of the system. Using Eshelby's example of an edge dislocation in a thin plate that can bend, we report the discovery of a non-trivial new class of material structures as an analogue to zero-stiffness structures. For extended positions of the edge dislocation in these structures, the dislocation experiences a zero image force. Salient features of these material structures along with the key differences from conventional zero-stiffness structures are pointed out.

  3. Spectroscopic study of solar twins and analogues

    NASA Astrophysics Data System (ADS)

    Datson, Juliet; Flynn, Chris; Portinari, Laura

    2015-02-01

    Context. Many large stellar surveys have been and are still being carried out, providing huge amounts of data, for which stellar physical parameters will be derived. Solar twins and analogues provide a means to test the calibration of these stellar catalogues because the Sun is the best-studied star and provides precise fundamental parameters. Solar twins should be centred on the solar values. Aims: This spectroscopic study of solar analogues selected from the Geneva-Copenhagen Survey (GCS) at a resolution of 48 000 provides effective temperatures and metallicities for these stars. We test whether our spectroscopic parameters, as well as the previous photometric calibrations, are properly centred on the Sun. In addition, we search for more solar twins in our sample. Methods: The methods used in this work are based on literature methods for solar twin searches and on methods we developed in previous work to distinguish the metallicity-temperature degeneracies in the differential comparison of spectra of solar analogues versus a reference solar reflection spectrum. Results: We derive spectroscopic parameters for 148 solar analogues (about 70 are new entries to the literature) and verify with a-posteriori differential tests that our values are well-centred on the solar values. We use our dataset to assess the two alternative calibrations of the GCS parameters; our methods favour the latest revision. We show that the choice of spectral line list or the choice of asteroid or time of observation does not affect the results. We also identify seven solar twins in our sample, three of which are published here for the first time. Conclusions: Our methods provide an independent means to differentially test the calibration of stellar catalogues around the values of a well-known benchmark star, which makes our work interesting for calibration tests of upcoming Galactic surveys. Based on observations made with ESO Telescopes at the La Silla Observatory under programme ID 077.D

  4. Analogue models of pull-apart basins

    NASA Astrophysics Data System (ADS)

    McClay, Ken; Dooley, Tim

    1995-08-01

    Sandbox analogue models of pull-apart basins that developed in sedimentary strata above releasing steps in underlying basement faults are characterized by rhombic basins that are flat-bottomed box grabens with a subhorizontal synkinematic basin infill. Steep to nearly vertical, sigmoidal oblique-slip and segmented oblique-extensional faults are the dominant bounding structures of the pull-apart basins. Cross-basin, short-cut faults link the offset principal displacement zones that are characterized by flower structure development. The structural architectures of the physical models compare directly in form and dimensions to natural examples of strike-slip pull-apart basins.

  5. 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.

  6. 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.

  7. 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.

  8. Expression of Plasmodium vivax crt-o Is Related to Parasite Stage but Not Ex Vivo Chloroquine Susceptibility.

    PubMed

    Pava, Zuleima; Handayuni, Irene; Wirjanata, Grennady; To, Sheren; Trianty, Leily; Noviyanti, Rintis; Poespoprodjo, Jeanne Rini; Auburn, Sarah; Price, Ric N; Marfurt, Jutta

    2016-01-01

    Chloroquine (CQ)-resistant Plasmodium vivax is present in most countries where P. vivax infection is endemic, but the underlying molecular mechanisms responsible remain unknown. Increased expression of P. vivax crt-o (pvcrt-o) has been correlated with in vivo CQ resistance in an area with low-grade resistance. We assessed pvcrt-o expression in isolates from Papua (Indonesia), where P. vivax is highly CQ resistant. Ex vivo drug susceptibilities to CQ, amodiaquine, piperaquine, mefloquine, and artesunate were determined using a modified schizont maturation assay. Expression levels of pvcrt-o were measured using a novel real-time quantitative reverse transcription-PCR method. Large variations in pvcrt-o expression were observed across the 51 isolates evaluated, with the fold change in expression level ranging from 0.01 to 59 relative to that seen with the P. vivax β-tubulin gene and from 0.01 to 24 relative to that seen with the P. vivax aldolase gene. Expression was significantly higher in isolates with the majority of parasites at the ring stage of development (median fold change, 1.7) compared to those at the trophozoite stage (median fold change, 0.5; P < 0.001). Twenty-nine isolates fulfilled the criteria for ex vivo drug susceptibility testing and showed high variability in CQ responses (median, 107.9 [range, 6.5 to 345.7] nM). After controlling for the parasite stage, we found that pvcrt-o expression levels did not correlate with the ex vivo response to CQ or with that to any of the other antimalarials tested. Our results highlight the importance of development-stage composition for measuring pvcrt-o expression and suggest that pvcrt-o transcription is not a primary determinant of ex vivo drug susceptibility. A comprehensive transcriptomic approach is warranted for an in-depth investigation of the role of gene expression levels and P. vivax drug resistance. PMID:26525783

  9. Inhibition of cholesterol metabolism underlies synergy between mTOR pathway inhibition and chloroquine in bladder cancer cells

    PubMed Central

    King, M A; Ganley, I G; Flemington, V

    2016-01-01

    Mutations to fibroblast growth factor receptor 3 (FGFR3) and phosphatase and tensin homologue (PTEN) signalling pathway components (for example, PTEN loss, PIK3CA, AKT1, TSC1/2) are common in bladder cancer, yet small-molecule inhibitors of these nodes (FGFR/PTENi) show only modest activity in preclinical models. As activation of autophagy is proposed to promote survival under FGFR/PTENi, we have investigated this relationship in a panel of 18 genetically diverse bladder cell lines. We found that autophagy inhibition does not sensitise bladder cell lines to FGFR/PTENi, but newly identify an autophagy-independent cell death synergy in FGFR3-mutant cell lines between mTOR (mammalian target of rapamycin) pathway inhibitors and chloroquine (CQ)—an anti-malarial drug used as a cancer therapy adjuvant in over 30 clinical trials. The mechanism of synergy is consistent with lysosomal cell death (LCD), including cathepsin-driven caspase activation, and correlates with suppression of cSREBP1 and cholesterol biosynthesis in sensitive cell lines. Remarkably, loss of viability can be rescued by saturating cellular membranes with cholesterol or recapitulated by statin-mediated inhibition, or small interfering RNA knockdown, of enzymes regulating cholesterol metabolism. Modulation of CQ-induced cell death by atorvastatin and cholesterol is reproduced across numerous cell lines, confirming a novel and fundamental role for cholesterol biosynthesis in regulating LCD. Thus, we have catalogued the molecular events underlying cell death induced by CQ in combination with an anticancer therapeutic. Moreover, by revealing a hitherto unknown aspect of lysosomal biology under stress, we propose that suppression of cholesterol metabolism in cancer cells should elicit synergy with CQ and define a novel approach to future cancer treatments. PMID:26853465

  10. 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

  11. Acidic extracellular pH neutralizes the autophagy-inhibiting activity of chloroquine: implications for cancer therapies.

    PubMed

    Pellegrini, Paola; Strambi, Angela; Zipoli, Chiara; Hägg-Olofsson, Maria; Buoncervello, Maria; Linder, Stig; De Milito, Angelo

    2014-04-01

    Acidic pH is an important feature of tumor microenvironment and a major determinant of tumor progression. We reported that cancer cells upregulate autophagy as a survival mechanism to acidic stress. Inhibition of autophagy by administration of chloroquine (CQ) in combination anticancer therapies is currently evaluated in clinical trials. We observed in 3 different human cancer cell lines cultured at acidic pH that autophagic flux is not blocked by CQ. This was consistent with a complete resistance to CQ toxicity in cells cultured in acidic conditions. Conversely, the autophagy-inhibiting activity of Lys-01, a novel CQ derivative, was still detectable at low pH. The lack of CQ activity was likely dependent on a dramatically reduced cellular uptake at acidic pH. Using cell lines stably adapted to chronic acidosis we could confirm that CQ lack of activity was merely caused by acidic pH. Moreover, unlike CQ, Lys-01 was able to kill low pH-adapted cell lines, although higher concentrations were required as compared with cells cultured at normal pH conditions. Notably, buffering medium pH in low pH-adapted cell lines reverted CQ resistance. In vivo analysis of tumors treated with CQ showed that accumulation of strong LC3 signals was observed only in normoxic areas but not in hypoxic/acidic regions. Our observations suggest that targeting autophagy in the tumor environment by CQ may be limited to well-perfused regions but not achieved in acidic regions, predicting possible limitations in efficacy of CQ in antitumor therapies. PMID:24492472

  12. Inhibition of cholesterol metabolism underlies synergy between mTOR pathway inhibition and chloroquine in bladder cancer cells.

    PubMed

    King, M A; Ganley, I G; Flemington, V

    2016-08-25

    Mutations to fibroblast growth factor receptor 3 (FGFR3) and phosphatase and tensin homologue (PTEN) signalling pathway components (for example, PTEN loss, PIK3CA, AKT1, TSC1/2) are common in bladder cancer, yet small-molecule inhibitors of these nodes (FGFR/PTENi) show only modest activity in preclinical models. As activation of autophagy is proposed to promote survival under FGFR/PTENi, we have investigated this relationship in a panel of 18 genetically diverse bladder cell lines. We found that autophagy inhibition does not sensitise bladder cell lines to FGFR/PTENi, but newly identify an autophagy-independent cell death synergy in FGFR3-mutant cell lines between mTOR (mammalian target of rapamycin) pathway inhibitors and chloroquine (CQ)-an anti-malarial drug used as a cancer therapy adjuvant in over 30 clinical trials. The mechanism of synergy is consistent with lysosomal cell death (LCD), including cathepsin-driven caspase activation, and correlates with suppression of cSREBP1 and cholesterol biosynthesis in sensitive cell lines. Remarkably, loss of viability can be rescued by saturating cellular membranes with cholesterol or recapitulated by statin-mediated inhibition, or small interfering RNA knockdown, of enzymes regulating cholesterol metabolism. Modulation of CQ-induced cell death by atorvastatin and cholesterol is reproduced across numerous cell lines, confirming a novel and fundamental role for cholesterol biosynthesis in regulating LCD. Thus, we have catalogued the molecular events underlying cell death induced by CQ in combination with an anticancer therapeutic. Moreover, by revealing a hitherto unknown aspect of lysosomal biology under stress, we propose that suppression of cholesterol metabolism in cancer cells should elicit synergy with CQ and define a novel approach to future cancer treatments. PMID:26853465

  13. Chloroquine and its analogs: a new promise of an old drug for effective and safe cancer therapies.

    PubMed

    Solomon, V Raja; Lee, Hoyun

    2009-12-25

    Chloroquine (CQ), N'-(7-chloroquinolin-4-yl)-N,N-diethyl-pentane-1,4-diamine, is widely used as an effective and safe anti-malarial and anti-rheumatoid agent. CQ was discovered 1934 as "Resochin" by Andersag and co-workers at the Bayer laboratories. Ironically, CQ was initially ignored for a decade because it was considered too toxic to use in humans. CQ was "re-discovered" during World War II in the United States in the course of anti-malarial drug development. The US government-sponsored clinical trials during this period showed unequivocally that CQ has a significant therapeutic value as an anti-malarial drug. Consequently, CQ was introduced into clinical practice in 1947 for the prophylaxis treatment of malaria (Plasmodium vivax, ovale and malariae). CQ still remains the drug of choice for malaria chemotherapy because it is highly effective and well tolerated by humans. In addition, CQ is widely used as an anti-inflammatory agent for the treatment of rheumatoid arthritis, lupus erythematosus and amoebic hepatitis. More recently, CQ has been studied for its potential as an enhancing agent in cancer therapies. Accumulating lines of evidence now suggest that CQ can effectively sensitize cell-killing effects by ionizing radiation and chemotherapeutic agents in a cancer-specific manner. The lysosomotrophic property of CQ appears to be important for the increase in efficacy and specificity. Although more studies are needed, CQ may be one of the most effective and safe sensitizers for cancer therapies. Taken together, it appears that the efficacy of conventional cancer therapies can be dramatically enhanced if used in combination with CQ and its analogs. PMID:19836374

  14. Resistance of colon cancer to 5-fluorouracil may be overcome by combination with chloroquine, an in vivo study.

    PubMed

    Sasaki, Kazuhito; Tsuno, Nelson H; Sunami, Eiji; Kawai, Kazushige; Hongo, Kumiko; Hiyoshi, Masaya; Kaneko, Manabu; Murono, Koji; Tada, Noriko; Nirei, Takako; Takahashi, Koki; Kitayama, Joji

    2012-08-01

    Autophagy is a complex of adaptive cellular response that enhances cancer cell survival in the face of cellular stresses such as chemotherapy. Recently, chloroquine diphosphate (CQ), a widely used antimalarial drug, has been studied as a potential inhibitor of autophagy. Here, we aimed to investigate the role of CQ in potentiating the effect of 5-fluorouracil (5-FU), the chemotherapeutic agent of first choice for the treatment of colorectal cancer, in an animal model of colon cancer. The mouse colon cancer cell line colon26 was used. For the in-vivo study, colon26 cells were injected subcutaneously into BALB/c mice, which were treated with saline as a control, CQ (50 mg/kg/day), 5-FU (30 mg/kg/day), or the combination therapy (CQ plus 5-FU). The tumor volume ratio and body weight were monitored. After the sacrifice, tumor tissue protein extracts and tumor sections were prepared and subjected to immunoblotting for the analysis of autophagy-related and apoptosis-related proteins, and the terminal transferase uridyl end labeling assay. The combination of CQ resulted in the inhibition of 5-FU-induced autophagy and a significant enhancement in the 5-FU-induced inhibition of tumor growth. Furthermore, the combination treatment of CQ and 5-FU resulted in a significant increase in the ratio of apoptotic cells compared with other treatments. The expression levels of the proapoptotic proteins, namely Bad and Bax, were increased by the CQ treatment in the protein extracts from tumors. Our findings suggest that the combination therapy of CQ and 5-FU should be considered as an effective strategy for the treatment of colorectal cancer. PMID:22561420

  15. Excitation and Modulation of TRPA1, TRPV1, and TRPM8 Channel-expressing Sensory Neurons by the Pruritogen Chloroquine*

    PubMed Central

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

    2013-01-01

    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. PMID:23508958

  16. Expression of Plasmodium vivax crt-o Is Related to Parasite Stage but Not Ex Vivo Chloroquine Susceptibility.

    PubMed

    Pava, Zuleima; Handayuni, Irene; Wirjanata, Grennady; To, Sheren; Trianty, Leily; Noviyanti, Rintis; Poespoprodjo, Jeanne Rini; Auburn, Sarah; Price, Ric N; Marfurt, Jutta

    2015-11-02

    Chloroquine (CQ)-resistant Plasmodium vivax is present in most countries where P. vivax infection is endemic, but the underlying molecular mechanisms responsible remain unknown. Increased expression of P. vivax crt-o (pvcrt-o) has been correlated with in vivo CQ resistance in an area with low-grade resistance. We assessed pvcrt-o expression in isolates from Papua (Indonesia), where P. vivax is highly CQ resistant. Ex vivo drug susceptibilities to CQ, amodiaquine, piperaquine, mefloquine, and artesunate were determined using a modified schizont maturation assay. Expression levels of pvcrt-o were measured using a novel real-time quantitative reverse transcription-PCR method. Large variations in pvcrt-o expression were observed across the 51 isolates evaluated, with the fold change in expression level ranging from 0.01 to 59 relative to that seen with the P. vivax β-tubulin gene and from 0.01 to 24 relative to that seen with the P. vivax aldolase gene. Expression was significantly higher in isolates with the majority of parasites at the ring stage of development (median fold change, 1.7) compared to those at the trophozoite stage (median fold change, 0.5; P < 0.001). Twenty-nine isolates fulfilled the criteria for ex vivo drug susceptibility testing and showed high variability in CQ responses (median, 107.9 [range, 6.5 to 345.7] nM). After controlling for the parasite stage, we found that pvcrt-o expression levels did not correlate with the ex vivo response to CQ or with that to any of the other antimalarials tested. Our results highlight the importance of development-stage composition for measuring pvcrt-o expression and suggest that pvcrt-o transcription is not a primary determinant of ex vivo drug susceptibility. A comprehensive transcriptomic approach is warranted for an in-depth investigation of the role of gene expression levels and P. vivax drug resistance.

  17. Role of Pfmdr1 in In Vitro Plasmodium falciparum Susceptibility to Chloroquine, Quinine, Monodesethylamodiaquine, Mefloquine, Lumefantrine, and Dihydroartemisinin

    PubMed Central

    Wurtz, Nathalie; Fall, Bécaye; Pascual, Aurélie; Fall, Mansour; Baret, Eric; Camara, Cheikhou; Nakoulima, Aminata; Diatta, Bakary; Fall, Khadidiatou Ba; Mbaye, Pape Saliou; Diémé, Yaya; Bercion, Raymond; Wade, Boubacar

    2014-01-01

    The involvement of Pfmdr1 (Plasmodium falciparum multidrug resistance 1) polymorphisms in antimalarial drug resistance is still debated. Here, we evaluate the association between polymorphisms in Pfmdr1 (N86Y, Y184F, S1034C, N1042D, and D1246Y) and Pfcrt (K76T) and in vitro responses to chloroquine (CQ), mefloquine (MQ), lumefantrine (LMF), quinine (QN), monodesethylamodiaquine (MDAQ), and dihydroartemisinin (DHA) in 174 Plasmodium falciparum isolates from Dakar, Senegal. The Pfmdr1 86Y mutation was identified in 14.9% of the samples, and the 184F mutation was identified in 71.8% of the isolates. No 1034C, 1042N, or 1246Y mutations were detected. The Pfmdr1 86Y mutation was significantly associated with increased susceptibility to MDAQ (P = 0.0023), LMF (P = 0.0001), DHA (P = 0.0387), and MQ (P = 0.00002). The N86Y mutation was not associated with CQ (P = 0.214) or QN (P = 0.287) responses. The Pfmdr1 184F mutation was not associated with various susceptibility responses to the 6 antimalarial drugs (P = 0.168 for CQ, 0.778 for MDAQ, 0.324 for LMF, 0.961 for DHA, 0.084 for QN, and 0.298 for MQ). The Pfmdr1 86Y-Y184 haplotype was significantly associated with increased susceptibility to MDAQ (P = 0.0136), LMF (P = 0.0019), and MQ (P = 0.0001). The additional Pfmdr1 86Y mutation increased significantly the in vitro susceptibility to MDAQ (P < 0.0001), LMF (P < 0.0001), MQ (P < 0.0001), and QN (P = 0.0026) in wild-type Pfcrt K76 parasites. The additional Pfmdr1 86Y mutation significantly increased the in vitro susceptibility to CQ (P = 0.0179) in Pfcrt 76T CQ-resistant parasites. PMID:25199781

  18. 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. PMID:27010713

  19. 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.

  20. Magnetohydrodynamical Analogue of a Black Hole

    NASA Astrophysics Data System (ADS)

    Zamorano, Nelson; Asenjo, Felipe

    2014-03-01

    We study the conditions that a plasma fluid and its container should meet to generate a magneto-acoustic horizon. This effect becomes an alternative to the analogue black hole found in a transonic fluid flow setting. In this context we use the magnetohydrodynamic formalism (MHD) to analyze the evolution of an irrotational plasma fluid interacting with an external constant magnetic field. Under certain plausible approximations, the dynamic of the field perturbations is described by a scalar field potential that follows a second order differential equation. As we prove here, this equation corresponds to the wave equation associated to a scalar field in a curved space-time. This horizon emerges when the local speed of the medium grows larger than the sound velocity. The magnetic field generates an effective pressure which contributes to the magneto-acoustic speed. We compare these results with the known physics of analogue black holes. We will also refer to our ongoing experiment that, in its first stage, attempts to reproduce the wave horizons found in an open channel with an obstacle: PRL 106, 021302 (2011).

  1. Stability studies of a somatostatin analogue in biodegradable implants.

    PubMed

    Rothen-Weinhold, A; Besseghir, K; Vuaridel, E; Sublet, E; Oudry, N; Gurny, R

    1999-02-15

    In recent years, peptides and proteins have received much attention as drug candidates. For many polypeptides, particularly hormones, it is desirable to release the drug continuously at a controlled rate over a period of weeks or even months, and thus a controlled release system is needed. Polylactic acid (PLA) is a biocompatible and biodegradable material with wide utility for many applications, including the design of controlled release systems for pharmaceutical agents. Pharmaceutical development of these delivery systems presents new problems in the area of stability assessment, especially for peptide drugs. In this study, we aimed to investigate the influence of different steps, during the manufacturing of an implant, on peptide stability in the polymeric matrix. Polylactic acid implants containing vapreotide, a somatostatin analogue, were prepared by extrusion. The effects of time, extrusion and temperature on the peptide stability were studied. The influence of various gamma sterilization doses, as well as the conditions under which the implants were irradiated, were also investigated. Peptide stability in the polymeric matrix was evaluated at various temperatures and at various time intervals up to 9 months. PMID:10205641

  2. The role of axisymmetric flow configuration in the estimation of the analogue surface gravity and related Hawking like temperature

    NASA Astrophysics Data System (ADS)

    Bilić, Neven; Choudhary, Arpita; Das, Tapas K.; Nag, Sankhasubhra

    2014-02-01

    We investigate the salient features of the acoustic geometry corresponding to the axially symmetric accretion of dissipationless inhomogeneous fluid onto a non-rotating astrophysical black hole under the influence of a generalized pseudo-Schwarzschild gravitational potential. For a few chosen flow configurations, we determine the location of the acoustic horizon and calculate analytically the corresponding analogue surface gravity κ and the associated analogue Hawking temperature TAH. We study the dependence of κ on various boundary conditions and geometry governing the dynamic and thermodynamic properties of the background flow.

  3. Rapamycin and Chloroquine: The In Vitro and In Vivo Effects of Autophagy-Modifying Drugs Show Promising Results in Valosin Containing Protein Multisystem Proteinopathy

    PubMed Central

    Nalbandian, Angèle; Llewellyn, Katrina J.; Nguyen, Christopher; Yazdi, Puya G.; Kimonis, Virginia E.

    2015-01-01

    Mutations in the valosin containing protein (VCP) gene cause hereditary Inclusion body myopathy (hIBM) associated with Paget disease of bone (PDB), frontotemporal dementia (FTD), more recently termed multisystem proteinopathy (MSP). Affected individuals exhibit scapular winging and die from progressive muscle weakness, and cardiac and respiratory failure, typically in their 40s to 50s. Histologically, patients show the presence of rimmed vacuoles and TAR DNA-binding protein 43 (TDP-43)-positive large ubiquitinated inclusion bodies in the muscles. We have generated a VCPR155H/+ mouse model which recapitulates the disease phenotype and impaired autophagy typically observed in patients with VCP disease. Autophagy-modifying agents, such as rapamycin and chloroquine, at pharmacological doses have previously shown to alter the autophagic flux. Herein, we report results of administration of rapamycin, a specific inhibitor of the mechanistic target of rapamycin (mTOR) signaling pathway, and chloroquine, a lysosomal inhibitor which reverses autophagy by accumulating in lysosomes, responsible for blocking autophagy in 20-month old VCPR155H/+ mice. Rapamycin-treated mice demonstrated significant improvement in muscle performance, quadriceps histological analysis, and rescue of ubiquitin, and TDP-43 pathology and defective autophagy as indicated by decreased protein expression levels of LC3-I/II, p62/SQSTM1, optineurin and inhibiting the mTORC1 substrates. Conversely, chloroquine-treated VCPR155H/+ mice revealed progressive muscle weakness, cytoplasmic accumulation of TDP-43, ubiquitin-positive inclusion bodies and increased LC3-I/II, p62/SQSTM1, and optineurin expression levels. Our in vitro patient myoblasts studies treated with rapamycin demonstrated an overall improvement in the autophagy markers. Targeting the mTOR pathway ameliorates an increasing list of disorders, and these findings suggest that VCP disease and related neurodegenerative multisystem proteinopathies can

  4. Immunostimulatory CpG oligodeoxynucleotides stimulate expression of IL-1beta and interferon-like cytokines in rainbow trout macrophages via a chloroquine-sensitive mechanism.

    PubMed

    Jørgensen, J B; Zou, J; Johansen, A; Secombes, C J

    2001-11-01

    Synthetic oligodeoxynucleotides (ODNs) containing unmethylated CpG motifs are known to stimulate immune responses and are potent adjuvants in higher vertebrates, but so far the effects in fish are poorly described. We here report that CpG ODNs induce IL-1beta expression and production of interferon-like cytokines in rainbow trout head-kidney macrophages, whereas ODNs with an inverted motif (GpC) have a much less stimulatory effect. We further demonstrate that endosomal maturation is essential for CpG signalling, as chloroquine, a compound known to block endosomal acidification, inhibits cytokine expression in the macrophages. PMID:11759038

  5. Modern Climate Analogues of Late-Quaternary Paleoclimates for the Western United States.

    NASA Astrophysics Data System (ADS)

    Mock, Cary Jeffrey

    This study examined spatial variations of modern and late-Quaternary climates for the western United States. Synoptic climatological analyses of the modern record identified the predominate climatic controls that normally produce the principal modes of spatial climatic variability. They also provided a modern standard to assess past climates. Maps of the month-to-month changes in 500 mb heights, sea-level pressure, temperature, and precipitation illustrated how different climatic controls govern the annual cycle of climatic response. The patterns of precipitation ratios, precipitation bar graphs, and the seasonal precipitation maximum provided additional insight into how different climatic controls influence spatial climatic variations. Synoptic-scale patterns from general circulation model (GCM) simulations or from analyses of climatic indices were used as the basis for finding modern climate analogues for 18 ka and 9 ka. Composite anomaly maps of atmospheric circulation, precipitation, and temperature were compared with effective moisture maps compiled from proxy data to infer how the patterns, which were evident from the proxy data, were generated. The analyses of the modern synoptic climatology indicate that smaller-scale climatic controls must be considered along with larger-scale ones in order to explain patterns of spatial climate heterogeneity. Climatic extremes indicate that changes in the spatial patterns of precipitation seasonality are the exception rather than the rule, reflecting the strong influence of smaller-scale controls. Modern climate analogues for both 18 ka and 9 ka clearly depict the dry Northwest/wet Southwest contrast that is suggested by GCM simulations and paleoclimatic evidence. 18 ka analogues also show the importance of smaller-scale climatic controls in explaining spatial climatic variation in the Northwest and northern Great Plains. 9 ka analogues provide climatological explanations for patterns of spatial heterogeneity over several

  6. Solution Processed PEDOT Analogues in Electrochemical Supercapacitors.

    PubMed

    Österholm, Anna M; Ponder, James F; Kerszulis, Justin A; Reynolds, John R

    2016-06-01

    We have designed fully soluble ProDOTx-EDOTy copolymers that are electrochemically equivalent to electropolymerized PEDOT without using any surfactants or dispersants. We show that these copolymers can be incorporated as active layers in solution processed thin film supercapacitors to demonstrate capacitance, stability, and voltage similar to the values of those that use electrodeposited PEDOT as the active material with the added advantage of the possibility for large scale, high-throughput processing. These Type I supercapacitors provide exceptional cell voltages (up to 1.6 V), highly symmetrical charge/discharge behavior, promising long-term stability exceeding 50 000 charge/discharge cycles, as well as energy (4-18 Wh/kg) and power densities (0.8-3.3 kW/kg) that are comparable to those of electrochemically synthesized analogues. PMID:27195798

  7. Jupiter analogues and planets of active stars

    NASA Astrophysics Data System (ADS)

    Kürster, M.; Zechmeister, M.; Endl, M.; Lo Curto, G.; Hartman, H.; Nilsson, H.; Henning, T.; Hatzes, A. P.; Cochran, W. D.

    2013-04-01

    Combined results are now available from a 15 year long search for Jupiter analogues around solar-type stars using the ESO CAT + CES, ESO 3.6 m + CES, and ESO 3.6 m + HARPS instruments. They comprise planet (co-)discoveries (ι Hor and HR 506) and confirmations (three planets in HR 3259) as well as non-confirmations of planets (HR 4523 and ɛ Eri) announced elsewhere. A long-term trend in ɛ Ind found by our survey is probably attributable to a Jovian planet with a period >30 yr, but we cannot fully exclude stellar activity effects as the cause. A 3.8 year periodic variation in HR 8323 can be attributed to stellar activity.

  8. 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.

  9. 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.

  10. 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.

  11. Safety, Immunogenicity, and Protective Efficacy of Intradermal Immunization with Aseptic, Purified, Cryopreserved Plasmodium falciparum Sporozoites in Volunteers under Chloroquine Prophylaxis: A Randomized Controlled Trial

    PubMed Central

    Bastiaens, Guido J. H.; van Meer, Maurits P. A.; Scholzen, Anja; Obiero, Joshua M.; Vatanshenassan, Mansoureh; van Grinsven, Tim; Kim Lee Sim, B.; Billingsley, Peter F.; James, Eric R.; Gunasekera, Anusha; Bijker, Else M.; van Gemert, Geert-Jan; van de Vegte-Bolmer, Marga; Graumans, Wouter; Hermsen, Cornelus C.; de Mast, Quirijn; van der Ven, André J. A. M.; Hoffman, Stephen L.; Sauerwein, Robert W.

    2016-01-01

    Immunization of volunteers under chloroquine prophylaxis by bites of Plasmodium falciparum sporozoite (PfSPZ)–infected mosquitoes induces > 90% protection against controlled human malaria infection (CHMI). We studied intradermal immunization with cryopreserved, infectious PfSPZ in volunteers taking chloroquine (PfSPZ chemoprophylaxis vaccine [CVac]). Vaccine groups 1 and 3 received 3× monthly immunizations with 7.5 × 104 PfSPZ. Control groups 2 and 4 received normal saline. Groups 1 and 2 underwent CHMI (#1) by mosquito bite 60 days after the third immunization. Groups 3 and 4 were boosted 168 days after the third immunization and underwent CHMI (#2) 137 days later. Vaccinees (11/20, 55%) and controls (6/10, 60%) had the same percentage of mild to moderate solicited adverse events. After CHMI #1, 8/10 vaccinees (group 1) and 5/5 controls (group 2) became parasitemic by microscopy; the two negatives were positive by quantitative real-time polymerase chain reaction (qPCR). After CHMI #2, all vaccinees in group 3 and controls in group 4 were parasitemic by qPCR. Vaccinees showed weak antibody and no detectable cellular immune responses. Intradermal immunization with up to 3 × 105 PfSPZ-CVac was safe, but induced only minimal immune responses and no sterile protection against Pf CHMI. PMID:26711509

  12. Monitoring of malaria parasite resistance to chloroquine and sulphadoxine-pyrimethamine in the Solomon Islands by DNA microarray technology

    PubMed Central

    2010-01-01

    Background Little information is available on resistance to anti-malarial drugs in the Solomon Islands (SI). The analysis of single nucleotide polymorphisms (SNPs) in drug resistance associated parasite genes is a potential alternative to classical time- and resource-consuming in vivo studies to monitor drug resistance. Mutations in pfmdr1 and pfcrt were shown to indicate chloroquine (CQ) resistance, mutations in pfdhfr and pfdhps indicate sulphadoxine-pyrimethamine (SP) resistance, and mutations in pfATPase6 indicate resistance to artemisinin derivatives. Methods The relationship between the rate of treatment failure among 25 symptomatic Plasmodium falciparum-infected patients presenting at the clinic and the pattern of resistance-associated SNPs in P. falciparum infecting 76 asymptomatic individuals from the surrounding population was investigated. The study was conducted in the SI in 2004. Patients presenting at a local clinic with microscopically confirmed P. falciparum malaria were recruited and treated with CQ+SP. Rates of treatment failure were estimated during a 28-day follow-up period. In parallel, a DNA microarray technology was used to analyse mutations associated with CQ, SP, and artemisinin derivative resistance among samples from the asymptomatic community. Mutation and haplotype frequencies were determined, as well as the multiplicity of infection. Results The in vivo study showed an efficacy of 88% for CQ+SP to treat P. falciparum infections. DNA microarray analyses indicated a low diversity in the parasite population with one major haplotype present in 98.7% of the cases. It was composed of fixed mutations at position 86 in pfmdr1, positions 72, 75, 76, 220, 326 and 356 in pfcrt, and positions 59 and 108 in pfdhfr. No mutation was observed in pfdhps or in pfATPase6. The mean multiplicity of infection was 1.39. Conclusion This work provides the first insight into drug resistance markers of P. falciparum in the SI. The obtained results indicated the

  13. In Vivo Efficacy of Artemether-Lumefantrine and Chloroquine against Plasmodium vivax: A Randomized Open Label Trial in Central Ethiopia

    PubMed Central

    Reithinger, Richard; Tekleyohannes, Samuel Girma; Takele Teshi; Birhanu, Sintayehu Gebresillasie; Demeke, Leykun; Hoos, David; Melaku, Zenebe; Kassa, Moges; Jima, Daddi; Malone, Joseph L.; Nettey, Henry; Green, Michael; Poe, Amanda; Akinyi, Sheila; Udhayakumar, Venkatachalam; Kachur, S. Patrick; Filler, Scott

    2013-01-01

    Background In vivo efficacy assessments of antimalarials are essential for ensuring effective case management. In Ethiopia, chloroquine (CQ) without primaquine is the first-line treatment for Plasmodium vivax in malarious areas, but artemether-lumefantrine (AL) is also commonly used. Methods and Findings In 2009, we conducted a 42-day efficacy study of AL or CQ for P. vivax in Oromia Regional State, Ethiopia. Individuals with P. vivax monoinfection were enrolled. Primary endpoint was day 28 cure rate. In patients with recurrent parasitemia, drug level and genotyping using microsatellite markers were assessed. Using survival analysis, uncorrected patient cure rates at day 28 were 75.7% (95% confidence interval (CI) 66.8–82.5) for AL and 90.8% (95% CI 83.6–94.9) for CQ. During the 42 days of follow-up, 41.6% (47/113) of patients in the AL arm and 31.8% (34/107) in the CQ arm presented with recurrent P. vivax infection, with the median number of days to recurrence of 28 compared to 35 days in the AL and CQ arm, respectively. Using microsatellite markers to reclassify recurrent parasitemias with a different genotype as non-treatment failures, day 28 cure rates were genotype adjusted to 91.1% (95% CI 84.1–95.1) for AL and to 97.2% (91.6–99.1) for CQ. Three patients (2.8%) with recurrent parasitemia by day 28 in the CQ arm were noted to have drug levels above 100 ng/ml. Conclusions In the short term, both AL and CQ were effective and well-tolerated for P. vivax malaria, but high rates of recurrent parasitemia were noted with both drugs. CQ provided longer post-treatment prophylaxis than AL, resulting in delayed recurrence of parasitemia. Although the current policy of species-specific treatment can be maintained for Ethiopia, the co-administration of primaquine for treatment of P. vivax malaria needs to be urgently considered to prevent relapse infections. Trial Registration ClinicalTrials.gov NCT01052584 PMID:23717423

  14. Chloroquine potentiates the anti-cancer effect of lidamycin on non-small cell lung cancer cells in vitro

    PubMed Central

    Liu, Fang; Shang, Yue; Chen, Shu-zhen

    2014-01-01

    Aim: To assess the synergistic actions of lidamycin (LDM) and chloroquine (CQ), a lysosomal enzyme inhibitor, in human non-small cell lung cancer (NSCLC) cells, and to elucidate the potential mechanisms. Methods: Human NSCLC cell lines A549 and H460 were treated with CQ and/or LDM. Cell proliferation was analyzed using MTT assay, and apoptosis was quantified using flow cytometry. Western blotting was used to detect the protein levels of caspase 3, PARP, Bcl-2, Bax, p53, LC3-I and LC3-II. A H460 cell xenograft model in BALB/c nude mice was used to evaluate the anticancer efficacy of CQ and LDM in vivo. Results: Both LDM and CQ concentration-dependently suppressed the proliferation of A549 and H460 cells in vitro (the IC50 values of LDM were 1.70±0.75 and 0.043±0.026 nmol/L, respectively, while the IC50 values of CQ were 71.3±6.1 and 55.6±12.5 μmol/L, respectively). CQ sensitized both NSCLC cell lines to LDM, and the majority of the coefficients of drug interaction (CDIs) for combination-doses were less than 1. The ratio of apoptosis of H460 cells induced by a combined treatment of CQ and LDM (77.0%±5.2%) was significantly higher than those caused by CQ (23.1%±4.2%) or by LDM (65.1%±4.1%) alone. Furthermore, the combined treatment markedly increased the cleaved PARP and cleaved caspase 3 in H460 cells, which were partly reversed by pretreatment with the caspase inhibitor zVAD.fmk. zVAD.fmk also partially reversed the inhibitory effect of the combination treatment on the proliferation of H460 cells. The combination therapy group had a notable increase in expression of Bax and a very slight decrease in expression of Bcl-2 and p53 protein. LDM alone scarcely affected the level of LC3-II in H460 cells, but slightly reduced CQ-induced LC3-II expression. 3-MA, an autophagy inhibitor also sensitized H460 cells to LDM. In nude mice bearing H460 cell xenograft, administration of LDM (25 μg/kg, iv) and CQ (60 mg/kg, ip) suppressed tumor growth by 57.14% and 73

  15. Anti-malarial Drugs Primaquine and Chloroquine Have Different Sensitization Effects with Anti-mitotic Drugs in Resistant Cancer Cells.

    PubMed

    Choi, Ae-Ran; Kim, Ju-Hwa; Woo, Yeon Hwa; Kim, Hyung Sik; Yoon, Sungpil

    2016-04-01

    The purpose of this study was to identify conditions that would increase the sensitivity of drug-resistant cancer cells. Previously, two anti-malarial drugs, chloroquine (CHL) and primaquine (PRI), showed different sensitization effects for vinblastine (VIB)-resistant cancer cells. Herein, we tested co-treatment of cells with CHL or PRI and other microtubule-targeting cancer drugs, namely, vinorelbine (VIO), paclitaxel (PAC), docetaxel (DOC), vincristine (VIC), or halaven (HAL). We found that PRI sensitized P-glycoprotein (P-gp)-overexpressing drug-resistant KBV20C cells to all six anti-mitotic drugs to a similar extent. CHL had a similar sensitization effect only for co-treatment with PAC, DOC, VIC, and HAL, while the sensitization effect was less marked for co-treatment with VIB or VIO. FACS analysis and western blot analysis revealed that G2arrest and apoptosis showed only a slight increase on co-treatment with VIB or VIO and CHL. We also found that phospho-histone H3 and pRb were markedly increased only by PRI-VIB co-treatment, but not by CHL-VIB co-treatment. This suggests that reduction in the expression of these proteins correlates with decreased G2arrest in CHL-VIB co-treatment. We further compared the effect of another anti-malarial drug, mefloquine (MEF), in combination with the six anti-mitotic drugs. We found that MEF and PRI had similar sensitization effects in co-treatment with these anti-mitotic drugs. PRI and MEF had generally similar sensitization effects in co-treatment with anti-mitotic drugs, suggesting that they do not have any preferred anti-mitotic drug partner in co-treatment. This indicates that only CHL shows specificity in co-treatment with anti-mitotic drugs in resistant cancer cells. Our results may contribute to the choice of anti-mitotic drugs to be used in co-treatment of resistant cancer cells with the anti-malarial drugs, CHL, PRI, and MEF. PMID:27069141

  16. DNA information: from digital code to analogue structure.

    PubMed

    Travers, A A; Muskhelishvili, G; Thompson, J M T

    2012-06-28

    The digital linear coding carried by the base pairs in the DNA double helix is now known to have an important component that acts by altering, along its length, the natural shape and stiffness of the molecule. In this way, one region of DNA is structurally distinguished from another, constituting an additional form of encoded information manifest in three-dimensional space. These shape and stiffness variations help in guiding and facilitating the DNA during its three-dimensional spatial interactions. Such interactions with itself allow communication between genes and enhanced wrapping and histone-octamer binding within the nucleosome core particle. Meanwhile, interactions with proteins can have a reduced entropic binding penalty owing to advantageous sequence-dependent bending anisotropy. Sequence periodicity within the DNA, giving a corresponding structural periodicity of shape and stiffness, also influences the supercoiling of the molecule, which, in turn, plays an important facilitating role. In effect, the super-helical density acts as an analogue regulatory mode in contrast to the more commonly acknowledged purely digital mode. Many of these ideas are still poorly understood, and represent a fundamental and outstanding biological question. This review gives an overview of very recent developments, and hopefully identifies promising future lines of enquiry. PMID:22615471

  17. Bead-Based Microfluidic Sediment Analogues: Fabrication and Colloid Transport.

    PubMed

    Guo, Yang; Huang, Jingwei; Xiao, Feng; Yin, Xiaolong; Chun, Jaehun; Um, Wooyong; Neeves, Keith B; Wu, Ning

    2016-09-13

    Mobile colloids can act as carriers for low-solubility contaminants in the environment. However, the dominant mechanism for this colloid-facilitated transport of chemicals is unclear. Therefore, we developed a bead-based microfluidic platform of sediment analogues and measured both single and population transport of model colloids. The porous medium is assembled through a bead-by-bead injection method. This approach has the versatility to build both electrostatically homogeneous and heterogeneous media at the pore scale. A T-junction at the exit also allowed for encapsulation and enumeration of colloids effluent at single particle resolution to give population dynamics. Tortuosity calculated from pore-scale trajectory analysis and its comparison with lattice Boltzmann simulations revealed that transport of colloids was influenced by the size exclusion effect. The porous media packed by positively and negatively charged beads into two layers showed distinctive colloidal particle retention and significant remobilization and re-adsorption of particles during water flushing. We demonstrated the potential of our method to fabricate porous media with surface heterogeneities at the pore scale. With both single and population dynamics measurement, our platform has the potential to connect pore-scale and macroscale colloid transport on a lab scale and to quantify the impact of grain surface heterogeneities that are natural in the subsurface environment. PMID:27548505

  18. Synthesis and biological evaluations of a series of thaxtomin analogues.

    PubMed

    Zhang, Hongbo; Wang, Qingpeng; Ning, Xin; Hang, Hang; Ma, Jing; Yang, Xiande; Lu, Xiaolin; Zhang, Jiabao; Li, Yonghong; Niu, Congwei; Song, Haoran; Wang, Xin; Wang, Peng George

    2015-04-15

    Thaxtomins are a unique family of phytotoxins with unique 4-nitroindole and diketopiperazine fragments possessing potential herbicidal activities. This work presents the total synthesis of natural product thaxtomin C and its analogues. The extensive structure-activity relationship study screens four effective compounds, including thaxtomin A and thaxtomin C. It is indicated that 4-nitro indole fragment is essential for phytotoxicity, while benzyl and m-hydroxybenzyl substituents on the diketopiperazine ring are favorable for the efficacy. The N-methylations on indole and diketopiperazine show weak influence on the herbicidal activities. The four selected compounds show effective herbicidal activities against Brassica campestris, Amaranthus retroflexus, and Abutilon theophrasti, which are comparable or better than dichlobenil, even at a dosage of 187.5 g ha(-1). Moreover, these four compounds show good crop-selective properties to different crops and exhibit moderate protoporphyrinogen oxidase (PPO) enzyme inhibition. The antifungal results indicate that thaxtomin C displays inhibition to a wide range of fungi. PMID:25804187

  19. Effect of ATP analogues on the actin-myosin interface.

    PubMed

    Van Dijk, J; Fernandez, C; Chaussepied, P

    1998-06-01

    The interaction between skeletal myosin subfragment 1 (S1) and filamentous actin was examined at various intermediate states of the actomyosin ATPase cycle by chemical cross-linking experiments. Reaction of the actin-S1 complex with 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide and N-hydroxysuccinimide generated products with molecular masses of 165 and 175 kDa, in which S1 loops of residues 626-647 and 567-578 were cross-linked independently to the N-terminal segment of residues 1-12 of one actin monomer, and of 265 kDa, in which the two loops were bound to the N termini of two adjacent monomers. In strong-binding complexes, i.e., without nucleotide or with ADP, S1 was sequentially cross-linked to one and then to two actin monomers. In the weak-binding complexes, two types of cross-linking pattern were observed. First, during steady-state hydrolysis of ATP or ATPgammaS at 20 degreesC, the cross-linking reaction gave rise to a small amount of unknown 200 kDa product. Second, in the presence of AMPPNP, ADP.BeFx, ADP.AlF4-, or ADP.VO43- or with S1 internally cross-linked by N,N'-p-phenylenedimaleimide, only the 265 kDa product was obtained. The presence of 200 mM salt inhibited cross-linking reactions in both weak- and strong-binding states, while it dissociated only weak-binding complexes. These results indicate that, in the weak-binding state populated with the ADP.Pi analogues, skeletal S1 interacts predominantly and with an apparent equal affinity with the N termini of two adjacent actin monomers, while these ionic contacts are much less significant in stabilizing the rigor actin-S1 complexes. They also suggest that the electrostatic actin-S1 interface is not influenced by the type of ADP.Pi analogue bound to the active site.

  20. 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

    2016-10-01

    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. PMID:27267000

  1. 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

    2016-10-01

    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.

  2. 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.

  3. Synthetic and Organocatalytic Studies of Quinidine Analogues with Ring-Size Modifications in the Quinuclidine Moiety.

    PubMed

    Breman, Arjen C; van der Heijden, Gydo; van Maarseveen, Jan H; Ingemann, Steen; Hiemstra, Henk

    2016-09-26

    Six highly enantiopure analogues of [2.2.2] were synthesized with five- or seven-membered rings in the (original) quinuclidine skeleton. Five of these compounds were prepared through epoxide opening by a secondary cyclic amine, providing the nor- and homoquinuclidine moieties through five- and six-membered ring formation. This method failed in the case of seven-membered ring formation, so for that particular ring size a different synthetic route starting from 3-quinuclidone was applied. The six novel analogues were examined as organocatalysts in four asymmetric conjugate addition reactions and the results compared with those of known cinchona alkaloid catalysts. This study shows that modification of the quinuclidine ring can have a substantial influence on catalyst activity and enantioselectivity. To acquire more insight into the characteristics of the new catalysts, the pKaH values were determined by means of fluorescence spectroscopy. Furthermore, relative reaction rates of conjugate thiol additions reactions catalyzed by these quinidine analogues were measured through polarimetry. PMID:27531315

  4. Protective effects of TRH and its analogues in chemical and genetic models of seizures.

    PubMed

    Przewłocka, B; Labuz, D; Mika, J; Lipkowski, A; van Luijtelaar, G; Coenen, A; Lasoń, W

    1997-01-01

    TRH shows strong influence on neuronal excitability and may participate in the regulation of seizures. We investigated the effect of TRH and its stable analogues on seizures induced by intravenous (i.v.) infusion of pentetrazole in rats. The data showed that i.v. administration of TRH (10 and 20 mg/kg), RGH-2202 (0.1 mg/kg) and Z-p-Glu-His-Pro-NH2 (10 mg/kg) increased threshold for pentetrazole-induced clonic seizures, but did not affect the tonic ones. Another stable analogue of TRH, 1p-Glu-Tyr-Pro-NH2 (0.1-10 mg/kg), had no effect on pentetrazole-induced seizures. In further study, effects of TRH and RGH-2202 were examined in WAG/Rij rats, a genetic model of absence epilepsy. TRH (25 and 50 micrograms i.c.v.) decreased dose-dependently the number and mean duration of spike-wave discharges in cortical EEG of WAG/Rij rats at 90 and 120 min after the peptide administration. On the other hand, RGH-2202 (1 microgram i.c.v.) significantly decreased only the number of spike-wave discharges at 60 min post-injection. These results confirm that TRH and some of its analogues have moderate antiepileptic activity. PMID:9566039

  5. 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

  6. 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,

  7. Insulin, insulin analogues and diabetic retinopathy.

    PubMed

    Chantelau, Ernst; Kimmerle, Renate; Meyer-Schwickerath, Rolf

    2008-02-01

    Insulin is absolutely vital for living beings. It is not only involved in metabolism, but also in the regulation of growth factors, e.g. IGF-1. In this review we address the role insulin has in the natural evolution of diabetic retinopathy. On the one hand, chronic deficiency of insulin and IGF-1 at the retina is thought to cause capillary degeneration, with subsequent ischaemia. On the other hand, acute abundance of (exogenously administered) insulin and IGF-1 enhances ischaemia-induced VEGF expression. A critical ratio of tissue VEGF-susceptibility: VEGF-availability triggers vascular proliferation (i.e. of micro-aneurysms and/or abnormal vessels). The patent-protected insulin analogues Lispro, Glulisine, Aspart, Glargine and Detemir are artificial insulin derivatives with altered biological responses compared to natural insulin (e.g. divergent insulin and /or IGF-1 receptor-binding characteristics, signalling patterns, and mitogenicity). Their safety profiles concerning diabetic retinopathy remain to be established by randomised controlled trials. Anecdotal reports and circumstantial evidence suggest that Lispro and Glargine might worsen diabetic retinopathy.

  8. Actions of Thyroid Hormone Analogues on Chemokines.

    PubMed

    Davis, Paul J; Glinsky, Gennadi V; Lin, Hung-Yun; Mousa, Shaker A

    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

  9. Inhibition of monoamine oxidase by benzoxathiolone analogues.

    PubMed

    Mostert, Samantha; Petzer, Anél; Petzer, Jacobus P

    2016-02-15

    Inhibitors of the monoamine oxidase (MAO) enzymes are considered useful therapeutic agents, and are used in the clinic for the treatment of depressive illness and Parkinson's disease. In addition, MAO inhibitors are also under investigation for the treatment of certain cardiovascular pathologies and as possible aids to smoking cessation. In an attempt to discover novel classes of compounds that inhibit the MAOs, the current study examines the human MAO inhibitory properties of a small series of 2H-1,3-benzoxathiol-2-one analogues. The results show that the benzoxathiolones are potent MAO-B inhibitors with IC50 values ranging from 0.003 to 0.051 μM. Although the benzoxathiolones are selective for the MAO-B isoform, two compounds display good MAO-A inhibition with IC50 values of 0.189 and 0.424 μM. Dialysis studies show that a selected compound inhibits the MAOs reversibly. It may thus be concluded that the benzoxathiolone class is suitable for the design and development of MAO-B inhibitors, and that in some instances good MAO-A inhibition may also be achieved.

  10. 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

    2015-03-01

    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.

  11. Inhibition of firefly luciferase by alkane analogues.

    PubMed

    Takehara, Kô; Kamaya, Hiroshi; Ueda, Issaku

    2005-01-18

    We reported that anesthetics increased the partial molal volume of firefly luciferase (FFL), while long-chain fatty acids (LCFA) decreased it. The present study measured the actions of dodecanol (neutral), dodecanoic acid (negatively charged), and dodecylamine (positively charged) hydrophobic molecules on FFL. The interaction modes are measured by (1) ATP-induced bioluminescence of FFL and (2) fluorescence of 2-(p-toluidino)naphthalene-6-sulfonate (TNS). TNS fluoresces brightly in hydrophobic media. It competes with the substrate luciferin on the FFL binding. From the Scatchard plot of TNS titration, the maximum binding number of TNS was 0.83, and its binding constant was 8.27 x 10(5) M(-1). Job's plot also showed that the binding number is 0.89. From the TNS titration of FFL, the binding constant was estimated to be 8.8 x 10(5) M(-1). Dodecanoic acid quenched the TNS fluorescence entirely. Dodecanol quenched about 25% of the fluorescence, whereas dodecylamine increased it. By comparing the fluorescence of TNS and bioluminescence of FFL, the binding modes and the inhibition mechanisms of these dodecane analogues are classified in three different modes: competitive (dodecanoic acid), noncompetitive (dodecylamine), and mixed (dodecanol).

  12. Radiolabeled Somatostatin Analogue Therapy Of Gastroenteropancreatic Cancer.

    PubMed

    Bodei, Lisa; Kwekkeboom, Dik J; Kidd, Mark; Modlin, Irvin M; Krenning, Eric P

    2016-05-01

    Peptide receptor radionuclide therapy (PRRT) has been utilized for more than two decades and has been accepted as an effective therapeutic modality in the treatment of inoperable or metastatic gastroenteropancreatic neuroendocrine neoplasms (NENs) or neuroendocrine tumors (NETs). The two most commonly used radiopeptides for PRRT, (90)Y-octreotide and (177)Lu-octreotate, produce disease-control rates of 68%-94%, with progression-free survival rates that compare favorably with chemotherapy, somatostatin analogues, and newer targeted therapies. In addition, biochemical and symptomatic responses are commonly observed. In general, PRRT is well tolerated with only low to moderate toxicity in most individuals. In line with the need to place PRRT in the therapeutic sequence of gastroenteropancreatic NENs, a recently sponsored phase III randomized trial in small intestine NENs treated with (177)Lu-octreotate vs high-dose octreotide long-acting release demonstrated that (177)Lu-octreotate significantly improved progression-free survival. Other strategies that are presently being developed include combinations with targeted therapies or chemotherapy, intra-arterial PRRT, and salvage treatments. Sophisticated molecular tools need to be incorporated into the management strategy to more effectively define therapeutic efficacy and for an early identification of adverse events. The strategy of randomized controlled trials is a key issue to standardize the treatment and establish the position of PRRT in the therapeutic algorithm of NENs. PMID:27067503

  13. 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

  14. 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.

  15. Anomeric selectivity and influenza A virus inhibition study on methoxylated analogues of Pentagalloylglucose.

    PubMed

    Qurat-ul-ain, Shaikh; Wang, Wei; Yang, Meiting; Du, Na; Wan, Shengbiao; Zhang, Lijuan; Jiang, Tao

    2015-01-30

    Anomeric selectivity in galloylation of D-glucose and D-mannose with carboxylic acid was explored under steglich conditions. Base catalyst 4-dimethylaminopyridine favored the formation of alpha-anomers, while adding an acid and carbodiimide favored the formation of beta-anomers. Steric hindrance between α,β-unsaturated acid and C-2 OH stereochemistry (adjacent carbon to anomeric) influenced anomeric selectivity for both D-glucose and D-mannose. The influenza A virus inhibition activities of the synthesized compounds were evaluated in Madin-Darby canine kidney cell line using the cytopathic effect inhibition assay. All the synthetic methoxylated analogues showed more considerable activity against influenza A virus than their corresponding acids, which indicated the sugar core as key functionality for anti-viral activity. The activities of trimethoxy-cinnamic acid Pentagalloylglucose analogues, 3α, 3β, 4α, and 4β (IC50, 109.1 μM, 134.4 μM, 119.5 μM, 111.1 μM, respectively) were better than those of trimethoxy-benzoic acid Pentagalloylglucose analogues, 1-αβ and 2α, 2β (IC50, 209.8 μM, 132.9 μM, 161.2 μM, respectively), which suggested that the double bond in cinnamic acid Pentagalloylglucose analogues makes the major contribution for influenza A virus inhibitory activity. Notably, several anomeric mixtures showed better activities than pure alpha or beta anomer and were almost two times more effective than Ribavirin, a clinically used anti-viral drug. PMID:25498015

  16. Chloroquine Phosphate Oral

    MedlinePlus

    ... erythematosus, scleroderma, pemphigus, lichen planus, polymyositis, sarcoidosis, and porphyria cutanea tarda. Talk to your doctor about the ... liver disease, G-6-PD deficiency, hearing problems, porphyria or other blood disorders, psoriasis, vision changes, weakness ...

  17. 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.

  18. 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. PMID:26277415

  19. Efficacy of oral and intravenous artesunate in male Tanzanian adults with Plasmodium falciparum malaria and in vitro susceptibility to artemisinin, chloroquine, and mefloquine.

    PubMed

    Alin, M H; Kihamia, C M; Bjorkman, A; Bwijo, B A; Premji, Z; Mtey, G J; Ashton, M

    1995-12-01

    The clinical efficacy of oral and intravenous (iv) artesunate was compared in an open randomized trial in 50 male adult patients with uncomplicated Plasmodium falciparum malaria in Kibaha, Tanzania. Oral artesunate treatment was started with 2 x 50 mg initially followed by 50 mg 12 hr later and then 50 mg twice a day for four days (total dose = 550 mg or 9.6 mg/kg). Intravenous artesunate administration began with 2 x 0.8 mg/kg initially followed by 0.8 mg/kg 12 hr later and then 0.8 mg/kg twice a day for four days (total dose = 8.8 mg/kg). The mean +/- SD parasite clearance times (PCTs) were nearly identical at 23.4 +/- 5.9 hr and 24.2 +/- 7.2 hr after oral and iv administration, respectively. Mean +/- SD fever subsidence times (FSTs) were also similar at 18.7 +/- 8.3 hr and 21.0 +/- 4.8 hr, respectively. All patients remained negative for P. falciparum for at least 14 days. Recrudescence/reinfection occurred between days 21 and 28 in five of 25 patients (20%) after oral treatment and in four of 25 patients (16%) after iv treatment. The mean erythrocyte count and hemoglobin concentration were slightly reduced after iv treatment but remained in the normal range. Otherwise, there was no change in blood biochemistry, hematology, and electrocardiograms monitored prior to and during the last dose. It is concluded that treatment with oral and iv artesunate was equally efficacious and well tolerated. A 24-hr in vitro susceptibility test of P. falciparum to artemisinin, chloroquine, and mefloquine was performed in samples from all patients. The three compounds exhibited 100% inhibition with the exception of three isolates, which showed chloroquine resistance. Parameter estimates of a sigmoid Emax model (drug concentration at which 50% of the growth inhibition occurs [EC50]), the sigmoidicity factor s and EC95 fitted to the growth inhibition data differed between compounds and isolates, indicating different sensitivity of P. falciparum isolates. There was no correlation

  20. 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?

  1. Cell-Cycle Analyses Using Thymidine Analogues in Fission Yeast

    PubMed Central

    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. PMID:24551125

  2. 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? PMID:27262103

  3. Effects of Prostaglandin Analogues on Aqueous Humor Outflow Pathways

    PubMed Central

    Winkler, Nelson S.

    2014-01-01

    Abstract Elevated intraocular pressure (IOP) is the most prevalent risk factor for glaucoma. All treatments, whether surgical or pharmaceutical, are aimed at lowering IOP. Prostaglandin analogues are a first line therapy for glaucoma due to their ability to reduce IOP, once-daily dosing, efficacy, and minimal side-effect profile. Whereas prostaglandin analogues have been known to alter aqueous humor outflow through the unconventional (uveoscleral) pathway, more recent evidence suggests their action also occurs through the conventional (trabecular) pathway. Understanding how prostaglandin analogues successfully lower IOP is important, as this information may lead to the discovery of new molecular targets for future therapeutic intervention. This review explores the current understanding of prostaglandin analogue biology as it pertains to IOP reduction and improved aqueous humor outflow facility. PMID:24359106

  4. Analogues for Wild2: Carbonaceous Chondrites Shot into Aerogel

    NASA Astrophysics Data System (ADS)

    Hicks, L. J.; Bridges, J. C.; MacArthur, J. L.; Wickham-Eade, J. E.; Price, M. C.; Burchell, M. J.; Butterworth, A. L.; Baker, S. H.

    2016-08-01

    Comet Wild2 particles show similarities to carbonaceous chondrites. We compare Wild2 grains to analogue shots of CV3 and CR2 powders in aerogel tracks, using the same techniques, to make accurate comparisons.

  5. Mars Methane Analogue Mission (M3): Analytical Techniques and Operations

    NASA Astrophysics Data System (ADS)

    Cloutis, E.; Vrionis, H.; Qadi, A.; Bell, J. F.; Berard, G.; Boivin, A.; Ellery, A.; Jamroz, W.; Kruzelecky, R.; Mann, P.; Samson, C.; Stromberg, J.; Strong, K.; Tremblay, A.; Whyte, L.; Wing, B.

    2011-03-01

    The Mars Methane Analogue Mission (M3) project is designed to simulate a rover-based search for, and analysis of, methane sources on Mars at a serpentinite open pit mine in Quebec, using a variety of instruments.

  6. 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.

  7. Photochemical synthesis of nucleoside analogues from cyclobutanones: bicyclic and isonucleosides.

    PubMed

    Jaffer, Mileina; Ebead, Abdelaziz; Lee-Ruff, Edward

    2010-05-26

    The preparation of two nucleoside analogues are reported. Both syntheses involve a key photochemical ring-expansion of cyclobutanones to an oxacarbene and its subsequent scavenging by 6-chloropurine. The synthesis of a bicyclic (locked) purine starts from a oxabicycloheptanone with a hydroxymethyl pendant. The preparation of an isonucleoside uses a cyclobutanone with an alpha-substituted 6-chloropurine. Irradiation of the latter produces an isonucleoside and acyclic nucleoside analogues.

  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. Carbacaprazamycins: Chemically Stable Analogues of the Caprazamycin Nucleoside Antibiotics.

    PubMed

    Ichikawa, Satoshi; Yamaguchi, Mayumi; Hsuan, Lee Shang; Kato, Yuta; Matsuda, Akira

    2015-04-10

    Carbacaprazamycins, which are chemically stable analogues of caprazamycins, were designed and synthesized. These analogues were active against drug-resistant bacterial pathogens such as methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci, and their activities were comparable to those of the parent caprazamycins. The effect of treatment with carbacaprazamycin on morphological changes in S. aureus indicated that the mode of action was completely different from those of existing peptidoglycan inhibitors. PMID:27622529

  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. Quinine conjugates and quinine analogues as potential antimalarial agents.

    PubMed

    Jones, Rachel A; Panda, Siva S; Hall, C Dennis

    2015-06-01

    Malaria is a tropical disease, prevalent in Southeast Asia and Africa, resulting in over half a million deaths annually; efforts to develop new antimalarial agents are therefore particularly important. Quinine continues to play a role in the fight against malaria, but quinoline derivatives are more widely used. Drugs based on the quinoline scaffold include chloroquine and primaquine, which are able to act against the blood and liver stages of the parasite's life cycle. The purpose of this review is to discuss reported biologically active compounds based on either the quinine or quinoline scaffold that may have enhanced antimalarial activity. The review emphasises hybrid molecules, and covers advances made in the last five years. The review is divided into three sections: modifications to the quinine scaffold, modifications to aminoquinolines and finally metal-containing antimalarial compounds.

  12. 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

  13. 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

  14. Chemotactic peptide analogues. Synthesis and chemotactic activity of N-formyl-Met-Leu-Phe analogues containing (S)-phenylalaninol derivatives.

    PubMed

    Zecchini, G P; Paradisi, M P; Torrini, I; Spisani, S

    1995-09-01

    The synthesis and the biological activity towards human neutrophils of some N-formyl-Met-Leu-Phe-OMe analogues containing (S)-phenylalaninol (Pheol) or its derivatives in place of the native phenylalanine are reported. While the analogue containing Pheol (4) was found to be devoid of significant biological activity, its esters 3 and 5, although inactive as chemoattractants, are able to strongly stimulate superoxide production and are active with a lower efficacy in the lysozyme release. PMID:7487425

  15. 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.

  16. Effects of pyrimethamine-sulphadoxine, chloroquine plus chlorpheniramine, and amodiaquine plus pyrimethamine-sulphadoxine on gametocytes during and after treatment of acute, uncomplicated malaria in children.

    PubMed

    Sowunmi, A; Adedeji, A A; Gbotosho, G O; Fateye, B A; Happi, T C

    2006-12-01

    The effects of pyrimethamine-sulphadoxine (PS), chloroquine plus chlorpheniramine, a H1 receptor antagonist that reverses chloroquine resistance in Plasmodium falciparum in vitro and in vivo (CQCP), and amodiaquine plus pyrimethamine-sulphadoxine (AQPS) on gametocyte production were evaluated in 157 children with acute, symptomatic, uncomplicated falciparum malaria who were treated with these drugs. PS was significantly less effective than CQCP or AQPS at clearing asexual parasitaemia or other symptoms of malaria. Gametocyte carriage on days 3, 7, and 14 were significantly higher in those treated with PS. The ratio of the density (per microl blood) of peripheral young gametocyte (PYG), that is, < or = stage III to peripheral mature gametocyte (PMG), that is, stage IV and V, an index of continuing generation of gametocytes, rose to 1 by day 7 of treatment in those treated with PS, but remained consistently below 1 in the other treatment groups. PYG-PMG density ratio increased significantly from day 0-14 in those treated with PS and CQCP (chi2 = 76, P = 0.000001 and chi2 = 42.2, P = 0.00001, respectively) but decreased significantly in those treated with AQPS (chi2 = 53.2, P = 0.000001). Both PS-sensitive and -resistant infections generated PYG (18 of 29 vs 13 of 20, chi2 = 0.04, P = 0.93) but PYG was present only in those with resistant response to CQCP. Combination of PS with amodiaquine (AQ), that is, (AQPS) resulted in less production of PYG, but in this setting, PYG was not indicative of response to AQPS. These data indicate that PS enhanced production or release of young gametocytes when used alone, but generated less young gametocytes when used in combination with AQ. PYG may be used as an indicator of response to CQCP but not PS or PS-based combination drugs.

  17. Dietary supplementation of chloroquine with nigella sativa seed and oil extracts in the treatment of malaria induced in mice with plasmodium berghei

    PubMed Central

    Emeka, Promise Madu; Badger-Emeka, Lorina Ineta; Eneh, Chiamaka Maryann; Khan, Tahir Mahmood

    2014-01-01

    Background: The aim of the study was to investigate the effects of dietary combination of Nigella sativa seed and oil extracts with chloroquine (CQ), and how these combinations enhance CQ efficacy in mice infected with Plasmodium berghei and their survival rates. Materials and Methods: Chloroquine sensitive P. berghei, NK65 strain was used for the study. This was passaged intraperitoneally into albino mice with a 0.2ml standard inoculum consisting of 106 parasitized erythrocyte suspension in phosphate buffer solution (PBS). Parasitaemia was ascertained by microscopical examination of blood films under oil immersion at X100 magnification. Results: Nigella sativa seed in feed (NSSF), NSSF + CQ on day 4, produced 86.1% and 86.0% suppression respectively, while Nigella sativa oil extract in feed (NSOF) and in combination with CQ had 86.0% and 99.9% suppression respectively. The degree of suppression with the combination was significantly higher compared to CQ alone (P < 0.001) (36.1%). Complete parasitaemia clearance was obtained on the 20th and 15th day of treatment for NSSF, NSSF + CQ respectively, while that for NSOF and NSOF + CQ was on days 26 and 12 respectively. For CQ parasite clearance was 12 days with treatment. Also, the combinastion of 10 mg/kg Nigella sativa oil treatment injected intraperitoneally with oral CQ produced very significant parasite suppression (P < 0.0001) (93%). Survival rate in NSSF and NSOF and in combination with CQ groups was 100 and 60.0% for CQ alone. Conclusions: This study shows that the use of Nigella sativa seed and oil extract as dietary supplements in combination with CQ has a potential in enhancing the efficacy of CQ and could be of benefit in management of malaria. PMID:24991115

  18. 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

  19. 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.

  20. Physicochemical and biological characterization of synthetic phosphatidylinositol dimannosides and analogues.

    PubMed

    Hubert, Madlen; Compton, Benjamin J; Hayman, Colin M; Larsen, David S; Painter, Gavin F; Rades, Thomas; Hook, Sarah

    2013-05-01

    Native phosphatidylinositol mannosides (PIMs), isolated from the cell wall of Mycobacterium bovis, and synthetic PIM analogues have been reported to offer a variety of immunomodulating properties, including both suppressive and stimulatory activity. While numerous studies have examined the biological activity of these molecules, the aim of this research was to assess the physicochemical properties at a molecular level and correlate these characteristics with biological activity in a mouse model of airway eosinophilia. To accomplish this, we varied the flexibility and lipophilicity of synthetic PIMs by changing the polar headgroup (inositol- vs glycerol-based core) and the length of the acyl chains of the fatty acid residues (C0, C10, C16, and C18). A series of six phosphatidylinositol dimannosides (PIM2s) and phosphatidylglycerol dimannosides (PGM2s) were synthesized and characterized in this study. Langmuir monolayer studies showed that surface pressure-area (π-A) isotherms were greatly influenced by the length of the lipid acyl chains as well as the steric hindrance and volume of the headgroups. In aqueous solution, lipidated PIM2 and PGM2 compounds were observed to self-assemble into circular aggregates, as confirmed by dynamic light scattering and transmission electron microscopic investigations. Removal of the inositol ring but retention of the three-carbon glycerol unit maintained biological activity. We found that the deacylated PGM2, which did not show self-organization, had no effect on the eosinophil numbers but did have an impact on the expansion of OVA-specific CD4(+) Vα2Vβ5 T cells. PMID:23469864

  1. Incorporation of tryptophan analogues into the lantibiotic nisin.

    PubMed

    Zhou, Liang; Shao, Jinfeng; Li, Qian; van Heel, Auke J; de Vries, Marcel P; Broos, Jaap; Kuipers, Oscar P

    2016-05-01

    Lantibiotics are posttranslationally modified peptides with efficient inhibitory activity against various Gram-positive bacteria. In addition to the original modifications, incorporation of non-canonical amino acids can render new properties and functions to lantibiotics. Nisin is the most studied lantibiotic and contains no tryptophan residues. In this study, a system was constructed to incorporate tryptophan analogues into nisin, which included the modification machinery (NisBTC) and the overexpression of tryptophanyl-tRNA synthetase (TrpRS). Tryptophan and three different tryptophan analogues (5-fluoroTrp (5FW), 5-hydroxyTrp (5HW) and 5-methylTrp (5MeW)) were successfully incorporated at four different positions of nisin (I1W, I4W, M17W and V32W). The incorporation efficiency of tryptophan analogues into mutants I1W, M17W and V32W was over 97 %, while the mutant I4W showed relatively low incorporation efficiency (69-93 %). The variants with 5FW showed relatively higher production yield, while 5MeW-containing variants showed the lowest yield. The dehydration efficiency of serines or threonines was affected by the tryptophan mutants of I4W and V32W. The affinity of the peptides for the cation-ion exchange and reverse phase chromatography columns was significantly reduced when 5HW was incorporated. The antimicrobial activity of IIW and its 5FW analogue both decreased two times compared to that of nisin, while that of its 5HW analogue decreased four times. The 5FW analogue of I4W also showed two times decreased activity than nisin. However, the mutant M17W and its 5HW analogue both showed 32 times reduced activity relative to that of nisin.

  2. Synthesis and biological activities of new side chain and backbone cyclic bradykinin analogues.

    PubMed

    Schumann, C; Seyfarth, L; Greiner, G; Paegelow, I; Reissmann, S

    2002-08-01

    A series of conformationally constrained cyclic analogues of the peptide hormone bradykinin (BK, Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg) was synthesized to check different turned structures proposed for the bioactive conformation of BK agonists and antagonists. Cycles differing in the size and direction of the lactam bridge were performed at the C- and N-terminal sequences of the molecule. Glutamic acid and lysine were introduced into the native BK sequence at different positions for cyclization through their side chains. Backbone cyclic analogues were synthesized by incorporation of N-carboxy alkylated and N-amino alkylated amino acids into the peptide chain. Although the coupling of Fmoc-glycine to the N-alkylated phenylalanine derivatives was effected with DIC/HOAt in SPPS, the dipeptide building units with more bulky amino acids were pre-built in solution. For backbone cyclization at the C-terminus an alternative building unit with an acylated reduced peptide bond was preformed in solution. Both types of building units were handled in the SPPS in the same manner as amino acids. The agonistic and antagonistic activities of the cyclic BK analogues were determined in rat uterus (RUT) and guinea-pig ileum (GPI) assays. Additionally, the potentiation of the BK-induced effects was examined. Among the series of cyclic BK agonists only compound 3 with backbone cyclization between positions 2 and 5 shows a significant agonistic activity on RUT. To study the influence of intramolecular ring closure we used an antagonistic analogue with weak activity, [D-Phe7]-BK. Side chain as well as backbone cyclization in the N-terminus of [D-Phe7]-BK resulted in analogues with moderate antagonistic activity on RUT. Also, compound 18 in which a lactam bridge between positions 6 and 9 was achieved via an acylated reduced peptide bond has moderate antagonistic activity on RUT. These results support the hypothesis of turn structures in both parts of the molecule as a requirement for BK

  3. Dihydrobenzofuran analogues of hallucinogens. 4. Mescaline derivatives.

    PubMed

    Monte, A P; Waldman, S R; Marona-Lewicka, D; Wainscott, D B; Nelson, D L; Sanders-Bush, E; Nichols, D E

    1997-09-12

    hallucinogens, that such compounds must be full agonists at the 5-HT2A receptor subtype. In contrast to the 2,5-dimethoxy-substituted phenethylamines, where rigidification of the methoxy groups had no deleterious effect on activity, the loss of activity in the 3,4,5-trioxygenated mescaline analogues may suggest that the 3 and 5 methoxy groups must remain conformationally mobile to enable receptor activation.

  4. 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

  5. Spectral analysis of lunar analogue samples

    NASA Astrophysics Data System (ADS)

    Offringa, Marloes; Foing, Bernard

    2016-04-01

    Analyses of samples derived from terrestrial analogue sites are used to study lunar processes in their geological context (Foing, Stoker, Ehrenfreund, 2011). For this study samples from the volcanic region of the Eifel, Germany collected during field campaigns (Foing et al., 2010), are analyzed with a variety of spectrometers. The aim is to obtain a database of analyzed samples that could be used as a reference for future in situ measurements. Equipment used in the laboratory consists of a Fourier Transform Infrared (FTIR) spectrometer, an X-Ray Fluorescence (XRF) spectrometer, a Raman laser spectrometer, as well as UV-VIS and NIR reflectance spectrometers. The Raman, UV-VIS and NIR are also used in combination with the EXoGeoLab mock-up lander during field campaigns (Foing, Stoker, Ehrenfreund, 2011). Calibration of the UV-VIS and NIR reflectance spectrometers is the main focus of this research in order to obtain the clearest spectra. The calibration of the UV-VIS and NIR reflectance spectrometers requires the use of a good light source as well as suitable optical fibers to create a signal that covers the widest range in wavelengths available. To eliminate noise towards the edges of this range, multiple measurements are averaged and data is processed by dividing the signal by reference spectra. Calibration of the devices by creating a new dark and reference spectra has to take place after every sample measurement. In this way we take into account changes that occur in the signal due to the eating of the devices during the measurements. Moreover, the integration time is adjusted to obtain a clear signal without leading to oversaturation in the reflectance spectrum. The typical integration times for the UV-VIS reflectance spectrometer vary between 1 - 18 s, depending on the amount of daylight during experiments. For the NIR reflectance spectrometer the integration time resulting in the best signals is approximately 150 ms in combination with a broad spectrum light

  6. Iron isotopes in an Archean ocean analogue

    NASA Astrophysics Data System (ADS)

    Busigny, Vincent; Planavsky, Noah J.; Jézéquel, Didier; Crowe, Sean; Louvat, Pascale; Moureau, Julien; Viollier, Eric; Lyons, Timothy W.

    2014-05-01

    Iron isotopes have been extensively used to trace the history of microbial metabolisms and the redox evolution of the oceans. Archean sedimentary rocks display greater variability in iron isotope ratios and more markedly negative values than those deposited in the Proterozoic and Phanerozoic. This increased variability has been linked to changes in either water column iron cycling or the extent of benthic microbial iron reduction through time. We tested these contrasting scenarios through a detailed study of anoxic and ferruginous Lac Pavin (France), which can serve as a modern analogue of the Archean ocean. A depth-profile in the water column of Lac Pavin shows a remarkable increase in dissolved Fe concentration (0.1-1200 μM) and δ56Fe values (-2.14‰ to +0.31‰) across the oxic-anoxic boundary to the lake bottom. The largest Fe isotope variability is found at the redox boundary and is related to partial oxidation of dissolved ferrous iron, leaving the residual Fe enriched in light isotopes. The analysis of four sediment cores collected along a lateral profile (one in the oxic layer, one at the redox boundary, one in the anoxic zone, and one at the bottom of the lake) indicates that bulk sediments, porewaters, and reactive Fe mostly have δ56Fe values near 0.0 ± 0.2‰, similar to detrital iron. In contrast, pyrite δ56Fe values in sub-chemocline cores (60, 65, and 92 m) are highly variable and show significant deviations from the detrital iron isotope composition (δ56Fepyrite between -1.51‰ and +0.09‰; average -0.93‰). Importantly, the pyrite δ56Fe values mirror the δ56Fe of dissolved iron at the redox boundary—where near quantitative sulfate and sulfide drawdown occurs—suggesting limited iron isotope fractionation during iron sulfide formation. This finding has important implications for the Archean environment. Specifically, this work suggests that in a ferruginous system, most of the Fe isotope variability observed in sedimentary pyrites can

  7. 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.

  8. 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

  9. Conformational preferences of 1-amino-2-phenylcyclohexanecarboxylic acid, a phenylalanine cyclohexane analogue.

    PubMed

    Alemán, Carlos; Jiménez, Ana I; Cativiela, Carlos; Nussinov, Ruth; Casanovas, Jordi

    2009-10-16

    The intrinsic conformational preferences of the restricted phenylalanine analogue generated by including the alpha and beta carbon atoms into a cyclohexane ring (1-amino-2-phenylcyclohexanecarboxylic acid, c(6)Phe) have been determined using quantum mechanical calculations. Specifically, the conformational profile of the N-acetyl-N'-methylamide derivative of the c(6)Phe 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 pi 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.

  10. 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).

  11. 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

  12. Analogue and numerical models coupled with structural analysis to investigate the runout of dry granular flows.

    NASA Astrophysics Data System (ADS)

    Céline, Longchamp; Irène, Manzella; Abellan, Antonio; Caspar, Olivier; Podladchikov, Yury; Jaboyedoff, Michel

    2016-04-01

    The objective of this research is to better understand the propagation of dry granular flows by coupling analogue modelling, structural analysis of deposit and numerical modelling, as follows: (a) The analogue modelling use laboratory experiments to investigate both the fluid-like flow of a granular mass falling down a slope and the influence of certain parameters such as the basal roughness, mobilized volume and slope angle. The experimental setup allows unconfined flow which spreads freely on a horizontal surface. Different grainsizes (115, 545 and 2605 μm) and substratum roughness (simulates by aluminium and sandpapers with grainsize from 16 to 425 μm) were used in order to understand their influence on the motion of a granular mass. During our experiments, the runout varied between 4.5cm and 11cm, with an increase of the basal roughness. When the volume varied between 300 and 600cm3 the runout was comprised between 9.2cm and 11.7cm. Finally when the slope angle was increased from 35° to 60°, the observed runout was between 5.3cm and 20cm. (b) Rock avalanche dynamic is analysed by means of a detailed structural analysis of the analogue modelling deposits. A series of 3D measurements were carried out on the deposit and a median filter and a gradient operator along the direction of propagation were applied to the 3D datasets. Treatment yield a more precise mapping of the longitudinal and transversal displacement features observed at the surface of the deposits. (c) The numerical modelling performed during this research is based both on continuum mechanics approach and on solving the shallow water equations. The avalanche was described from an Eulerian point of view within a continuum framework as single phase of incompressible granular material following Mohr-Coulomb friction law. The results obtained with the numerical model resemble those observed with the analogue modelling mentioned above. By coupling these three approaches, we obtained a complete scheme

  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. Synthesis and Biological Evaluation of Carbocyclic Analogues of Pachastrissamine

    PubMed Central

    Kwon, Yongseok; Song, Jayoung; Bae, Hoon; Kim, Woo-Jung; Lee, Joo-Youn; Han, Geun-Hee; Lee, Sang Kook; Kim, Sanghee

    2015-01-01

    A series of carbocyclic analogues of naturally-occurring marine sphingolipid pachastrissamine were prepared and biologically evaluated. The analogues were efficiently synthesized via a tandem enyne/diene-ene metathesis reaction as a key step. We found that the analogue 4b exhibited comparable cytotoxicity and more potent inhibitory activity against sphingosine kinases, compared to pachastrissamine. Molecular modeling studies were conducted to provide more detailed insight into the binding mode of 4b in sphingosine kinase. In our docking model, pachastrissamine and 4b were able to effectively bind to the binding pocket of sphingosine kinase 1 as co-crystalized sphingosine. However, 4b showed a hydrophobic interaction with Phe192, which suggests that it contributes to its increased inhibitory activity against sphingosine kinase 1. PMID:25654428

  15. Migrastatin analogues target fascin to block tumour metastasis

    SciTech Connect

    Chen, L.; Jakoncic, J.; Yang, S.; Zhang, J.; Huang, X.Y.

    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.

  16. 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.

  17. Synthesis and cytotoxic activities of semisynthetic zearalenone analogues.

    PubMed

    Tadpetch, Kwanruthai; Kaewmee, Benyapa; Chantakaew, Kittisak; Kantee, Kawalee; Rukachaisirikul, Vatcharin; Phongpaichit, Souwalak

    2016-08-01

    Zearalenone is a β-resorcylic acid macrolide with various biological activities. Herein we report the synthesis and cytotoxic activities of 34 zearalenone analogues against human oral epidermoid carcinoma (KB) and human breast adenocarcinoma (MCF-7) cells as well as noncancerous Vero cells. Some zearalenone analogues showed moderately enhanced cytotoxic activities against the two cancer cell lines. We have discovered the potential lead compounds with diminished or no cytotoxicity to Vero cells. Preliminary structure-activity relationship studies revealed that the double bond at the 1' and 2' positions of zearalenone core was crucial for cytotoxic activities on both cell lines. In addition, for zearalenol analogues, the unprotected hydroxyl group at C-2 and an alkoxy substituent at C-4 played key roles on cytotoxic effects of both cell lines.

  18. 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.

  19. Synthesis and Biological Evaluation of New (-)-Englerin Analogues.

    PubMed

    López-Suárez, Laura; Riesgo, Lorena; Bravo, Fernando; Ransom, Tanya T; Beutler, John A; Echavarren, Antonio M

    2016-05-01

    We report the synthesis and biological evaluation of a series of (-)-englerin A analogues obtained along our previously reported synthetic route based on a stereoselective gold(I) cycloaddition process. This synthetic route is a convenient platform to access analogues with broad structural diversity and has led us to the discovery of unprecedented and easier-to-synthesize derivatives with an unsaturation in the cyclopentyl ring between C4 and C5. We also introduce novel analogues in which the original isopropyl motif has been substituted with cyclohexyl, phenyl, and cyclopropyl moieties. The high selectivity and growth-inhibitory activity shown by these new derivatives in renal cancer cell lines opens new ways toward the final goal of finding effective drugs for the treatment of renal cell carcinoma (RCC).

  20. Non-natural acetogenin analogues as potent Trypanosoma brucei inhibitors.

    PubMed

    Florence, Gordon J; Fraser, Andrew L; Gould, Eoin R; King, Elizabeth F B; Menzies, Stefanie K; Morris, Joanne C; Tulloch, Lindsay B; Smith, Terry K

    2014-11-01

    Neglected tropical diseases remain a serious global health concern. Here, a series of novel bis-tetrahydropyran 1,4-triazole analogues based on the framework of chamuvarinin, a polyketide natural product isolated from the annonaceae plant species are detailed. The analogues synthesized display low micromolar trypanocidal activities towards both bloodstream and insect forms of Trypanosoma brucei, the causative agent of African sleeping sickness, also known as Human African Trypanosomiasis (HAT). 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. Together, the biological potency and calculated lipophilicity values indicate that while there is room for improvement, these derivatives may represent a promising novel class of anti-HAT agents.

  1. 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

  2. Synthesis of prenylated benzaldehydes and their use in the synthesis of analogues of licochalcone A.

    PubMed

    Kromann, Hasse; Larsen, Mogens; Boesen, Thomas; Schønning, Kristian; Nielsen, Simon Feldbaek

    2004-11-01

    In this paper, a general applicable synthesis of prenylated aromatic compounds exemplified by prenylated benzaldehydes starting from readily available acetophenones is described. The synthesized benzaldehydes are used to prepare a number of novel analogues of Licochalcone A, a known antibacterial compound, and for the exploration of the pharmacophoric elements that are essential for the antibacterial activity. It is shown that the hydroxyl group in the A ring is essential for the activity and that the hydroxyl group in the B ring has no influence on the antibacterial effect of Licochalcone A. Furthermore, it is shown that the prenyl group at the position 5 of the B ring also has a dominating influence on the activity. This aliphatic group can be replaced by other lipophilic long chained substituents in order to maintain the activity.

  3. Upregulation of transmitter release probability improves a conversion of synaptic analogue signals into neuronal digital spikes

    PubMed Central

    2012-01-01

    Action potentials at the neurons and graded signals at the synapses are primary codes in the brain. In terms of their functional interaction, the studies were focused on the influence of presynaptic spike patterns on synaptic activities. How the synapse dynamics quantitatively regulates the encoding of postsynaptic digital spikes remains unclear. We investigated this question at unitary glutamatergic synapses on cortical GABAergic neurons, especially the quantitative influences of release probability on synapse dynamics and neuronal encoding. Glutamate release probability and synaptic strength are proportionally upregulated by presynaptic sequential spikes. The upregulation of release probability and the efficiency of probability-driven synaptic facilitation are strengthened by elevating presynaptic spike frequency and Ca2+. The upregulation of release probability improves spike capacity and timing precision at postsynaptic neuron. These results suggest that the upregulation of presynaptic glutamate release facilitates a conversion of synaptic analogue signals into digital spikes in postsynaptic neurons, i.e., a functional compatibility between presynaptic and postsynaptic partners. PMID:22852823

  4. Analogues of luteinizing hormone-releasing hormone containing cytotoxic groups.

    PubMed Central

    Janáky, T; Juhász, A; Bajusz, S; Csernus, V; Srkalovic, G; Bokser, L; Milovanovic, S; Redding, T W; Rékási, Z; Nagy, A

    1992-01-01

    In an attempt to produce better cytotoxic analogues, chemotherapeutic antineoplastic radicals including an alkylating nitrogen mustard derivative of D-phenylalanine (D-melphalan), reactive cyclopropane, anthraquinone derivatives [2-(hydroxymethyl)anthraquinone and the anticancer antibiotic doxorubicin], and an antimetabolite (methotrexate) were coupled to suitably modified agonists and antagonists of luteinizing hormone-releasing hormone (LH-RH). Analogues with D-lysine6 and D-ornithine6 or N epsilon-(2,3-diaminopropionyl)-D-lysine and N delta-(2,3-diaminopropionyl)-D-ornithine were used as carriers for one or two cytotoxic moieties. The enhanced biological activities produced by the incorporation of D amino acids into position 6 of the agonistic analogues were further increased by the attachment of hydrophobic cytotoxic groups, resulting in compounds with 10-50 times higher activity than LH-RH. Most of the monosubstituted agonistic analogues showed high affinities for the membrane receptors of human breast cancer cells, while the receptor binding affinities of peptides containing two cytotoxic side chains were lower. Antagonistic carriers [Ac-D-Nal(2)1,D-Phe(4Cl)2,D-Trp3,Arg5,D-Lys6,D-Ala10] LH-RH [where Nal(2) is 3-(2-naphthyl)alanine], [Ac-D-Nal(2)1,D-Phe(4Cl)2,D-Trp3,Arg5,N epsilon-(2,3-diaminopropionyl)-D-Lys6,D-Ala10]LH-RH, and their D-Pal(3)3 homologs [Pal(3) is 3-(3-pyridyl)alanine] as well as [Ac-D-Nal(2)1,D-Phe(4Cl)2,D-Pal(3)3,Tyr5,N epsilon-(2,3-diamino-propionyl)-D-Lys6,D-Ala10]LH-RH were linked to cytotoxic compounds. The hybrid molecules inhibited ovulation in rats at doses of 10 micrograms and suppressed LH release in vitro. The receptor binding of cytotoxic analogues was decreased compared to the precursor peptides, although analogues with 2-(hydroxymethyl)anthraquinone hemiglutarate had high affinities. All of the cytotoxic analogues tested inhibited [3H]thymidine incorporation into DNA in cultures of human breast and prostate cancer cell lines

  5. Five new discodermolide analogues from the marine sponge Discodermia species.

    PubMed

    Gunasekera, Sarath P; Paul, Gopal K; Longley, Ross E; Isbrucker, Richard A; Pomponi, Shirley A

    2002-11-01

    Discodermolide (1) and five new discodermolide analogues trivially named 2-epi-discodermolide (2), 2-des-methyldiscodermolide (3), 5-hydroxymethyldiscodermolate (4), 19-des-aminocarbonyldiscodermolide (5), and 9(13)-cyclodiscodermolide (6) have been isolated from marine sponges belonging to the genus Discodermia collected from the Caribbean Sea. The isolation, structure elucidation, and biological activities of 2-6 are described. The natural analogues, which were isolated in trace amounts, exhibited significant variation of cytotoxicity against the cultured murine P-388 leukemia and A-549 human adenocarcinoma cells and suggested the importance of the C(7) through C(17) moiety for potency against cultured tumor cell lines.

  6. Synthesis and Cytotoxicity of Semisynthetic Withalongolide A Analogues

    PubMed Central

    2013-01-01

    The natural product withaferin A exhibits potent antitumor activity and other diverse pharmacological activities. The recently discovered withalongolide A, a C-19 hydroxylated congener of withaferin A, was recently reported to possess cytotoxic activity against head and neck squamous cell carcinomas. Semisynthetic acetylated analogues of withalongolide A were shown to be considerably more cytotoxic than the parent compound. To further explore the structure–activity relationships, 20 new semisynthetic analogues of withalongolide A were synthesized and evaluated for cytotoxic activity against four different cancer cell lines. A number of derivatives were found to be more potent than the parent compound and withaferin A. PMID:24273633

  7. Tumor imaging and therapy using radiolabeled somatostatin analogues.

    PubMed

    de Jong, Marion; Breeman, Wout A P; Kwekkeboom, Dik J; Valkema, Roelf; Krenning, Eric P

    2009-07-21

    Molecular imaging plays an essential role in balancing the clinical benefits and risks of radionuclide-based cancer therapy. To effectively treat individual patients, careful assessment of biodistribution, dosimetry, and toxicity is essential. In this Account, we describe advances that combine features of molecular imaging and radionuclide therapy to provide new avenues toward individualized cancer treatment. Selective receptor-targeting radiopeptides have emerged as an important class of radiopharmaceuticals for molecular imaging and therapy of tumors that overexpress peptide receptors on the cell membrane. After such peptides labeled with gamma-emitting radionuclides bind to their receptors, they allow clinicians to visualize receptor-expressing tumors non-invasively. Peptides labeled with beta-particle emitters could also eradicate receptor-expressing tumors. The somatostatin receptors, which are overexpressed in a majority of neuroendocrine tumors, represent the first and best example of targets for radiopeptide-based imaging and radionuclide therapy. The somatostatin analogue (111)In-octreotide permits the localization and staging of neuroendocrine tumors that express the appropriate somatostatin receptors. Newer modified somatostatin analogues, including Tyr(3)-octreotide and Tyr(3)-octreotate, are successfully being used for tumor imaging and radionuclide therapy. Because there are few effective therapies for patients with inoperable or metastasized neuroendocrine tumors, this therapy is a promising novel treatment option for these patients. Peptide receptor imaging and radionuclide therapy can be combined in a single probe, called a "theranostic". To select patients who are likely to benefit from this type of intervention, we first use a peptide analogue labeled with a diagnostic radionuclide to obtain a scan. Selected patients will be treated using the same or a similar peptide analogue labeled with a therapeutic radionuclide. The development of such

  8. 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.

  9. 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.

  10. 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.

  11. [Ca++ ion transport blockers as reversants of the drug resistance of malarial parasites. 2. The effect of praziquantel on the resistance to chloroquine and compound R-70-Zh of Plasmodium berghei].

    PubMed

    Orlov, V S; Rabinovich, S A; Bukhtin, B A; Dadasheva, N R; Maksakovskaia, E V

    1998-01-01

    The reversing action of anthelminthic praziquantel (P) on the effect of chloroquine (C) and compound R-70-Zh (styrylquinazoline) was revealed on a Plasmodium berghei model (white inbred mice), using a LNK65 isolate with naturally reduced sensitivity to chloroquine and its polyresistant line LNK65CHLFR with acquired resistance to chloroquine/fansidar (selected in our laboratory). P (125 mg/kg) in combination with C showed a potentiating effect not only on the LNK65 isolate, but also on the LNK65CHLFR line, while investigated separately on this line, both drugs were not effective in tested doses. Moreover, the similar effect of C on the LNK65CHLFR line was achieved in the dose that was 4 times higher than that of P/C combination. P in a standard dose on the LNK65 isolate showed a more marked activation of compound R-70-Zh that on C. The potentiating effect was manifested in combination with R-70-Zh in the dose half as high as that of C; this phenomenon was also reflected by the efficiency index (5.0 against the 4.0) accepted in our laboratory and may be associated with the higher sensitivity of the LNK65 isolate to R-70-Zh. P showed some antimalarial action which manifested itself only by morphological changes on P. berghei parasites similar to those observed under the action of some dihydropholate reductase inhibitors, such as pyrimethamine. PMID:9608206

  12. A feasible approach to evaluate the relative reactivity of NHS-ester activated group with primary amine-derivatized DNA analogue and non-derivatized impurity.

    PubMed

    Dou, Shuping; Virostko, John; Greiner, Dale L; Powers, Alvin C; Liu, Guozheng

    2015-01-01

    Synthetic DNA analogues with improved stability are widely used in life science. The 3'and/or 5' equivalent terminuses are often derivatized by attaching an active group for further modification, but a certain amount of non-derivatized impurity often remains. It is important to know to what extent the impurity would influence further modification. The reaction of an NHS ester with primary amine is one of the most widely used options to modify DNA analogues. In this short communication, a 3'-(NH2-biotin)-derivatized morpholino DNA analogue (MORF) was utilized as the model derivatized DNA analogue. Inclusion of a biotin concomitant with the primary amine at the 3'-terminus allows for the use of streptavidin to discriminate between the products from the derivatized MORF and non-derivatized MORF impurity. To detect the MORF reaction with NHS ester, S-acetyl NHS-MAG3 was conjugated to the DNA analogue for labeling with (99m)Tc, a widely used nuclide in the clinic. It was found that the non-derivatized MORF also reacted with the S-acetyl NHS-MAG3. Radiolabeling of the product yielded an equally high labeling efficiency. Nevertheless, streptavidin binding indicated that under the conditions of this investigation, the non-derivatized MORF was five times less reactive than the amine-derivatized MORF. PMID:25621701

  13. A FEASIBLE APPROACH TO EVALUATE THE RELATIVE REACTIVITY OF NHS-ESTER ACTIVATED GROUP WITH PRIMARY AMINE-DERIVATIZED DNA ANALOGUE AND NON-DERIVATIZED IMPURITY

    PubMed Central

    Dou, Shuping; Virostko, John; Greiner, Dale L.; Powers, Alvin C.; Liu, Guozheng

    2015-01-01

    Synthetic DNA analogues with improved stability are widely used in life science. The 3′ and/or 5′ equivalent terminuses are often derivatized by attaching an active group for further modification, but a certain amount of non-derivatized impurity often remains. It is important to know to what extent the impurity would influence further modification. The reaction of an NHS ester with primary amine is one of the most widely used options to modify DNA analogues. In this short communication, a 3′-(NH2-biotin)-derivatized morpholino DNA analogue (MORF) was utilized as the model derivatized DNA analogue. Inclusion of a biotin concomitant with the primary amine at the 3′-terminus allows for the use of streptavidin to discriminate between the products from the derivatized MORF and non-derivatized MORF impurity. To detect the MORF reaction with NHS ester, S-acetyl NHS-MAG3 was conjugated to the DNA analogue for labeling with 99mTc, a widely used nuclide in the clinic. It was found that the non-derivatized MORF also reacted with the S-acetyl NHS-MAG3. Radiolabeling of the product yielded an equally high labeling efficiency. Nevertheless, streptavidin binding indicated that under the conditions of this investigation, the non-derivatized MORF was five times less reactive than the amine-derivatized MORF. PMID:25621701

  14. 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

  15. Comparative efficacy of chloroquine plus chlorpheniramine alone and in a sequential combination with sulfadoxine-pyrimethamine, for the treatment of acute, uncomplicated, falciparum malaria in children.

    PubMed

    Sowunmi, A; Fehintola, F A; Adedeji, A A; Falade, A G; Falade, C O; Akinyinka, O O; Oduola, A M

    2000-04-01

    One hundred and eight children with acute, symptomatic, uncomplicated, falciparum malaria were randomized to receive chloroquine (for 3 days) plus chlorpheniramine alone (for seven days) (CQ-CP group; N = 55) or, in a sequential treatment, chloroquine plus chlorpheniramine for 3 days followed, on the fourth day, by a single oral dose of sulfadoxine-pyrimethamine (25 mg sulfadoxine/kg) (CQ-CP-SP group; N = 53). The mean (S.D.) parasite-clearance time in the CQ-CP group [2.1 (0.7) days; range = 1-5 days] was similar to that in the CQ-CP-SP [2.1 (0.8) days; range = 1-5 days]. The fever-clearance times were also similar: 1.2 (0.1) days (range = 1-3 days) v. 1.1 (0.4) days (range = 1-3 days). The cure rates on days 14, 21 and 28 were 98.2%, 96.3% and 92.7%, respectively in the CQ-CP group, and 100%, 100% and 96.2%, respectively, in the CQ-CP-SP group. The rates of gametocyte carriage were low and similar (5.4% in the CQ-CP group and 3.8% in the CQ-CP-SP group) throughout the duration of the study. Both treatment regimens were relatively well tolerated, the main adverse reactions being similar: sleepiness (on day 1) and pruritus (on days 1-3). No adverse effect was attributable to SP. The results indicate that sequential treatment, for 3 days with CQ and CP, followed by a single dose of SP, is effective and well tolerated in children with acute, uncomplicated, falciparum malaria and may be an alternative treatment for CQ- and/or SP-resistant falciparum malaria. Treatment with a CQ-CP combination (CQ and CP for 3 days and then CP alone for another 4 days) is also effective but requires continuing administration after the signs and symptoms of acute malaria have disappeared.

  16. 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. PMID:26910798

  17. 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.

  18. 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. PMID:27460418

  19. 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

  20. 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.

  1. 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…

  2. 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).

  3. Synthesis of 4” manipulated Lewis X trisaccharide analogues

    PubMed Central

    Moore, Christopher J

    2012-01-01

    Summary Three analogues of the Lex trisaccharide antigen (β-D-Galp(1→4)[α-L-Fucp(1→3)]-D-GlcNAcp) in which the galactosyl residue is modified at O-4 as a methyloxy, deoxychloro or deoxyfluoro, were synthesized. We first report the preparation of the modified 4-OMe, 4-Cl and 4-F trichloroacetimidate galactosyl donors and then report their use in the glycosylation of an N-acetylglucosamine glycosyl acceptor. Thus, we observed that the reactivity of these donors towards the BF3·OEt2-promoted glycosylation at O-4 of the N-acetylglucosamine glycosyl acceptors followed the ranking 4-F > 4-OAc ≈ 4-OMe > 4-Cl. The resulting disaccharides were deprotected at O-3 of the glucosamine residue and fucosylated, giving access to the desired protected Lex analogues. One-step global deprotection (Na/NH3) of the protected 4”-methoxy analogue, and two-step deprotections (removal of a p-methoxybenzyl with DDQ, then Zemplén deacylation) of the 4”-deoxychloro and 4”-deoxyfluoro protected Lex analogues gave the desired compounds in good yields. PMID:23019441

  4. 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…

  5. 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…

  6. New phosphorus analogues of nitrogen classics--no carbon copies.

    PubMed

    Gudat, Dietrich

    2014-05-01

    Getting heavy: The recently prepared phosphorus analogues of two old acquaintances, urea and dinitrogen tetroxide, bear some structural resemblance to their archetypes but are no carbon copies. Their syntheses and chemical properties reveal rather certain peculiarities, which back the doctrine that the electronic properties of the heavier elements in a group differ from those of the lightest congener. PMID:24718995

  7. 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

  8. Natural analogue studies: present status and performance assessment implications

    NASA Astrophysics Data System (ADS)

    Smellie, John A. T.; Karlsson, Fred; Alexander, W. Russell

    1997-04-01

    Studies of natural geological and archaeological systems as analogues to long-term processes, which are predicted to occur within a radioactive waste repository environment, have become increasingly popular over the last 10 years or so, to the extent that such studies form an integral part of many national programmes for radioactive waste disposal. There is now a common consensus that the natural analogue approach is a very useful scientific methodology to: (a) identify and understand processes and mechanisms analogous to those which could occur in the vicinity of a repository over realistic timescales, (b) derive input data which have been successfully used to test some of the laboratory-based models which form the basis of long-term repository performance assessment, and (c) to produce data which can be input directly to performance assessment models. Increasingly, analogues are playing an important role in public awareness, enabling the layman to understand better the concept of radioactive disposal and demonstrating the reliability of the disposal system over long periods of geological time. The complexity of geological systems means that it is very often difficult and sometimes impossible to quantify precisely the physico-chemical boundary conditions necessary to model a particular geochemical process or mechanism. Consequently, the availability of quantitative analogue data is limited when repository performance assessments are considered. However, this in no way detracts from their value in building confidence by demonstrating that important processes do exist and by showing qualitatively that they behave in a way predicted by models based on laboratory-derived data. The transfer of natural analogue data from the complexity of field studies to simplistic models which, by necessity, are used in performance assessments, is an area of activity which is presently being addressed. Field analogue studies are now being planned to interface with laboratory

  9. Amido analogues of zincocenes and cadmocenes.

    PubMed

    Blake, Alexander J; Lewis, William; McMaster, Jonathan; Moorhouse, Rhiannon S; Moxey, Graeme J; Kays, Deborah L

    2011-02-28

    The synthesis and characterisation of low-coordinate zinc and cadmium complexes of the sterically demanding 1,3,6,8-tetra-tert-butylcarbazol-9-yl ligand ((t)Bu(4)carb(-)) are reported. ((t)Bu(4)carb)(2)M (M = Zn 1; M = Cd 2) are the first examples of formally two-coordinate bis-carbazol-9-yl complexes of the Group 12 metals and 2 is the first crystallographically characterised two-coordinate amido complex of cadmium. The structure and bonding within these complexes are explored via a combination of X-ray crystallography and DFT calculations. The solid state structures for these zinc and cadmium complexes differ greatly from each other; not only do the steric demands of the peripheral tert-butyl substituents in these systems act to inhibit solvent coordination, but they also influence the coordination geometry around the metal centres. PMID:21249248

  10. 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.

  11. 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.

  12. Metric optimisation for analogue forecasting by simulated annealing

    NASA Astrophysics Data System (ADS)

    Bliefernicht, J.; Bárdo