Science.gov

Sample records for chloroquine analogues influence

  1. Synthesis and Antiplasmodial Activity of Novel Chloroquine Analogues with Bulky Basic Side Chains.

    PubMed

    Tasso, Bruno; Novelli, Federica; Tonelli, Michele; Barteselli, Anna; Basilico, Nicoletta; Parapini, Silvia; Taramelli, Donatella; Sparatore, Anna; Sparatore, Fabio

    2015-09-01

    Chloroquine is commonly used in the treatment and prevention of malaria, but Plasmodium falciparum, the main species responsible for malaria-related deaths, has developed resistance against this drug. Twenty-seven novel chloroquine (CQ) analogues characterized by a side chain terminated with a bulky basic head group, i.e., octahydro-2H-quinolizine and 1,2,3,4,5,6-hexahydro-1,5-methano-8H-pyrido[1,2-a][1,5]diazocin-8-one, were synthesized and tested for activity against D-10 (CQ-susceptible) and W-2 (CQ-resistant) strains of P. falciparum. Most compounds were found to be active against both strains with nanomolar or sub-micromolar IC50 values. Eleven compounds were found to be 2.7- to 13.4-fold more potent than CQ against the W-2 strain; among them, four cytisine derivatives appear to be of particular interest, as they combine high potency with low cytotoxicity against two human cell lines (HMEC-1 and HepG2) along with easier synthetic accessibility. Replacement of the 4-NH group with a sulfur bridge maintained antiplasmodial activity at a lower level, but produced an improvement in the resistance factor. These compounds warrant further investigation as potential drugs for use in the fight against malaria. PMID:26213237

  2. Ruthenium(II) arene complexes with chelating chloroquine analogue ligands: Synthesis, characterization and in vitro antimalarial activity†

    PubMed Central

    Glans, Lotta; Ehnbom, Andreas; de Kock, Carmen; Martínez, Alberto; Estrada, Jesús; Smith, Peter J.; Haukka, Matti; Sánchez-Delgado, Roberto A.; Nordlander, Ebbe

    2012-01-01

    Three new ruthenium complexes with bidentate chloroquine analogue ligands, [Ru(η6-cym)(L1)Cl]Cl (1, cym = p-cymene, L1 = N-(2-((pyridin-2-yl)methylamino)ethyl)-7-chloroquinolin-4-amine), [Ru(η6-cym)(L2)Cl]Cl (2, L2 = N-(2-((1-methyl-1H-imidazol-2-yl)methylamino)ethyl)-7-chloroquinolin-4-amine) and [Ru(η6-cym)(L3)Cl] (3, L3 = N-(2-((2-hydroxyphenyl)methylimino)ethyl)-7-chloroquinolin-4-amine) have been synthesized and characterized. In addition, the X-ray crystal structure of 2 is reported. The antimalarial activity of complexes 1–3 and ligands L1, L2 and L3, as well as the compound N-(2-(bis((pyridin-2-yl)methyl)amino)ethyl)-7-chloroquinolin-4-amine (L4), against chloroquine sensitive and chloroquine resistant Plasmodium falciparum malaria strains was evaluated. While 1 and 2 are less active than the corresponding ligands, 3 exhibits high antimalarial activity. The chloroquine analogue L2 also shows good activity against both the choloroquine sensitive and the chloroquine resistant strains. Heme aggregation inhibition activity (HAIA) at an aqueous buffer/n-octanol interface (HAIR50) and lipophilicity (D, as measured by water/n-octanol distribution coefficients) have been measured for all ligands and metal complexes. A direct correlation between the D and HAIR50 properties cannot be made because of the relative structural diversity of the complexes, but it may be noted that these properties are enhanced upon complexation of the inactive ligand L3 to ruthenium, to give a metal complex (3) with promising antimalarial activity. PMID:22249579

  3. Chlorpheniramine Analogues Reverse Chloroquine Resistance in Plasmodium falciparum by Inhibiting PfCRT

    PubMed Central

    2014-01-01

    The emergence and spread of malaria parasites that are resistant to chloroquine (CQ) has been a disaster for world health. The antihistamine chlorpheniramine (CP) partially resensitizes CQ-resistant (CQR) parasites to CQ but possesses little intrinsic antiplasmodial activity. Mutations in the parasite’s CQ resistance transporter (PfCRT) confer resistance to CQ by enabling the protein to transport the drug away from its site of action, and it is thought that resistance-reversers such as CP exert their effect by blocking this CQ transport activity. Here, a series of new structural analogues and homologues of CP have been synthesized. We show that these compounds (along with other in vitro CQ resistance-reversers) inhibit the transport of CQ via a resistance-conferring form of PfCRT expressed in Xenopus laevis oocytes. Furthermore, the level of PfCRT-inhibition was found to correlate well with both the restoration of CQ accumulation and the level of CQ resensitization in CQR parasites. PMID:24900883

  4. [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

  5. Recycling of chloroquine and its hydroxyl analogue to face bacterial, fungal and viral infections in the 21st century.

    PubMed

    Rolain, Jean-Marc; Colson, Philippe; Raoult, Didier

    2007-10-01

    Chloroquine (CQ) and its hydroxyl analogue hydroxychloroquine (HCQ) are weak bases with a half-century long use as antimalarial agents. Apart from this antimalarial activity, CQ and HCQ have gained interest in the field of other infectious diseases. One of the most interesting mechanisms of action is that CQ leads to alkalinisation of acid vesicles that inhibit the growth of several intracellular bacteria and fungi. The proof of concept of this effect was first used to restore intracellular pH allowing antibiotic efficacy for Coxiella burnetii, the agent of Q fever, and doxycycline plus HCQ is now the reference treatment for chronic Q fever. There is also strong evidence of a similar effect in vitro against Tropheryma whipplei, the agent of Whipple's disease, and a clinical trial is in progress. Other bacteria and fungi multiply in an acidic environment and encouraging in vitro data suggest that this concept may be generalised for all intracellular organisms that multiply in an acidic environment. For viruses, CQ led to inhibition of uncoating and/or alteration of post-translational modifications of newly synthesised proteins, especially inhibition of glycosylation. These effects have been well described in vitro for many viruses, with human immunodeficiency virus (HIV) being the most studied. Preliminary in vivo clinical trials suggest that CQ alone or in combination with antiretroviral drugs might represent an interesting way to treat HIV infection. In conclusion, our review re-emphasises the paradigm that activities mediated by lysosomotropic agents may offer an interesting weapon to face present and future infectious diseases worldwide. PMID:17629679

  6. 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

  7. Chloroquine Phosphate Oral

    MedlinePlus

    ... allergic to chloroquine phosphate, chloroquine hydrochloride (Aralen HCl), hydroxychloroquine (Plaquenil), or any other drugs.tell your doctor ... taking chloroquine phosphate, chloroquine hydrochloride (Aralen HCl), or hydroxychloroquine (Plaquenil).tell your doctor if you are pregnant ...

  8. Chloroquine Phosphate Oral

    MedlinePlus

    ... allergic to chloroquine phosphate, chloroquine hydrochloride (Aralen HCl), hydroxychloroquine (Plaquenil), or any other drugs.tell your doctor and ... taking chloroquine phosphate, chloroquine hydrochloride (Aralen HCl), or hydroxychloroquine (Plaquenil).tell your doctor if you are pregnant ...

  9. 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

  10. 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

  11. 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

  12. Delayed-onset chloroquine retinopathy.

    PubMed Central

    Ehrenfeld, M; Nesher, R; Merin, S

    1986-01-01

    Delayed-onset chloroquine retinopathy was diagnosed in a patient seven years after cessation of treatment by a total dose of 730 g of chloroquine for rheumatoid arthritis. Visual functions continued to deteriorate after the diagnosis. Periodic examinations by ophthalmoscopy and by functional tests such as EOG and visual fields should be continued in patients at risk of delayed-onset chloroquine retinopathy after discontinuance of the drug. PMID:3964626

  13. 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

  14. Ocular Complications of Chloroquine Therapy

    PubMed Central

    Tamler, Edward

    1965-01-01

    Long-term therapy with chloroquine can lead to irreversible retinal damage and serious loss of visual acuity and visual field. Not only are the retinal changes irreversible but they may continue to progress after discontinuance of the drug. Work is proceeding on the development of electrophysiological techniques for early detection of toxic effect before significant retinal damage occurs. Another possibility for minimizing the toxic effect of chloroquine is the use of other drugs which increase the excretion of chloroquine from the body. ImagesFigure 1. PMID:14336789

  15. The Influence of Topical Prostaglandin Analogues in Inflammation After Selective Laser Trabeculoplasty Treatment

    PubMed Central

    Chen, Enping

    2012-01-01

    Abstract Purpose Reducing intraocular pressure (IOP) seems to be the only treatment that slows progression in glaucoma. The IOP can be decreased by pharmaceutical treatment, laser [selective laser trabeculoplasty (SLT)] treatment, or surgery. Prostaglandin analogues have been postulated to share action mechanisms with SLT and to possibly diminish the effects of SLT treatment. The aim of the current study was to investigate the effects of prostaglandin analogues in inflammation and IOP reduction after SLT treatment. Methods Prospective nonrandomized study. One hundred and eighteen patients were included in the study. Inclusion criteria: Glaucoma (open-angle or pseudoexfoliation glaucoma) patients who will be treated with SLT. Inflammation was measured with a laser flare meter (Kowa FM-500). Measurements were made before SLT and then 2 h, 1 week, and 1 month after SLT treatment. IOP was also checked at the same time intervals. The SLT treatment was performed over 90°. All patients were divided into two groups: those receiving prostaglandins analogues and those treated with nonprostaglandin analogues. Results Inflammation before and after SLT showed no significant difference between the groups at all the time intervals studied (t-test, before: P=0.16; 2 h: P=0.14; 1 week: P=0.12; and 1 month: P=0.36). IOP reduction showed no significant difference between the groups (t-test, P=0.31). Conclusions SLT treatment effects do not seem to be influenced by the use of prostaglandin analogues. PMID:22087857

  16. 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

  17. Delayed Onset Chloroquine Retinopathy Presenting 10 Years after Long-Term Usage of Chloroquine

    PubMed Central

    Kazi, Mohmmad Salman; Saurabh, Kumar; Rishi, Pukhraj; Rishi, Ekta

    2013-01-01

    Chloroquine retinopathy is a known complication of long-term use of chloroquine. This retinopathy can appear even after usage of chloroquine has stopped. The present case report describes the history and clinical features of chloroquine retinopathy developing a decade after discontinuing the drug. PMID:23580861

  18. Chloroquine psychosis: a chemical psychosis?

    PubMed

    Mohan, D; Mohandas, E; Rajat, R

    1981-11-01

    Psychotic states are mimicked by the use of many drugs including amphetamines, cannabis, lysergic acid diethylamide, psilocybin, mescaline, isoniazid, and L-dopa. A paranoid psychotic picture in a clear sensorium is characteristic of amphetamine psychosis. In developing countries, malaria among other diseases is a frequent indicator of chloroquine administration. The present communication reports a series of chloroquine-induced psychosis in a clear sensorium simulating affective illness, such as mania, mixed affective states, or depression. The psychosis disappeared after cessation of the drug, combined with or without the use of low dosage phenothiazines in excited patients. From our cases, two types of presentation of chloroquine psychosis could be seen: (1) psychic with clear sensorium, mood changes, alteration in motor activity, delusions, and hallucinations; and (2) psycho-organic with clouded sensorium, disorientation, and fleeting hallucinations. The precise nature of the mechanism of the psychosis is not clear because of the limited number of reported cases. PMID:7310924

  19. Ocular Complications of Chloroquine Therapy

    PubMed Central

    Lloyd, Lois A.; Hiltz, John W.

    1965-01-01

    Ocular complications of long-term chloroquine therapy were observed in 18 of 45 patients so treated. This therapy was used in patients with rheumatoid arthritis, lupus erythematosus, sarcoidosis, discoid lupus and other chronic “collagen disease”. Thirteen patients had reversible corneal opacifications, and seven had irreversible retinal changes, with visual loss and visual field defects. Pathological evidence of chloroquine retinopathy was obtained in one patient. Physicians are therefore warned to use this drug only after careful consideration. If it is used, repeated ocular examinations should include assessment of visual acuity, visual fields on a tangent screen and fundus examination through a dilated pupil. ImagesFig. 4Fig. 7Fig. 8 PMID:14275038

  20. Ultrasonic chorioretinopathy: a chloroquine vs control study.

    PubMed

    Kaplan, L J; Holasek, E

    1983-12-01

    High frequency ultrasound was used to produce chorioretinal lesions in two groups of pigmented rabbits. The control group received no medications. The other group was treated with subretinotoxic doses of chloroquine. Our experiment showed that the untreated group developed focal chorioretinal lesions and ricochet lesions at lower energies than did the chloroquinated group. We postulated that chloroquine, a melanin binding drug, altered melanin's ability to process ultrasonic energy by sonic-thermal conversion. This work suggests that chloroquine, even in subretinotoxic doses, may still exert an effect on the retina by chemically binding melanin and preventing its function as an energy transport system. PMID:6660693

  1. Conformationally restrained aromatic analogues of fosmidomycin and FR900098.

    PubMed

    Kurz, Thomas; Schlüter, Katrin; Pein, Miriam; Behrendt, Christoph; Bergmann, Bärbel; Walter, Rolf D

    2007-07-01

    The synthesis and in-vitro antimalarial activity of conformationally restrained bis(pivaloyloxymethyl) ester analogues of the natural product fosmidomycin is presented. In contrast to alpha-aryl-substituted analogues, conformationally restrained aromatic analogues exhibit only moderate in-vitro antimalarial activity against the chloroquine-sensitive strain 3D7 of Plasmodium falciparum. The most active derivative displays an IC(50) value of 47 microM. PMID:17611943

  2. 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

  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. 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

  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. 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

  7. 21 CFR 522.810 - Embutramide, chloroquine, and lidocaine solution.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 6 2010-04-01 2010-04-01 false Embutramide, chloroquine, and lidocaine solution... ANIMAL DRUGS § 522.810 Embutramide, chloroquine, and lidocaine solution. (a) Specifications. Each milliliter (mL) of solution contains 135 milligrams (mg) embutramide; 45 mg chloroquine phosphate,...

  8. 21 CFR 522.810 - Embutramide, chloroquine, and lidocaine solution.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 6 2011-04-01 2011-04-01 false Embutramide, chloroquine, and lidocaine solution... ANIMAL DRUGS § 522.810 Embutramide, chloroquine, and lidocaine solution. (a) Specifications. Each milliliter (mL) of solution contains 135 milligrams (mg) embutramide; 45 mg chloroquine phosphate,...

  9. 21 CFR 522.810 - Embutramide, chloroquine, and lidocaine solution.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 6 2013-04-01 2013-04-01 false Embutramide, chloroquine, and lidocaine solution... ANIMAL DRUGS § 522.810 Embutramide, chloroquine, and lidocaine solution. (a) Specifications. Each milliliter (mL) of solution contains 135 milligrams (mg) embutramide; 45 mg chloroquine phosphate,...

  10. 21 CFR 522.810 - Embutramide, chloroquine, and lidocaine solution.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 6 2014-04-01 2014-04-01 false Embutramide, chloroquine, and lidocaine solution... ANIMAL DRUGS § 522.810 Embutramide, chloroquine, and lidocaine solution. (a) Specifications. Each milliliter (mL) of solution contains 135 milligrams (mg) embutramide; 45 mg chloroquine phosphate,...

  11. 21 CFR 522.810 - Embutramide, chloroquine, and lidocaine solution.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 6 2012-04-01 2012-04-01 false Embutramide, chloroquine, and lidocaine solution... ANIMAL DRUGS § 522.810 Embutramide, chloroquine, and lidocaine solution. (a) Specifications. Each milliliter (mL) of solution contains 135 milligrams (mg) embutramide; 45 mg chloroquine phosphate,...

  12. 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.

  13. 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

  14. 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

  15. 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

  16. Do analogues of gonadotrophin releasing hormone influence follicular fluid steroid levels, oocyte maturity and fertilization rates?

    PubMed

    Tavmergen, E; Tavmergen, E N; Capanoğlu, R

    1992-04-01

    One-hundred-and-twelve samples of follicular fluid from 32 patients undergoing in-vitro fertilization and embryo transfer were analysed in this study. The follicular fluids were analysed for any relationships between oestradiol, progesterone and 17 alpha-hydroxyprogesterone levels, the progesterone/oestradiol and 17 alpha-hydroxyprogesterone/oestradiol ratios and oocyte maturity and fertilization rates. In Group A, consisting of women who used analogues of gonadotrophin-releasing hormone during ovarian stimulation with human menopausal gonadotrophin, the progesterone/oestradiol ratio rose in parallel with the fertilization rate (P less than 0.05). Group B comprised patients treated with human menopausal gonadotrophin alone. No significant relationship was found between the other parameters, oocyte maturation and fertilization rates in either group. PMID:1387881

  17. 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

  18. 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

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

    PubMed

    Akpovwa, Hephzibah

    2016-06-01

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

  20. Analogue Study of Peer Influence on Risk-Taking Behavior in Older Adolescents

    PubMed Central

    Reynolds, Elizabeth K.; MacPherson, Laura; Schwartz, Sarah; Fox, Nathan A.; Lejuez, C. W.

    2013-01-01

    This experimental study aimed to examine whether adolescents act in a riskier manner in the presence of peers and whether peer presence alone influences risk behavior or if a direct influence process is necessary. Utilizing a behavioral task assessing risk-taking, 183 older adolescents (18–20 year olds) came to the laboratory alone once and then were randomized to one of three conditions: alone, peers present, peers encouraging. An interaction was found such that at baseline there were no significant differences between the three conditions but at the experimental session there was a significant increase in risk task scores particularly for the encouraging condition. These findings challenge proposed models of the interaction between peer influence and risk taking by providing evidence that adolescents take more risks when being encouraged by peers but that the presence of peers on its own does not lead to more risks than when completing the task alone. PMID:24122411

  1. 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…

  2. Keratopathy with low dose chloroquine therapy.

    PubMed

    Cullen, A P; Chou, B R

    1986-05-01

    Antimalarial drugs (4-aminoguinolines) are often used as non-steroidal anti-inflammatories and remission inducers in the treatment of rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). In this paper we report on ocular signs of aminoquinolinic toxicity among 39 patients, 31 with RA and 8 with SLE. These patients received either chloroquine 250 mg q.h.s. or hydroxychloroquine 200 mg b.i.d. No maculopathy was detected, however 75% of the patients showed various degrees of keratopathy ranging from epithelial haze to dense "whorl" deposits. No correlation was found between severity of the keratopathy and the estimated total amount of aminoquinoline administered. PMID:3711574

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

    NASA Astrophysics Data System (ADS)

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

    2013-06-01

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

  4. [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. PMID:21520638

  5. Synthesis and antimalarial activity of chain substituted pivaloyloxymethyl ester analogues of Fosmidomycin and FR900098.

    PubMed

    Kurz, Thomas; Schlüter, Katrin; Kaula, Uwe; Bergmann, Bärbel; Walter, Rolf D; Geffken, Detlef

    2006-08-01

    Fosmidomycin is a promising antimalarial drug candidate with a unique chemical structure and a novel mode of action. Chain substituted pivaloyloxymethyl ester derivatives of Fosmidomycin and its acetyl analogue FR900098 have been synthesized and their in vitro antimalarial activity versus the Chloroquine sensitive strain 3D7 of Plasmodium falciparum has been determined. PMID:16679022

  6. gamma-Substituted bis(pivaloyloxymethyl)ester analogues of fosmidomycin and FR900098.

    PubMed

    Kurz, Thomas; Behrendt, Christoph; Pein, Miriam; Kaula, Uwe; Bergmann, Bärbel; Walter, Rolf D

    2007-12-01

    The synthesis and in-vitro antimalarial activity of gamma-substituted bis(pivaloyloxymethyl)ester analogues of the drug candidate fosmidomycin have been investigated. In contrast to the high antimalarial activity of alpha-aryl substituted fosmidomycin analogues like alpha-phenylfosmidomycin, gamma-substituted derivatives display only weak to moderate activity against the chloroquine-sensitive strain 3D7 of Plasmodium falciparum. PMID:17994605

  7. Retinal toxicity of chloroquine hydrochloride administered by intraperitoneal injection.

    PubMed

    Gaynes, Bruce Ira; Torczynski, Elise; Varro, Zoltan; Grostern, Richard; Perlman, Jay

    2008-10-01

    Chloroquine is quinolone derivative known to exert dose-related retinal toxicity, albeit in a variable manner. It is thought that variability in the presentation of chloroquine retinopathy may be the result of perturbations in drug bioavailability subsequent to oral ingestion. In order to better understand the ramifications of bioavailability on the development of retinal injury subsequent to chloroquine use, this study investigated the relationship between retinal injury and chloroquine administration via intraperitoneal rather than oral administration. Four-week-old C57/6J mice underwent daily intraperitoneal injection of 10 mg kg(-1) chloroquine hydrochloride for a total of 62 days. Following treatment, tissue was fixed in preparation for analysis by light and transmission electron microscopy. Treated animals demonstrated marked abnormality of the outer retinal layers described as complete loss of the outer plexiform layer as well as photoreceptors and photoreceptor nuclei. The retinal pigmented epithelium demonstrated focal atrophy, loss of nuclei and pigment irregularity. Findings in the inner retina were notable for the loss of Müller cells and the presence of membranous cytoplasmic bodies. Retinae of control animals were entirely normal. In contrast to previous studies in the murine model examining chloroquine retinopathy subsequent to oral administration, this study suggests that intraperitoneal chloroquine administration facilitates retinal toxicity, presumably due to heightened drug absorption and bioavailability. It is posited that an increased rate of drug accumulation within the retina leads to an enhanced lysosomotrophic drug effect due to inability of the lysosome to compensate for chloroquine-induced elevation in pH through re-acidification of the intra-lysosomal content. PMID:18484088

  8. 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

  9. 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

  10. Internalized insulin-receptor complexes are unidirectionally translocated to chloroquine-sensitive degradative sites. Dependence on metabolic energy

    SciTech Connect

    Berhanu, P.

    1988-04-25

    Insulin receptors on the surface of isolated rat adipocytes were photoaffinity labeled at 12 degrees C with the iodinated photoreactive insulin analogue, 125I-B2 (2-nitro-4-azidophenylacetyl)-des-PheB1-insulin, and the pathways in the intracellular processing of the labeled receptors were studied at 37 degrees C. During 37 degrees C incubations, the labeled 440-kDa insulin receptors were continuously internalized (as assessed by trypsin inaccessibility) and degraded such that up to 50% of the initially labeled receptors were lost by 120 min. Metabolic poisons (0.125-0.75 mM 2,4-dinitrophenol (DNP) and 1-10 mM NaF), which led to dose-dependent depletion of adipocyte ATP pools, inhibited receptor loss, and caused up to 3-fold increase in intracellular receptor accumulation. This effect was due to inhibition of intracellular receptor degradation, and there was no apparent effect of the metabolic poisons on initial internalization of the receptors. Following maximal intracellular accumulation of labeled insulin receptors in the presence of NaF or DNP, removal of these agents resulted in a subsequent, time-dependent degradation of the accumulated receptors. However, when the lysosomotropic agent, chloroquine (0.2 mM), was added immediately following removal of the metabolic poisons, further degradation of the intracellularly accumulated receptors was prevented, suggesting that the chloroquine-sensitive degradation of insulin receptors occurs distal to the site of inhibition by NaF or DNP. To confirm this, maximal intracellular accumulation of labeled receptors was first allowed to occur in the presence of chloroquine and the cells were then washed and reincubated in chloroquine-free media in the absence or presence of NaF or DNP. Under these conditions, degradation of the intracellularly accumulated receptors continued to occur, and NaF or DNP failed to block the degradation.

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

    PubMed

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

    2015-07-01

    Antimalarials chloroquine (CQ) and hydroxychloroquine (HCQ) are widely used as antiinflammatory drugs, but side effects include retinopathy and vision loss. The objective of this study was to examine the effect of CQ and HCQ on the barrier integrity of retinal pigment epithelial (RPE) cell monolayers in vitro. Permeability of ARPE-19 cell monolayers was determined using Fluorescein isothiocyanate (FITC)-labeled dextran. The influence of CQ and HCQ on cell death and the expression tight junction molecules was examined. CQ and HCQ significantly increased ARPE-19 monolayer permeability after 3 and 18 h, respectively, and enhanced mRNA levels for claudin-1 and occludin. Cytotoxicity was only observed after 18 h exposure. Thus, CQ and HCQ rapidly enhance RPE barrier permeability in vitro, independent of cytotoxicity or loss of zonula occludens-1, claudin-1, and occludin expression. Our findings suggest that CQ/HCQ-induced permeability of the RPE layer may contribute to blood-retinal barrier breakdown in case of CQ/HCQ-induced retinopathy. PMID:25752684

  12. Pharmacokinetics of Chloroquine and Monodesethylchloroquine in Pregnancy▿

    PubMed Central

    Karunajeewa, Harin A.; Salman, Sam; Mueller, Ivo; Baiwog, Francisca; Gomorrai, Servina; Law, Irwin; Page-Sharp, Madhu; Rogerson, Stephen; Siba, Peter; Ilett, Kenneth F.; Davis, Timothy M. E.

    2010-01-01

    In order to determine the pharmacokinetic disposition of chloroquine (CQ) and its active metabolite, desethylchloroquine (DECQ), when administered as intermittent presumptive treatment in pregnancy (IPTp) for malaria, 30 Papua New Guinean women in the second or third trimester of pregnancy and 30 age-matched nonpregnant women were administered three daily doses of 450 mg CQ (8.5 mg/kg of body weight/day) in addition to a single dose of sulfadoxine-pyrimethamine. For all women, blood was taken at baseline; at 1, 2, 4, 6, 12, 18, 24, 30, 48, and 72 h posttreatment; and at 7, 10, 14, 28, and 42 days posttreatment. Plasma was subsequently assayed for CQ and DECQ by high-performance liquid chromatography, and population pharmacokinetic modeling was performed. Pregnant subjects had significantly lower area under the plasma concentration-time curve for both CQ (35,750 versus 47,892 μg·h/liter, P < 0.001) and DECQ (23,073 versus 41,584 μg·h/liter, P < 0.001), reflecting significant differences in elimination half-lives and in volumes of distribution and clearances relative to bioavailability. Reduced plasma concentrations of both CQ and DECQ could compromise both curative efficacy and posttreatment prophylactic properties in pregnant patients. Higher IPTp CQ doses may be desirable but could increase the risk of adverse hemodynamic effects. PMID:20086162

  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. [Chloroquine and hydroxychloroquine: side effect profile of important therapeutic drugs].

    PubMed

    Ochsendorf, F R; Runne, U

    1991-03-01

    Precise knowledge of the undesirable effects of chloroquine and hydroxychloroquine allows better exploitation of their therapeutic effects. Retinopathy can be avoided by observing a maximum daily dosage of 3.5-4 mg/kg ideal body weight for chloroquine and 6-6.5 mg/kg for hydroxychloroquine. In this way, both can be used for long-term therapy. The pharmacokinetics of chloroquine (storage in deep compartments with long plasma half-life) means that it can cumulate, especially with higher dosages and in the presence of renal or hepatic insufficiency. A high plasma concentration reinforces the side-effects without reinforcing the therapeutic effects. Besides subjective symptoms (e.g. anorexia, diarrhoea, nausea), the following undesirable reactions are significant. On the skin exanthema, hyperpigmentation and photodynamic reactions can develop. The hair can become white in blonde and red-haired men. In the eye, chloroquine deposits in the cornea and disturbances of accommodation can occur, besides retinopathy. Neuromyopathy and central nervous system disturbances (e.g. psychosis) are rare, as is impairment of auditory function or blood cells. During pregnancy there is a risk of potential fetal damage (hearing loss, abortion). An acute overdose is extremely dangerous: the lethal dose is 1 g for children and 4 g for adults. As death occurs rapidly, chloroquine has to be stored where it is absolutely inaccessible to children. PMID:2055762

  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. Chloroquine: Ophthalmological Safety, and Clinical Assessment in Rheumatoid Arthritis

    PubMed Central

    Percival, S. P. B.; Meanock, I.

    1968-01-01

    272 patients on long-term chloroquine therapy were assessed with respect to ocular toxicity and clinical benefit. A simple scheme for rendering patients ophthalmologically safe is presented, employing the recording of central fields to red targets. Under this it was possible to diagnose a state of premaculopathy, which was reversible on stopping treatment. The incidence of premaculopathy was 41% in 143 patients who otherwise displayed no abnormality of the fundus oculi and who had received a mean total dose of 410 g. of chloroquine phosphate or the hydroxychloroquine sulphate equivalent. Under this joint ophthalmological and rheumatological supervision it was considered that the minor side-effects that may be caused by chloroquine are outweighed by its therapeutic value. ImagesFig. 3 PMID:4875645

  18. In Vivo Confocal Microscopy in Chloroquine-Induced Keratopathy

    PubMed Central

    Paladini, Iacopo; Menchini, Ugo; Mencucci, Rita

    2013-01-01

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

  19. Clinical efficacy of chloroquine followed by primaquine for Plasmodium vivax treatment in Azerbaijan.

    PubMed

    Valibayov, Abbas; Abdullayev, Farman; Mammadov, Suleyman; Gasimov, Elkhan; Sabatinelli, Guido; Kondrachine, Anatoli V; Ringwald, Pascal

    2003-09-01

    Efficacy of chloroquine followed by primaquine has been monitored in 153 patients in seven districts of Azerbaijan. Chloroquine is fully effective over the first 14 days and the combination of chloroquine and primaquine is 100% effective over 28 days. PMID:12943984

  20. 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

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

    PubMed Central

    Weinreb, Marvin S.

    1967-01-01

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

  2. 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. PMID:25716330

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

    NASA Astrophysics Data System (ADS)

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

    2015-04-01

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

  4. Effect of grapefruit juice on plasma chloroquine kinetics in mice.

    PubMed

    Ali, B H; Al-Qarawi, A; Mousa, H M

    2002-08-01

    1. It is known that grapefruit juice (GFJ) may interact with drugs concomitantly administered by inhibiting first-pass metabolism during the intestinal absorption phase. However, its interaction with chloroquine has not been studied previously. 2. Grapefruit juice (4 mL/kg) was given orally to mice 1 h prior to oral administration of chloroquine (100 mg/kg) and the concentration of the latter drug was measured fluorometrically in the plasma 0, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 12, 18 and 24 h after its administration. 3. The mean (+/-SEM) of area under the curve values after administration of water +/- control) and GFJ were 5.34 +/- 0.38 and 7.01 +/- 0.66 mg.h/L, respectively. The corresponding mean C(max) values were 763.4 +/- 39.1 and 859.2 +/- 45.2 mg/L and the corresponding T(max) values (median) were 2.65 and 2.95 h. 4. The results suggest that GFJ coingestion increased the plasma concentration of chloroquine and altered some kinetic parameters of chloroquine. The clinical significance of this interaction in patients with malaria needs to be investigated. PMID:12100003

  5. Regio- and stereoselective biomimetic synthesis of oligostilbenoid dimers from resveratrol analogues: influence of the solvent, oxidant, and substitution.

    PubMed

    Velu, Saraswati S; Buniyamin, Irmaizatussyehdany; Ching, Lee Kiew; Feroz, Fareeda; Noorbatcha, Ibrahim; Gee, Lim Chuan; Awang, Khalijah; Wahab, Ibtisam Abd; Weber, Jean-Frédéric Faizal

    2008-01-01

    Oligostilbenoids are polyphenols that are widely distributed in nature with multifaceted biological activities. To achieve biomimetic synthesis of unnatural derivatives, we subjected three resveratrol analogues to oligomerization by means of one-electron oxidants. Upon varying the metal oxidant (AgOAc, CuBr(2), FeCl(3)6 H(2)O, FeCl(3)6 H(2)O/NaI, PbO(2), VOF(3)), the solvent (over the whole range of polarities), and the oxygenated substitution pattern of the starting material, stilbenoid oligomers with totally different carbon skeletons were obtained. Here we propose to explain the determinism of the type of skeleton produced with the aid of hard and soft acid/base concepts in conjunction with the solvating properties of the solvents and the preferred alignment by the effect of pi stacking. PMID:19003831

  6. 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. PMID:23648708

  7. Impact of Chloroquine on Viral Load in Breast Milk

    PubMed Central

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

    2006-01-01

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

  8. Detecting chloroquine retinopathy: electro-oculogram versus colour vision

    PubMed Central

    Neubauer, A S; Samari-Kermani, K; Schaller, U; Welge-Lüβen, U; Rudolph, G; Berninger, T

    2003-01-01

    Aim: To investigate the relative sensitivity and specificity of two tests of retinal function (the electro-oculogram (EOG) and a computerised colour vision test) in screening for ocular toxicity caused by chloroquine and hydroxychloroquine. Methods: 93 patients with rheumatic diseases receiving long term chloroquine and hydroxychloroquine therapy were followed for an average of 2.6 years. Clinical examination, an EOG, and a quantitative test of colour vision were carried out every 6 months. Results: Mild fundus changes were observed in 38 patients. Four patients developed typical bull’s eye maculopathy, three of whom had received 250, 365, and 550 g total dose of chloroquine, and one 1500 g of hydroxychloroquine. Statistical analysis of all patients showed that for those with no fundus changes or stippled pigmentation a number showed elevation of tritan threshold, so that if macular stippling is a sign of mild retinopathy the test on tritan changes has a 64% sensitivity and 63% specificity for an upper threshold value of 7%. All four patients with bull’s eye lesions showed a marked disturbance of tritan colour vision, with a threshold of 14.8%, a sensitivity of 75%, and a specificity of 94%. For protan colour vision a threshold of 10% gives 75% sensitivity and 91% specificity. By contrast, neither an absolute nor a relative EOG reduction was a valid criterion for early or late chloroquine retinopathy. In advanced retinopathy an Arden coefficient (AQ) <180% yields 50% sensitivity and 54% specificity. When AQ <160% is the threshold, sensitivity does not increase but specificity rises to 82%. Occurrence of marked corneal deposits on clinical examination yields 50% sensitivity and 90% specificity in this situation. Conclusion: Screening for chloroquine retinopathy can be improved by using a sensitive colour test. Disturbance of the tritan axis appears to occur first. A normal test result on computerised colour testing virtually excludes any retinopathy by

  9. Molecular Mechanism of Renal Tubular Secretion of the Antimalarial Drug Chloroquine

    PubMed Central

    Müller, Fabian; König, Jörg; Glaeser, Hartmut; Schmidt, Ingrid; Zolk, Oliver; Fromm, Martin F.; Maas, Renke

    2011-01-01

    The antimalarial drug chloroquine is eliminated to a significant extent by renal tubular secretion. The molecular mechanism of renal chloroquine secretion remains unknown. We hypothesized that organic cation transporter 2 (OCT2) and multidrug and toxin extrusion protein 1 (MATE1), localized in the basolateral and luminal membranes of proximal tubule cells, respectively, are involved in chloroquine transport. The interaction of chloroquine with both transporters was investigated using single-transfected human embryonic kidney 293 (HEK293)-MATE1 cells in uptake experiments and single-transfected Madin-Darby canine kidney II (MDCK)-OCT2 and MDCK-MATE1 cells as well as double-transfected MDCK-OCT2-MATE1 cells grown as polarized monolayers on transwell filters. In HEK293-MATE1 cells, chloroquine competitively inhibited MATE1-mediated metformin uptake (Ki = 2.8 μM). Cellular accumulation of chloroquine was significantly lower (P < 0.001) and transcellular chloroquine transport was significantly increased (P < 0.001) in MDCK-MATE1 and MDCK-OCT2-MATE1 cells compared to vector control cells after basal addition of chloroquine (0.1 to 10 μM). In contrast, no difference in cellular accumulation or transcellular transport of chloroquine was observed between MDCK-OCT2 and vector control cells. In line with an oppositely directed proton gradient acting as a driving force for MATE1, basal-to-apical transport of chloroquine by MDCK-OCT2-MATE1 cells increased with decreasing apical pH from 7.8 to 6.0. Transcellular transport of chloroquine by MDCK-OCT2-MATE1 cells was inhibited by cimetidine, trimethoprim, and amitriptyline. Our data demonstrate that chloroquine is a substrate and potent competitive inhibitor of MATE1, whereas OCT2 seems to play no role in chloroquine uptake. Concomitantly administered MATE1 inhibitors are likely to modify the renal secretion of chloroquine. PMID:21518836

  10. The influence of thought suppression and cognitive load on intrusions and memory processes following an analogue stressor.

    PubMed

    Nixon, Reginald D V; Cain, Neralie; Nehmy, Thomas; Seymour, Melanie

    2009-12-01

    Ironic Process Theory and the role of thought suppression have been used in part to explain the phenomenon of intrusive memories in various disorders, including posttraumatic stress disorder. How thought suppression interacts with other cognitive processes believed to be instrumental in the development of traumatic intrusive memory is unclear. In an analogue study, thought suppression and cognitive processing was manipulated in 4 experimental groups after participants (n=80) viewed a trauma film. The impact of suppression was examined in relation to self-reported intrusive experiences as well as via more objective methods (word stem and dot probe tasks) to assess potential preferential encoding of negative material. Cognitive load appeared to undermine thought suppression ability, with these participants experiencing more intrusions over the week relative to participants in all other conditions. This group also showed greater priming to negative film-related words, and both suppression groups demonstrated enhanced memory for film-related content on recognition testing. Thought suppression mediated the relationship between negative interpretations of initial intrusions and later intrusions experienced over the week. The findings are discussed in the context of ironic process theory and cognitive models of posttraumatic stress. PMID:19892082

  11. 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

  12. Oxygen and exposure kinetics as factors influencing the cytotoxicity of porfiromycin, a mitomycin C analogue, in Chinese hamster ovary cells.

    PubMed

    Marshall, R S; Rauth, A M

    1988-10-15

    Some factors affecting the cytotoxicity of porfiromycin (PM), an analogue of mitomycin C (MMC), were investigated in suspension cultures of wild-type (AA8-4) and repair-deficient (UV-20) Chinese hamster ovary cells. Oxygen was an important modulator of PM toxicity in AA8-4 cells. The aerobic toxicity was significantly less, and toxicity under extremely hypoxic conditions was significantly greater for PM than MMC. Porfiromycin cytotoxicity at intermediate O2 levels was similar to that observed previously for MMC. While the aerobic/hypoxic ratio was greater for PM than MMC, survival at intermediate oxygen concentrations could limit the therapeutic utility of these drugs as adjuncts to radiotherapy. Ascorbic acid was found to increase the aerobic, but not hypoxic, cytotoxicity of PM in AA8-4 cells, as was observed previously for MMC. Investigation of various exposure times and drug concentrations revealed that drug toxicity for both aerobic and hypoxic cells was dependent on the product of drug concentration and time, and that the aerobic/hypoxic differential observed in AA8-4 cells was constant over a broad range of exposure conditions. The sensitivity of UV-20 cells was also a linear function of concentration and time, but no aerobic/hypoxic differential was observed in these cells. It is suggested that the sensitivity of UV-20 to PM and MMC, and its lack of an hypoxic/aerobic differential could result from lethality being due to a different lesion than in wild-type cells. PMID:3167822

  13. Chloroquine in the treatment of porphyria cutanea tarda.

    PubMed

    Tsega, E; Besrat, A; Damtew, B; Seyoum, E; Landells, J W

    1981-01-01

    Porphyria cutanea tarda (PCT) is common in Ethiopia and invariably affects the liver. Treatment by abstension from alcohol and avoidance of direct sunlight often failed to achieve lasting improvement. Phlebotomy is unacceptable to most of our patients and impractical as a routine therapy. Chloroquine phosphate 500 mg (300 mg base) given daily for 10 days to 24 patients with confirmed PCT, was found to be uniformly effective. Both clinical and biochemical remissions were complete, The side effects of chloroquine include fever, nausea, vomiting and myalgia which predictably occur on the third day of therapy and subside within 72 hours. Since all other modes of therapy are ineffective or impractical and since the response to chloroquine is prompt, effective and reproducible and the side effects are brief, mild and do not cause permanent hepatic damage, it is suggested that this drug is currently the most practical treatment for PCT in areas where repeated phlebotomy is unacceptable and patient follow-up is unsatisfactory. PMID:7324107

  14. 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

  15. Recent advances in topoisomerase I-targeting agents, camptothecin analogues.

    PubMed

    Kim, Dae-Kee; Lee, Namkyu

    2002-12-01

    The present review concentrates on camptothecin (CPT) analogues, the most extensively studied topoisomerase I (topo I) inhibitors, and provides concise information on the structural features of human topo I enzyme, mechanisms of interaction of CPT with topo I, structure-activity relationship study of CPT analogues including the influence of lactone stability on antitumor activity, and recent updates of valuable CPT analogues. PMID:12370044

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

    PubMed Central

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

    2008-01-01

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

  17. 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. PMID:22840888

  18. Chloroquine-Resistant Malaria in Travelers Returning from Haiti after 2010 Earthquake

    PubMed Central

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

    2012-01-01

    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. PMID:22840888

  19. 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

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

    PubMed

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

    2016-07-01

    Immune activation associated with HIV-1 infection contributes to morbidity and mortality. We studied whether chloroquine, through Toll-like receptor (TLR) antagonist properties, could reduce immune activation thought to be driven by TLR ligands, such as gut-derived bacterial elements and HIV-1 RNAs. AIDS Clinical Trials Group A5258 was a randomized, double-blind, placebo-controlled study in 33 HIV-1-infected participants off antiretroviral therapy (ART) and 37 participants on ART. Study participants in each cohort were randomized 1:1 to receive chloroquine 250 mg orally for the first 12 weeks then cross over to placebo for 12 weeks or placebo first and then chloroquine. Combining the periods of chloroquine use in both arms of the on-ART cohort yielded a modest reduction in the proportions of CD8 T cells co-expressing CD38 and DR (median decrease = 3.0%, p = .003). The effect on immune activation in the off-ART cohort was likely confounded by increased plasma HIV-1 RNA during chloroquine administration (median 0.29 log10 increase, p < .001). Transcriptional analyses in the off-ART cohort showed decreased expression of interferon-stimulated genes in 5 of 10 chloroquine-treated participants and modest decreases in CD38 and CCR5 RNAs in all chloroquine-treated participants. Chloroquine modestly reduced immune activation in ART-treated HIV-infected participants. Clinical Trials Registry Number: NCT00819390. PMID:26935044

  1. 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

  2. Metabolic QTL Analysis Links Chloroquine Resistance in Plasmodium falciparum to Impaired Hemoglobin Catabolism

    PubMed Central

    Olszewski, Kellen L.; Cobbold, Simon A.; Baska, Katelynn S.; Tan, Asako; Ferdig, Michael T.; Llinás, Manuel

    2014-01-01

    Drug resistant strains of the malaria parasite, Plasmodium falciparum, have rendered chloroquine ineffective throughout much of the world. In parts of Africa and Asia, the coordinated shift from chloroquine to other drugs has resulted in the near disappearance of chloroquine-resistant (CQR) parasites from the population. Currently, there is no molecular explanation for this phenomenon. Herein, we employ metabolic quantitative trait locus mapping (mQTL) to analyze progeny from a genetic cross between chloroquine-susceptible (CQS) and CQR parasites. We identify a family of hemoglobin-derived peptides that are elevated in CQR parasites and show that peptide accumulation, drug resistance, and reduced parasite fitness are all linked in vitro to CQR alleles of the P. falciparum chloroquine resistance transporter (pfcrt). These findings suggest that CQR parasites are less fit because mutations in pfcrt interfere with hemoglobin digestion by the parasite. Moreover, our findings may provide a molecular explanation for the reemergence of CQS parasites in wild populations. PMID:24391526

  3. 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

  4. Interruption of malaria transmission by chloroquinized salt in Guyana

    PubMed Central

    Giglioli, George; Rutten, Frans J.; Ramjattan, S.

    1967-01-01

    Malaria and its local vector, Anopheles darlingi, were eradicated from the coastlands and near interior of Guyana by DDT house-spraying in 1945-51. In the remote interior, where 10% of the population live, only partial control could be achieved, owing to the semi-silvatic habits of A. darlingi and the considerable movement of the sparse population; low malaria endemicity persisted in these areas with occasional localized outbreaks. In the south-west the problem was further complicated by the presence of malaria across the frontier. During the years 1961-65, the use of chloroquinized salt was made compulsory over an area of some 109 000 km2, covering a population of 48 500. Satisfactory results were obtained over 84% of this area within 6 months of the start of the campaign; only four cases of malaria were seen in four years. In the south-west, however, an initially favourable trend was reversed in 1962 with the introduction of a chloroquine-resistant strain of Plasmodium falciparum from Brazil. The situation was brought under control by house-spraying with DDT and interruption of transmission is expected. PMID:4864651

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

    PubMed Central

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

    2014-01-01

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

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

    PubMed

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

    2014-10-01

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

  7. Chloroquine-Resistant Haplotype Plasmodium falciparum Parasites, Haiti

    PubMed Central

    Londono, Berlin L.; Eisele, Thomas P.; Keating, Joseph; Bennett, Adam; Chattopadhyay, Chandon; Heyliger, Gaetan; Mack, Brian; Rawson, Ian; Vely, Jean-Francois; Désinor, Olbeg

    2009-01-01

    Plasmodium falciparum parasites have been endemic to Haiti for >40 years without evidence of chloroquine (CQ) resistance. In 2006 and 2007, we obtained blood smears for rapid diagnostic tests (RDTs) and filter paper blots of blood from 821 persons by passive and active case detection. P. falciparum infections diagnosed for 79 persons by blood smear or RDT were confirmed by PCR for the small subunit rRNA gene of P. falciparum. Amplification of the P. falciparum CQ resistance transporter (pfcrt) gene yielded 10 samples with amplicons resistant to cleavage by ApoI. A total of 5 of 9 samples had threonine at position 76 of pfcrt, which is consistent with CQ resistance (haplotypes at positions 72–76 were CVIET [n = 4] and CVMNT [n = 1]); 4 had only the wild-type haplotype associated with CQ susceptibility (CVMNK). These results indicate that CQ-resistant haplotype P. falciparum malaria parasites are present in Haiti. PMID:19402959

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

    PubMed

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

    2015-01-01

    The occurrence of treatment failures to first-line treatment for giardiasis, one of the most widespread although neglected parasitic disease, has long been recognised. Nowadays, it starts to represent a great challenge to clinicians, especially in endemic countries. This requires the introduction of new drug interventions, but the development of novel drugs is a time and money consuming effort with most of the compounds never reaching the market. Consequently, alternative strategies are needed, especially for the treatment of giardiasis. Chloroquine (CQ), a synthetic drug developed as antimalarial agent, has been shown to also exert antigiardial activity. Here, we present a mini-research summarizing results on the treatment of human clinical cases with CQ, going through in vitro research, case report, and case series to human clinical trials, highlighting the benefits and mentioning possible adverse effects. PMID:26365362

  9. Tumor vessel normalization by chloroquine independent of autophagy.

    PubMed

    Maes, Hannelore; Kuchnio, Anna; Peric, Aleksandar; Moens, Stijn; Nys, Kris; De Bock, Katrien; Quaegebeur, Annelies; Schoors, Sandra; Georgiadou, Maria; Wouters, Jasper; Vinckier, Stefan; Vankelecom, Hugo; Garmyn, Marjan; Vion, Anne-Clémence; Radtke, Freddy; Boulanger, Chantal; Gerhardt, Holger; Dejana, Elisabetta; Dewerchin, Mieke; Ghesquière, Bart; Annaert, Wim; Agostinis, Patrizia; Carmeliet, Peter

    2014-08-11

    Chloroquine (CQ) has been evaluated as an autophagy blocker for cancer treatment, but it is unknown if it acts solely by inhibiting cancer cell autophagy. We report that CQ reduced tumor growth but improved the tumor milieu. By normalizing tumor vessel structure and function and increasing perfusion, CQ reduced hypoxia, cancer cell invasion, and metastasis, while improving chemotherapy delivery and response. Inhibiting autophagy in cancer cells or endothelial cells (ECs) failed to induce such effects. CQ's vessel normalization activity relied mainly on alterations of endosomal Notch1 trafficking and signaling in ECs and was abrogated by Notch1 deletion in ECs in vivo. Thus, autophagy-independent vessel normalization by CQ restrains tumor invasion and metastasis while improving chemotherapy, supporting the use of CQ for anticancer treatment. PMID:25117709

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

    NASA Astrophysics Data System (ADS)

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

    2014-05-01

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

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

    PubMed Central

    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

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

    SciTech Connect

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

    1987-03-01

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

  13. The prescribing of chloroquine and hydroxychloroquine by consultant rheumatologists in the UK.

    PubMed

    Kay, E A; Rees, J A; Jayson, M I

    1987-10-01

    A questionnaire on chloroquine and hydroxychloroquine prescribing was circulated nationally to 212 consultant rheumatologists and 119 replies were analysed. Of all patients receiving second-line drugs, 10% were prescribed antimalarials, with hydroxychloroquine being used four times more frequently than chloroquine. Eighty-five per cent of rheumatologists always used the same dose of hydroxychloroquine or chloroquine. Only 5% considered patient's weight in deciding the dose. Fear of ocular toxicity was expressed by many physicians; 54% had experienced corneal deposits; 4% retinopathy and 40% believed cumulative dose determined toxicity. Much confusion existed over the necessity for and frequency of ophthalmological monitoring. Only 56% requested ophthalmological tests before commencing treatment, although 86% monitored the eyes during therapy. Other side-effects were believed to affect 1-10% of patients, with no anticipated difference between doses of 250 mg chloroquine and 400 mg hydroxychloroquine daily. PMID:3664163

  14. 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

  15. Chloroquine is effective against influenza A virus in vitro but not in vivo

    PubMed Central

    Vigerust, David J.; McCullers, Jonathan A.

    2008-01-01

    Background  Chloroquine is an inexpensive and widely available 9‐aminoquinolone used in the management of malaria. Recently, in vitro assays suggest that chloroquine may have utility in the treatment of several viral infections including influenza. Objectives  We sought to test whether chloroquine is effective against influenza in vivo in relevant animal models. Methods  The effectiveness of chloroquine at preventing or ameliorating influenza following viral challenge was assessed in established mouse and ferret disease models. Results  Although active against influenza viruses in vitro, chloroquine did not prevent the weight loss associated with influenza virus infection in mice after challenge with viruses expressing an H1 or H3 hemagglutinin protein. Similarly, clinical signs and viral replication in the nose of ferrets were not altered by treatment. Conclusions  Although in vitro results were promising, chloroquine was not effective as preventive therapy in vivo in standard mouse and ferret models of influenza virus infection. This dampens enthusiasm for the potential utility of the drug for humans with influenza. PMID:19453426

  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. 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

  18. 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. PMID:27041650

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

    PubMed Central

    Awasthi, Gauri; Das, Aparup

    2013-01-01

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

  20. Chloroquine rescues A549 cells from paraquat-induced death.

    PubMed

    Xu, Lingjie; Wang, Zhong

    2016-04-01

    Paraquat (PQ) is a widely used herbicide associated with a high mortality rate, yet, there are no effective treatments for PQ poisoning. PQ may damage alveolar type II cells leading to moderate to severe acute respiratory distress syndrome (ARDS). The present study was undertaken to show that PQ causes alveolar type II (A549) cell death and to evaluate whether chloroquine (CQ) can protect A549 cells against PQ-induced cell death. The results showed that high concentrations of PQ resulted in toxicity, as indicated by a decrease in cell viability. More importantly, for the first time, CQ was found to improve cell viability of PQ treated A549 cells. Moreover, our data demonstrated that CQ increased lysosome-associated membrane protein-1, lysosome-associated membrane protein-2 and light chain-3 expressions, suggesting that the mechanism by which CQ rescues PQ-induced cytotoxicity may be through protection of the lysosomal membrane or up-regulation of autophagy. In conclusion, our study indicates that CQ may be used as a potential drug to rescue PQ-induced ARDS. PMID:26154125

  1. 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

  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. 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. PMID:26832222

  4. 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

  5. Battling the malaria iceberg with chloroquine in India

    PubMed Central

    Sharma, Vinod P

    2007-01-01

    The National Vector Borne Disease Control Programme (NVBDCP) of the Ministry of Health, Government of India is reporting about 2 million parasite positive cases each year, although case incidence is 30-fold or more under-estimated. Forty five to fifty percent of Plasmodium infections are caused by Plasmodium falciparum, the killer parasite. Anti-malaria drug policy (2007) of the NVBDC recommends chloroquine (CQ) as the first line of drug for the treatment of all malarias. In a Primary Health Centre (PHC) reporting 10% or more cases of CQ resistance in P. falciparum, ACT blister pack is recommended and, so far, the policy has been adopted in 261 PHCs of 71 districts. The NVBDCP still depends on CQ to combat malaria and, as a result, P. falciparum has taken deep roots in malaria-endemic regions, causing unacceptable levels of morbidity and mortality. This policy was a subject of criticism in recent Nature and Lancet articles questioning the World Bank's decision to supply CQ to the NVBDCP. Continuation of an outdated drug in the treatment of P. falciparum is counterproductive in fighting drug resistant malaria and in the containment of P. falciparum. Switchover to Artemisinin-based Combination Therapy (ACT) in the treatment of all P. falciparum cases, ban on artemisinin monotherapy and effective vector control (treated nets/efficient insecticide spraying) would be a rational approach to malaria control in India. PMID:17683630

  6. Return of chloroquine-sensitive Plasmodium falciparum parasites and emergence of chloroquine-resistant Plasmodium vivax in Ethiopia

    PubMed Central

    2014-01-01

    Background Increased resistance by Plasmodium falciparum parasites led to the withdrawal of the antimalarial drugs chloroquine and sulphadoxine-pyrimethamine in Ethiopia. Since 2004 artemether-lumefantrine has served to treat uncomplicated P. falciparum malaria. However, increasing reports on delayed parasite clearance to artemisinin opens up a new challenge in anti-malarial therapy. With the complete withdrawal of CQ for the treatment of Plasmodium falciparum malaria, this study assessed the evolution of CQ resistance by investigating the prevalence of mutant alleles in the pfmdr1 and pfcrt genes in P. falciparum and pvmdr1 gene in Plasmodium vivax in Southern and Eastern Ethiopia. Methods Of the 1,416 febrile patients attending primary health facilities in Southern Ethiopia, 329 febrile patients positive for P. falciparum or P. vivax were recruited. Similarly of the 1,304 febrile patients from Eastern Ethiopia, 81 febrile patients positive for P. falciparum or P. vivax were included in the study. Of the 410 finger prick blood samples collected from malaria patients, we used direct sequencing to investigate the prevalence of mutations in pfcrt and pfmdr1. This included determining the gene copy number in pfmdr1 in 195 P. falciparum clinical isolates, and mutations in the pvmdr1 locus in 215 P. vivax clinical isolates. Results The pfcrt K76 CQ-sensitive allele was observed in 84.1% of the investigated P.falciparum clinical isolates. The pfcrt double mutations (K76T and C72S) were observed less than 3%. The pfcrt SVMNT haplotype was also found to be present in clinical isolates from Ethiopia. The pfcrt CVMNK-sensitive haplotypes were frequently observed (95.9%). The pfmdr1 mutation N86Y was observed only in 14.9% compared to 85.1% of the clinical isolates that carried sensitive alleles. Also, the sensitive pfmdr1 Y184 allele was more common, in 94.9% of clinical isolates. None of the investigated P. falciparum clinical isolates carried S1034C, N1042D and D1246Y

  7. 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. PMID:26149984

  8. 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.

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

    PubMed Central

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

    2002-01-01

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

  10. Synthesis and biological evaluation of tricyclic guanidine analogues of batzelladine K for antimalarial, antileishmanial, antibacterial, antifungal and anti-HIV activities

    PubMed Central

    Ahmed, Nafees; Brahmbhatt, Keyur G.; Khan, Shabana I.; Jacob, Melissa; Tekwani, Babu L.; Sabde, Sudeep; Mitra, Debashis; Singh, Inder Pal; Khan, Ikhlas A.; Bhutani, Kamlesh K.

    2012-01-01

    Fifty analogues of batzelladine K were synthesized and evaluated for in vitro antimalarial (Plasmodium falciparum), antileishmanial (Leishmania donovani), antimicrobial (panel of bacteria and fungi), antiviral (HIV-1) activities. Analogues 14h and 20l exhibited potential antimalarial activity against chloroquine-sensitive D6 strain with IC50 1.25 and 0.88 μM and chloroquine-resistant W2 strain with IC50 1.64 and 1.07 μM, respectively. Analogues 12c and 14c having nonyl substitution showed the most potent antileishmanial activity with IC50 2.39 and 2.78 μM and IC90 11.27 and 12.76 μM respectively. Three analogues 12c, 14c and 14i were the most active against various pathogenic bacteria and fungi with IC50 <3.02 μM and MIC/MBC/MFC <6 μM. Analogue 20l having pentyl and methyl substituents on tricycle showed promising activities against all pathogens. However, none was found active against HIV-1. Our study demonstrated that the tricyclic guanidine compounds provide new structral class for broad spectrum activity. PMID:23534411

  11. 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

  12. 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

  13. 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

  14. 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

  15. 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. PMID:26953199

  16. Selective elution of HLA antigens and beta 2-microglobulin from human platelets by chloroquine diphosphate

    SciTech Connect

    Kao, K.J.

    1988-01-01

    To determine whether chloroquine can specifically elute HLA antigens and beta 2-microglobulin (beta 2-M) from the platelet surface, quantitative immunofluorescence flow cytometry and monoclonal antibodies were used to show that HLA antigens and beta 2-M were proportionally eluted from the platelet surface without affecting the membrane glycoproteins IIb and IIIa. Second, an autoradiogram of electrophoresed I-125-labeled platelets showed that only beta 2-M but not other I-125-labeled membrane proteins could be eluted. Although HLA antigens were poorly labeled by I-125 and could not be detected on the autoradiogram, the eluted HLA antigens could be detected by anti-HLA monoclonal antibody and immunoblotting techniques. No loss of plasma membrane integrity was observed by transmission electron microscopy after chloroquine treatment of platelets. The results indicate that chloroquine selectively elutes HLA antigens and their noncovalently associated beta 2-M without affecting other integral platelet membrane proteins.

  17. Interaction between chloroquine sulphate and aqueous extract of Azadirachta indica A. Juss (Meliaceae) in rabbits.

    PubMed

    Nwafor, Sunday Vitalis; Akah, Peter Achunike; Okoli, Charles Obgonnaya; Onyirioha, Adaoma Chinaemerem; Nworu, Chukwuemeka Sylvesta

    2003-12-01

    This study was carried out to investigate the effect of concurrent oral administration of aqueous leaf extract of Azadirachta indica (Meliaceae) on the pharmacokinetic properties of chloroquine sulphate in experimental rabbits. The results indicated that concurrent administration of both agents resulted in a significant decrease in serum concentration, slower absorption and elimination as well as longer half-life of chloroquine sulphate. The highest relative decrease of 78.0% was recorded 4 hours after concurrent administration, while the smallest decrease (64.6%) occurred 24 hours after concurrent administration. Significant reductions were also noted in some pharmacokinetic parameters of chloroquine and included the area under the curve (71.9%), maximum serum concentration (69.8%), absorption rate constant (37.3%), elimination rate constant (53.9%), clearance rate (76.5%) and volume of distribution (47.2%). However, there was a pronounced increase in the half-life of the drug (125.7%). PMID:14769237

  18. 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.

  19. 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

  20. 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

  1. 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

  2. Acute Pretreatment with Chloroquine Attenuates Renal I/R Injury in Rats

    PubMed Central

    Todorovic, Zoran; Medic, Branislava; Basta-Jovanovic, Gordana; Radojevic Skodric, Sanja; Stojanovic, Radan; Rovcanin, Branislav; Prostran, Milica

    2014-01-01

    Background Acute kidney injury (AKI) still remains an unresolved problem in pharmacotherapy and renal inflammation is a major factor in its development. Chloroquine, a well-known antimalarial drug, posses pleitropic effects as well: antiinflammatory, anticoagulant and vascular actions. The effects of chloroquine on renal function may involve significant increase in urine flow rate, glomerular filtration rate and sodium excretion, as well as stimulation of nitric oxide synthase. However, its role in experimental models of renal I/R injury is unknown. We aimed to analyze the acute effects of a single-dose intravenous chloroquine administered at three different times in the experimental model of I/R injury in rat. Methods Rats were subjected to bilateral renal ischemia (45 min) followed by reperfusion with saline lasting 4 hours. Chloroquine was administered in doses of 0.3 mg/kg i.v. and 3 mg/kg i.v. 30 min before ischemia, 30 min before reperfusion and 5 min before reperfusion. Selected a hemodynamic, biochemical and morphological parameters were followed in the Sham-operated animals and rats subjected to I/R injury and pretreated with saline or chloroquine. Results Chloroquine (0.3 and 3 mg/kg, i.v.) protected the I/R injured kidney in an U-shaped manner. Both doses were protective regarding biochemical and histological markers of the I/R injury (serum urea, creatinine and fractional excretion of sodium, as well as total histological score, tubular necrosis score and KIM-1 staining score) (P<0.05 vs. corresponding controls, i.e. rats subjected to I/R injury and treated with saline only). The protective effects of the lower dose of chloroquine were more profound. Time-related differences between pretreatments were not observed (P>0.05, all). Conclusion Our study shows for the first time that a single dose of chloroquine (0.3 mg/kg i.v.) could afford significant protection of the injured rat kidney. PMID:24681567

  3. 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

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

    PubMed

    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

  5. 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

  6. Oxidant stress in malaria as probed by stable nitroxide radicals in erythrocytes infected with Plasmodium berghei. The effects of primaquine and chloroquine.

    PubMed

    Deslauriers, R; Butler, K; Smith, I C

    1987-12-10

    Erythrocytes from normal mice and mice infected with the malarial parasite Plasmodium berghei reduce the water-soluble spin probes 2,2,6,6-tetramethylpiperidine-4-hydroxy-N-oxyl (TEMPOL), 2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPO) and 2,2,6,6-tetramethylpiperidine-4-keto-N-oxyl (TEMPONE) at similar rates under both air and N2 atmospheres. The ESR signal of the lipid-soluble spin probe 5-doxyl-stearate is stable on incorporation into erythrocytes from normal mice. In contrast, parasitized red cells reduce this nitroxide probe, at a rate which increases with the level of parasitemia. Inhibitors of electron transport such as KCN and NaN3, increase the rate of reduction. We propose that nitroxide reduction occurs via the electron transport chain in the parasite. The antimalarial drug primaquine causes reduction of both water-soluble and lipid-soluble spin probes. This action of primaquine is independent of its ability to release H2O2 from oxyhemoglobin, and is ascribed to the ability of primaquine to accelerate flux through the hexose monophosphate shunt. The increased production of NADPH results in increased rates of reduction of the nitroxide radicals. Methylene blue, which also increases flux through the shunt, is even more effective than primaquine at reducing the nitroxides. Chloroquine has no such effect. Parasitized mice treated with chloroquine six hours prior to ESR measurements show less nitroxide reducing capacity than do untreated mice. Chloroquine is known to decrease flux through the hexose monophosphate shunt. The metabolic influences of the two antimalarial drugs are, thus, quite different. PMID:3315005

  7. 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

  8. 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. PMID:25898991

  9. N'Dribala (Cochlospermum planchonii) versus chloroquine for treatment of uncomplicated Plasmodium falciparum malaria.

    PubMed

    Benoit-Vical, F; Valentin, A; Da, B; Dakuyo, Z; Descamps, L; Mallié, M

    2003-11-01

    The aim of this work was to assess the efficacy of oral N'Dribala (tuberous roots decoction of Cochlospermum planchonii Hook) treatment versus chloroquine in non-severe malaria. The study included 85 patients with uncomplicated Plasmodium falciparum infection in Banfora, Burkina Faso. Forty-six patients that received N'Dribala beverage were compared to 21 patients treated with chloroquine. All patients were monitored with clinical examination and a parasitemia control by Giemsa-stained thick films. N'Dribala appeared safe and statistically as efficient as chloroquine for the treatment of uncomplicated Plasmodium falciparum malaria. At day 5 (D5), 57% of chloroquine-treated and 52% of N'Dribala-treated patients were cured with no detectable parasitemia (parasite density (Pd): 0) and more than 90% of whole patients were asymptomatic. N'Dribala is easily available in this country, cheap, without significant side effects and efficient with a clearly demonstrated activity on Plasmodium falciparum blood stages. This study enhances the traditional use of the Cochlospermum planchonii as alternative therapy for treatment of non-severe malaria. PMID:14522441

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

    PubMed Central

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

    2015-01-01

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

  11. Azithromycin plus chloroquine: combination therapy for protection against malaria and sexually transmitted infections in pregnancy

    PubMed Central

    Chico, R Matthew; Chandramohan, Daniel

    2011-01-01

    Introduction: The first-line therapy for the intermittent preventive treatment of malaria in pregnancy (IPTp) is sulphadoxine-pyrimethamine (SP). There is an urgent need to identify safe, well-tolerated and efficacious alternatives to SP due to widespread Plasmodium falciparum resistance. Combination therapy using azithromycin and chloroquine is one possibility that has demonstrated adequate parasitological response > 95% in clinical trials of non-pregnant adults in sub-Saharan Africa and where IPTp is a government policy in 33 countries. Areas covered: Key safety, tolerability and efficacy data are presented for azithromycin and chloroquine, alone and/or in combination, when used to prevent and/or treat P. falciparum, P. vivax, and several curable sexually transmitted and reproductive tract infections (STI/RTI). Pharmacokinetic evidence from pregnant women is also summarized for both compounds. Expert opinion: The azithromycin-chloroquine regimen that has demonstrated consistent efficacy in non-pregnant adults has been a 3-day course containing daily doses of 1 g of azithromycin and 600 mg base of chloroquine. The pharmacokinetic evidence of these compounds individually suggests that dose adjustments may not be necessary when used in combination for treatment efficacy against P. falciparum, P. vivax, as well as several curable STI/ RTI among pregnant women, although clinical confirmation will be necessary. Mass trachoma-treatment campaigns have shown that azithromycin selects for macrolide resistance in the pneumococcus, which reverses following the completion of therapy. Most importantly, no evidence to date suggests that azithromycin induces pneumococcal resistance to penicillin. PMID:21736423

  12. 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

  13. 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. PMID:25542171

  14. 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

  15. 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

    2015-01-01

    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

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

    SciTech Connect

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

    2009-02-16

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

  17. Simple analogues of qinghaosu (artemisinin).

    PubMed

    Li, Yun; Hao, Hong-Dong; Wittlin, Sergio; Wu, Yikang

    2012-08-01

    A series of 1,2,4-trioxanes were synthesized in which the key peroxy bonds were installed through a molybdenum-catalyzed perhydrolysis of the epoxy rings. A core structure was identified that may serve as a promising lead structure for further investigations because of its high antimalarial activity (comparable to that of artesunate and chloroquine), apparent potential for scale-up and derivatization, and facile monitoring/tracing by using UV light. PMID:22588969

  18. 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.

  19. Possible involvement of nitrergic and opioidergic systems in the modulatory effect of acute chloroquine treatment on pentylenetetrazol induced convulsions in mice.

    PubMed

    Hassanipour, Mahsa; Shirzadian, Armin; Boojar, Mahdi Mashhadi-Akbar; Abkhoo, Aminreza; Abkhoo, Alireza; Delazar, Sina; Amiri, Shayan; Rahimi, Nastaran; Ostadhadi, Sattar; Dehpour, Ahmad-Reza

    2016-03-01

    Chloroquine has long been used for the treatment of malaria and rheumatological disorders. Accumulating evidence suggests potential use of chloroquine as a neuroprotective agent. Several studies have reported that endogenous opioids and nitric oxide (NO) system mediate the chloroquine effects. In the present study, the involvements of endogenous opioids and NO in the modulatory effects of chloroquine on pentylenetetrazol-induced seizures were assessed in mice. Chloroquine 5mg/kg significantly increased the seizure threshold, but this effect was reversed with naltrexone 1mg/kg. Acute co-administration of l-NAME (non-selective NO synthase (NOS) inhibitor, 5mg/kg) or 7-NI (selective neuronal NOS inhibitor, 40mg/kg) with the effective dose of chloroquine completely inhibited its anticonvulsant effects. Acute single injection of a sub-effective dose of l-arginine (NO precursor, 60mg/kg) with a sub-effective dose of chloroquine 2.5mg/kg increased the seizure threshold but administration of l-arginine 60mg/kg with chloroquine 10mg/kg decreased the seizure threshold. Moreover, the combination of the lower doses of naltrexone (0.1mg/kg) and 7-NI (15mg/kg) showed additive effects in blocking the chloroquine-induced anticonvulsant properties. Chloroquine 5mg/kg enhanced the hippocampal nitrite levels. Chloroquine at the dose of 20mg/kg decreased the seizure threshold. This effect was inhibited through l-NAME (5mg/kg), 7-NI (40mg/kg) and naltrexone (1mg/kg) administration with this dose of chloroquine. In conclusion, NO signaling probably through neuronal NOS, but not inducible NOS could be involved in the opioid-dependent anticonvulsant effects of chloroquine in this model of seizures in mice. It seems that nitric oxide and opioid systems are involved in modulatory effect of chloroquine on seizures induced by pentylenetetrazol. PMID:26655695

  20. 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

  1. 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

  2. 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

  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. Dual role of chloroquine in liver ischemia reperfusion injury: reduction of liver damage in early phase, but aggravation in late phase.

    PubMed

    Fang, H; Liu, A; Dahmen, U; Dirsch, O

    2013-01-01

    The anti-malaria drug chloroquine is well known as autophagy inhibitor. Chloroquine has also been used as anti-inflammatory drugs to treat inflammatory diseases. We hypothesized that chloroquine could have a dual effect in liver ischemia/reperfusion (I/R) injury: chloroquine on the one hand could protect the liver against I/R injury via inhibition of inflammatory response, but on the other hand could aggravate liver I/R injury through inhibition of autophagy. Rats (n=6 per group) were pre-treated with chloroquine (60 mg/kg, i.p.) 1 h before warm ischemia, and they were continuously subjected to a daily chloroquine injection for up to 2 days. Rats were killed 0.5, 6, 24 and 48 h after reperfusion. At the early phase (i.e., 0-6 h after reperfusion), chloroquine treatment ameliorated liver I/R injury, as indicated by lower serum aminotransferase levels, lower hepatic inflammatory cytokines and fewer histopathologic changes. In contrast, chloroquine worsened liver injury at the late phase of reperfusion (i.e., 24-48 h after reperfusion). The mechanism of protective action of chloroquine appeared to involve its ability to modulate mitogen-activated protein kinase activation, reduce high-mobility group box 1 release and inflammatory cytokines production, whereas chloroquine worsened liver injury via inhibition of autophagy and induction of hepatic apoptosis at the late phase. In conclusion, chloroquine prevents ischemic liver damage at the early phase, but aggravates liver damage at the late phase in liver I/R injury. This dual role of chloroquine should be considered when using chloroquine as an inhibitor of inflammation or autophagy in I/R injury. PMID:23807223

  5. 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

  6. Structural Analogues of Selfotel.

    PubMed

    Dziuganowska, Zofia A; Ślepokura, Katarzyna; Volle, Jean-Noël; Virieux, David; Pirat, Jean-Luc; Kafarski, Paweł

    2016-06-17

    A small library of phosphonopiperidylcarboxylic acids, analogues of NMDA antagonist selfotel (CGS 19755), was synthesized. First, the series of aromatic esters was obtained via a palladium-catalyzed cross-coupling reaction (Hirao coupling) of dialkyl phosphites with bromopyridinecarboxylates, followed by their hydrolysis. Then, hydrogenation of the resulting phosphonopyridylcarboxylic acids over PtO2 yielded the desired phosphonopiperidylcarboxylic acids. NMR studies indicated that the hydrogenation reaction proceeds predominantly by cis addition. Several compounds were obtained as monocrystal structures. Preliminary biological studies performed on cultures of neurons suggest that the obtained compounds possess promising activity toward NMDA receptors. PMID:27187758

  7. 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

  8. Pigmented lichenoid drug eruption secondary to chloroquine therapy: an unusual presentation in lower lip.

    PubMed

    Moraes, P C; Noce, C W; Thomaz, L A; Cintra, M L; Correa, M E P

    2011-06-01

    Antimalarial drugs, like chloroquine, may produce hyperpigmentation of the oral mucosa, affecting most commonly the palate. Its pathogenesis is not clear; an increased production of melanin is currently believed to be the cause of this oral manifestation. The purpose of this study was to report a case of atypical oral mucosal hyperpigmentation secondary to antimalarial therapy. A 66-year-old, dark skinned woman was evaluated for oral pigmentation. The patient had a history of chloroquine therapy, and presented a diffuse blue-gray pigmentation in the hard palate and, mainly, in the lower lip. Diagnostic hypothesis were of physiologic pigmentation, drug-induced pigmentation, pigmentation associated with systemic diseases, smoker's melanosis and post-inflammatory pigmentation. Incisional biopsy was conducted and histopathological examination revealed lichenoid dermatitis and pigment incontinence. Fontana-Masson staining was positive for melanin, but Perl's iron staining was negative. The histopathological diagnosis was consistent with melanin incontinence related to drug-induced lichenoid reaction secondary to chloroquine therapy. Adequate correlation of clinical and microscopic aspects was essential for the definitive diagnosis, especially in atypical cases. This diagnosis is of great relevance for the patient, since the oral manifestation might be an early sign of ocular complications due to antimalarial therapy. Therefore, the identification of these oral manifestations indicates regular evaluations by an ophtalmologist, preventing greater complications of antimalarial therapy for the patient. PMID:21666569

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

    PubMed

    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

  10. 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

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

    PubMed Central

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

    2008-01-01

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

  12. 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.

  13. 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

  14. 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

  15. 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)

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

    PubMed Central

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

    2012-01-01

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

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

    PubMed

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

    2012-06-01

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

  18. Phosphonate analogues of aminoacyl adenylates.

    PubMed Central

    Southgate, C C; Dixon, H B

    1978-01-01

    Phosphonomethyl analogues of glycyl phosphate and valyl phosphate, i.e. NH2-CHR-CO-CH2-PO(OH)2, were synthesized and esterified with adenosine to give analogues of aminoacyl adenylates. The interaction of these adenylate analogues with valyl-tRNA synthetase from Escherichia coli was studied by fluorescence titration. The analogue of valyl phosphate has an affinity for the enzyme comparable with that of valine, but that of valyl adenylate is bound much less tightly than either valyl adenylate or corresponding derivative of valinol. The affinity of the analogue of glycyl adenylate was too low to be measured. We conclude that this enzyme interacts specifically with both the side chain and the anhydride linkage of the adenylate intermediate. PMID:743207

  19. 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

  20. 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

  1. 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.

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

    PubMed Central

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

    2010-01-01

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

  3. 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. PMID:26142781

  4. Multiple drugs compete for transport via the Plasmodium falciparum chloroquine resistance transporter at distinct but interdependent sites.

    PubMed

    Bellanca, Sebastiano; Summers, Robert L; Meyrath, Max; Dave, Anurag; Nash, Megan N; Dittmer, Martin; Sanchez, Cecilia P; Stein, Wilfred D; Martin, Rowena E; Lanzer, Michael

    2014-12-26

    Mutations in the "chloroquine resistance transporter" (PfCRT) are a major determinant of drug resistance in the malaria parasite Plasmodium falciparum. We have previously shown that mutant PfCRT transports the antimalarial drug chloroquine away from its target, whereas the wild-type form of PfCRT does not. However, little is understood about the transport of other drugs via PfCRT or the mechanism by which PfCRT recognizes different substrates. Here we show that mutant PfCRT also transports quinine, quinidine, and verapamil, indicating that the protein behaves as a multidrug resistance carrier. Detailed kinetic analyses revealed that chloroquine and quinine compete for transport via PfCRT in a manner that is consistent with mixed-type inhibition. Moreover, our analyses suggest that PfCRT accepts chloroquine and quinine at distinct but antagonistically interacting sites. We also found verapamil to be a partial mixed-type inhibitor of chloroquine transport via PfCRT, further supporting the idea that PfCRT possesses multiple substrate-binding sites. Our findings provide new mechanistic insights into the workings of PfCRT, which could be exploited to design potent inhibitors of this key mediator of drug resistance. PMID:25378409

  5. Synthesis, Characterization and in vitro Antimalarial and Antitumor Activity of New Ruthenium(II) Complexes of Chloroquine

    PubMed Central

    Rajapakse, Chandima S. K.; Martínez, Alberto; Naoulou, Becky; Jarzecki, Andrzej A.; Suárez, Liliana; Deregnaucourt, Christiane; Sinou, Véronique; Schrével, Joseph; Musi, Elgilda; Ambrosini, Grazia; Schwartz, Gary K.; Sánchez-Delgado, Roberto A.

    2009-01-01

    The new RuII chloroquine complexes [Ru(η6-arene)(CQ)Cl2] (CQ = chloroquine; arene = p-cymene 1, benzene 2), [Ru(η6-p-cymene)(CQ)(H2O)2][BF4]2 (3), [Ru(η6-p-cymene)(CQ)(en)][PF6]2 (en = ethylenediamine) (4), and [Ru(η6-p-cymene)(η6-CQDP)][BF4]2 (5, CQDP = chloroquine diphosphate) have been synthesized and characterized by use of a combination of NMR and FTIR spectroscopy with DFT calculations. Each complex is formed as a single coordination isomer: in compounds 1–4 chloroquine binds to ruthenium in the η1-N mode through the quinoline nitrogen atom whereas in complex 5 an unprecedented η6 bonding through the carbocyclic ring is observed. Compounds 1, 2, 3, and 5 are active against CQ-resistant (Dd2, K1 and W2) and CQ-sensitive (FcB1, PFB, F32 and 3D7) malaria parasites (Plasmodium falciparum); importantly, the potency of these complexes against resistant parasites is consistently higher than that of the standard drug chloroquine diphosphate. Complexes 1 and 5 also inhibit the growth of colon cancer cells, independently of the p53 status and of liposarcoma tumor cell lines with the latter showing increased sensitivity, especially to complex 1 (IC50 8 µM); this is significant because this type of tumor does not respond to currently employed chemotherapies. PMID:19119867

  6. 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.

  7. 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

  8. 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

  9. Attenuation of endoplasmic reticulum stress in Pelizaeus-Merzbacher disease by an anti-malaria drug, chloroquine.

    PubMed

    Morimura, Toshifumi; Numata, Yurika; Nakamura, Shoko; Hirano, Eriko; Gotoh, Leo; Goto, Yu-ich; Urushitani, Makoto; Inoue, Ken

    2014-04-01

    Pelizaeus-Merzbacher disease (PMD) is a hypomyelinating disorder caused by the duplication and missense mutations of the proteolipid protein 1 (PLP1) gene. PLP1 missense proteins accumulate in the endoplasmic reticulum (ER) of premature oligodendrocytes and induce severe ER stress followed by apoptosis of the cells. Here, we demonstrate that an anti-malaria drug, chloroquine, decreases the amount of an ER-resident mutant PLP1 containing an alanine-243 to valine (A243V) substitution, which induces severe PMD in human. By preventing mutant PLP1 translation through enhancing the phosphorylation of eukaryotic initiation factor 2 alpha, chloroquine ameliorated the ER stress induced by the mutant protein in HeLa cells. Chroloquine also attenuated ER stress in the primary oligodendrocytes obtained from myelin synthesis deficit (msd) mice, which carry the same PLP1 mutation. In the spinal cords of msd mice, chloroquine inhibited ER stress and upregulated the expression of marker genes of mature oligodendrocytes. Chloroquine-mediated attenuation of ER stress was observed in HeLa cells treated with tunicamycin, an N-glycosylation inhibitor, but not with thapsigargin, a sarco/ER Ca(2+)ATPase inhibitor, which confirms its efficacy against ER stress caused by nascent proteins. These findings indicate that chloroquine is an ER stress attenuator with potential use in treating PMD and possibly other ER stress-related diseases. PMID:24521562

  10. Dynamic of plasmodium falciparum chloroquine resistance transporter gene Pfcrt K76T mutation five years after withdrawal of chloroquine in Burkina Faso

    PubMed Central

    Sondo, Paul; Derra, Karim; Tarnagda, Zekiba; Nakanabo, Seydou Diallo; Zampa, Odile; Kazienga, Adama; Valea, Innocent; Sorgho, Hermann; Ouedraogo, Jean-Bosco; Guiguemde, Tinga Robert; Tinto, Halidou

    2015-01-01

    We investigated the evolution of Pfcrt K76T mutation five years after the withdrawal of chloroquine in Burkina Faso. A total of 675 clinical isolates collected from October 2010 to September 2012 were successfully genotyped. Single nucleotide polymorphism in Pfcrt (codon 76) gene was analyzed. The prevalence of resistant Pfcrt 76T allele was 20.55%. There was a progressive decrease of the proportion of mutant type pfcrt T76 from 2010 to 2012 (X2=5.508 p=0.0189). Our results suggest a progressive return of the wild type Pfcrt K76 in Burkina Faso but the prevalence of the mutants Pfcrt T76 still remains high. PMID:26516402

  11. Dynamic of plasmodium falciparum chloroquine resistance transporter gene Pfcrt K76T mutation five years after withdrawal of chloroquine in Burkina Faso.

    PubMed

    Sondo, Paul; Derra, Karim; Tarnagda, Zekiba; Nakanabo, Seydou Diallo; Zampa, Odile; Kazienga, Adama; Valea, Innocent; Sorgho, Hermann; Ouedraogo, Jean-Bosco; Guiguemde, Tinga Robert; Tinto, Halidou

    2015-01-01

    We investigated the evolution of Pfcrt K76T mutation five years after the withdrawal of chloroquine in Burkina Faso. A total of 675 clinical isolates collected from October 2010 to September 2012 were successfully genotyped. Single nucleotide polymorphism in Pfcrt (codon 76) gene was analyzed. The prevalence of resistant Pfcrt 76T allele was 20.55%. There was a progressive decrease of the proportion of mutant type pfcrt T76 from 2010 to 2012 (X2=5.508 p=0.0189). Our results suggest a progressive return of the wild type Pfcrt K76 in Burkina Faso but the prevalence of the mutants Pfcrt T76 still remains high. PMID:26516402

  12. 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

  13. 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

  14. Comparison of artemether and chloroquine for severe malaria in Gambian children.

    PubMed

    White, N J; Waller, D; Crawley, J; Nosten, F; Chapman, D; Brewster, D; Greenwood, B M

    1992-02-01

    Artemether is an oil-soluble methyl ether of artemesinin (qinghaosu). It has been studied extensively in China, where it has been shown to be rapidly effective in severe falciparum malaria. Nearly all the patients studied previously were adults. We have investigated the efficacy of artemether in children with moderate or severe falciparum malaria. In the preliminary study of moderately severe malaria, 30 Gambian children were randomised in pairs to receive either intramuscular artemether (4 mg/kg loading dose followed by 2 mg/kg daily) or intramuscular chloroquine ('Nivaquine') 3.5 mg base/kg every 6 h. Both drugs were well tolerated and rapidly effective. The times to parasite clearance were significantly shorter in the artemether recipients (mean 36.7 [SD 11.3] vs 48.4 [16.8] h, p less than 0.05). 43 children with severe malaria were then randomised to receive intramuscular treatment with the same regimens of artemether (n = 21) or chloroquine (n = 22) as used in the preliminary study. 8 children (19%) died. There were no significant differences between the two groups in the clinical, haematological, biochemical, or parasitological measures of therapeutic response in survivors and there was no evidence of local or systemic toxicity. Despite similar parasite counts on admission, clearance times overall were longer in severe malaria than in moderate malaria. Artemether is a well tolerated and rapidly effective parenteral treatment for severe malaria in children, and would be especially valuable in areas with chloroquine-resistant P falciparum. PMID:1346408

  15. 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

  16. Chloroquine resistance in Pakistan and the upsurge of falciparum malaria in Pakistani and Afghan refugee populations.

    PubMed

    Shah, I; Rowland, M; Mehmood, P; Mujahid, C; Razique, F; Hewitt, S; Durrani, N

    1997-09-01

    Surveys conducted in Pakistan during the last decade show that falciparum malaria has become resistant to chloroquine in Pakistani and Afghan refugee populations throughout the country. Although RI resistance is common everywhere (with a frequency of 30%-84%), RII is rarer (2%-36%), and RIII resistance has yet to be detected. The national policy is to prescribe chloroquine as first-line treatment of malaria. A repeated in-vivo survey in a sentinel village indicated that prescription of chloroquine can lead to a 15% increase in the frequency of resistance in a single year, and similar trends were observed in other districts. Coinciding with the spread of resistance is a 6-fold increase in the number of falciparum cases recorded nationally between 1982 and 1992 and a parallel, 5-fold increase in the number of cases recorded in the Afghan refugee population. Resistance contributes to this trend in various ways. Firstly, patients with resistant malaria make repeated visits to health centres. In the sentinel village, for example, where resistance was measured at 71%, recrudescent infections inflated by 66% the genuine incidence of new infections recorded at the health centre. Secondly, owing to ineffective treatment, resistant infections are often still patent during the post-transmission season. This may enlarge the 'overwintering' parasite reservoir, leading to a surge of new cases when transmission resumes. Other factors potentially contributing to the upsurge in falciparum include the decrease availability of insecticide for indoor spraying. Despite the problems posed by resistance for case management, the evidence from the vector-control programme among the refugees is that malaria control through well-targeted campaigns of insecticide spraying is still able to reduce the incidence of falciparum malaria to a level that existed before the advent of resistance. PMID:9425361

  17. 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

  18. 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

  19. 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. PMID:25075788

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

    PubMed Central

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

    2014-01-01

    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. PMID:25075788

  1. Transfer of chloroquine and desethylchloroquine across the placenta and into milk in Melanesian mothers

    PubMed Central

    Law, Irwin; Ilett, Kenneth F; Hackett, L Peter; Page-Sharp, Madhu; Baiwog, Francesca; Gomorrai, Servina; Mueller, Ivo; Karunajeewa, Harin A; Davis, Timothy M E

    2008-01-01

    AIMS To investigate the transfer of chloroquine and its major bioactive metabolite desethylchloroquine across the placenta and into breast milk. METHODS In Papua New Guinea, chloroquine (CQ; 25 mg base kg−1) is recommended for prophylaxis of malaria during pregnancy, and at the Alexishafen Health Centre women are routinely prescribed CQ at the time of delivery. Fetal-cord and maternal serum samples were collected at delivery (n = 19) and milk samples were collected from day 3 to day 17–21 after delivery (n = 16). CQ and its primary active metabolite desethylchloroquine (DECQ) were quantified by high-performance liquid chromatography. For both CQ and DECQ cord/maternal ratios (C/M) were calculated to characterize placental transfer, and infant exposure via milk was estimated by standard methods. RESULTS The median (interquartile range) C/M was 1.1 (0.9, 1.6) for CQ and 1.2 (0.5, 1.8) for DECQ. The average concentration in milk over the time of sampling was 167 μg l−1 (27, 340) for CQ and 54 μg l−1 (22, 106) for DECQ. Estimated absolute and relative infant doses were 34 μg kg−1 day−1 (7, 50) and 15 μg kg−1 day−1 (4, 26), and 2.3% (0.5, 3.6) and 1.0% (0.4, 2.0) for CQ and DECQ (as CQ equivalents), respectively. CONCLUSION Infant exposure to CQ and DECQ during pregnancy will be similar to that in the maternal circulation, and dependent on maternal dose and frequency. The median CQ + DECQ relative infant dose of 3.2% (as CQ equivalents) was low, confirming that use of CQ during lactation is compatible with breastfeeding. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT The literature on placental and milk transfer of chloroquine and its major bioactive metabolite desethylchloroquine is sparse and incomplete. WHAT THIS STUDY ADDS We have provided data on the transplacental transfer of chloroquine and desethylchloroquine in Melanesian women (n = 19), measured transfer of these drugs into breast milk (n = 16) and estimated absolute and relative infant doses for

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

    PubMed

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

    2015-12-01

    Hydroxychloroquine (HCQ) and chloroquine have been used for more than 50 years to treat systemic lupus erythematosus (SLE) and other rheumatic diseases. In general, these drugs are well tolerated and rarely need to be discontinued because of an adverse systemic reaction. However, both medications can be irreversibly toxic to the retina. A new study indicates that toxicity is not as rare as once believed, but depends critically on daily dosage and duration of use, as well as other risk factors. With attention to dosage and other factors, and with proper screening for early signs of toxicity, HCQ can be prescribed with relative safety even over long periods of time. PMID:25672591

  3. 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

  4. Chloroquine-induced scratching is mediated by NO/cGMP pathway in mice.

    PubMed

    Foroutan, Arash; Haddadi, Nazgol Sadat; Ostadhadi, Sattar; Sistany, Narges; Dehpour, Ahmad Reza

    2015-07-01

    Chloroquine (CQ), a 4-aminoquinoline drug, has long been used in the treatment and prevention of malaria. However its side effect generalized pruritus contributes to treatment failures, and consequently results in the development of chloroquine resistant strains of Plasmodium falciparum. It was proposed that the administration of CQ correlated with increase in nitric oxide (NO) production. Nitric oxide is involved in some pruritic disorders such as atopic dermatitis, psoriasis and scratching behavior evoked by pruritogens like substance P. Therefore, the aim of this study was to investigate the involvement of NO/cGMP pathway in CQ-induced scratching in mice. Scratching behaviors were recorded by a camera after intradermal (ID) injection of CQ in the shaved rostral back of the mice. The results obtained show that CQ elicited scratching in a dose-dependent manner with a peak effective dose of 400μg/site. Injection of non-specific NOS inhibitor, N-nitro-l-arginine methyl ester or neuronal NOS selective inhibitor and 7-nitroindazole, reduced CQ-induced scratching significantly. On the other hand, administration of aminoguanidine as inducible NOS inhibitor has no inhibitory effect on this behavior. Also, injection of l-arginine as a precursor of NO significantly increased this response. Conversely, accumulation of cGMP by sildenafil as a selective phosphodiesterase type 5 inhibitor, potentiated the scratching behavior by CQ. This study therefore shows that CQ-induced scratching behavior is mediated by the NO/cGMP pathway. PMID:25957523

  5. Killing of Staphylococcus aureus in murine macrophages by chloroquine used alone and in combination with ciprofloxacin or azithromycin

    PubMed Central

    Dey, Somrita; Bishayi, Biswadev

    2015-01-01

    This study aimed to determine any alteration in the killing of Staphylococcus aureus in murine peritoneal macrophages when chloroquine (CQ) is used alone compared with when it is used in combination with ciprofloxacin (CIP) or azithromycin (AZM). The study also aimed to find out the implication of reactive oxygen species (ROS) production and cytokine release in the intracellular killing of S. aureus in macrophages. We present here data obtained with a model of S. aureus-infected mouse peritoneal macrophages in which the intracellular growth of the bacteria and the influence of antibiotics was monitored for 30, 60, and 90 minutes in the presence or absence of CQ along with the production of ROS and alteration in levels of antioxidant enzymes and cytokines. It was observed that S. aureus-triggered cytokine response was regulated when macrophages were co-cultured with CQ and AZM as compared with CQ stimulation only. It can be suggested that action of AZM in mediating bacterial killing is enhanced by the presence of CQ, indicating enhanced uptake of AZM during early infection that may be essential for bacteria killing by AZM. Reduction of oxidative stress burden on the S. aureus-infected macrophages may pave the way for better killing of internalized S. aureus by CQ plus ciprofloxacin (CIP) or CQ plus AZM. Based on these observations, one may speculate that in an inflammatory milieu, CQ loaded with AZM elicits a stronger proinflammatory response by increasing the intracellular uptake of AZM or CIP, thus enabling the immune system to mount a more robust and prolonged response against intracellular pathogens. PMID:25653549

  6. 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

  7. Effects of pristane alone or combined with chloroquine on macrophage activation, oxidative stress, and TH1/TH2 skewness.

    PubMed

    Ouyang, Qiufang; Huang, Ziyang; Wang, Zhenhua; Chen, Xiaoqing; Ni, Jingqin; Lin, Ling

    2014-01-01

    We investigated the protective role of chloroquine against pristane-induced macrophage activation, oxidative stress, and Th1/Th2 skewness in C57BL/6J mice. Those mice were treated with pristane alone or combined with chloroquine. Hematological and biochemical parameters, macrophage phagocytic function, the oxidant/antioxidant index, cytokine for IFN-γ, TNF-α, IL-4, and IL-6, and the isotypes of IgG2a and IgG1 were determined. And the expression of T-bet/GATA-3 and IL-12/IL-10 mRNA in spleen were analyzed by real-time PCR. We found that pristane treatment for a period of 12 or 24 weeks triggered macrophage activation syndrome, characterized by hemophagocytosis in spleen and peripheral blood, enhanced lipid phagocytosis by peritoneal macrophages in vitro, erythropenia and leucopenia, increased anti-Smith, lactic dehydrogenase, triglyceride, and ferritin, as well as hypercytokinemia of IFN-γ, TNF-α, IL-4, and IL-6. In parallel, a significant increase in lipid peroxidation and a decrease in superoxide dismutase, glutathione, and catalase activity, as well as a skewed Th1/Th2 balance in spleen, were observed. However, chloroquine supplementation showed a remarkable amelioration of these abnormalities. Our data indicate that pristane administration induces macrophage activation, oxidative stress, and Th1/Th2 skewness, which can be attenuated by chloroquine. PMID:25136646

  8. 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

  9. Phosphonomethyl analogues of hexose phosphates.

    PubMed

    Webster, D; Jondorf, W R; Dixon, H B

    1976-05-01

    The analogue of fructose 1,6-bisphosphate in which the phosphate group, -O-PO3H2, on C-6 is replaced by the phosphonomethyl group, -CH2-PO3H2, was made enzymically from the corresponding analogue of 3-phosphoglycerate. It was a substrate for aldolase, which was used to form it, but not for fructose 1,6-bisphosphatase. It was hydrolysed chemically to yield the corresponding analogue of fructose 6-phosphate [i.e. 6-deoxy-6-(phosphonomethyl)-D-fructose, or, more strictly, 6,7-dideoxy-7-phosphono-D-arabino-2-heptulose]. This proved to be a substrate for the sequential actions of glucose 6-phosphate isomerase, glucose-6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase. Thus seven out of the nine enzymes of the glycolytic and pentose phosphate pathways so far tested catalyse the reactions of the phosphonomethyl isosteres of their substrates. PMID:7247

  10. 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

  11. Prevalence and patterns of antifolate and chloroquine drug resistance markers in Plasmodium vivax across Pakistan

    PubMed Central

    2013-01-01

    Background Plasmodium vivax is the most prevalent malaria species in Pakistan, with a distribution that coincides with Plasmodium falciparum in many parts of the country. Both species are likely exposed to drug pressure from a number of anti-malarials including chloroquine, sulphadoxine-pyrimethamine (SP), and artemisinin combination therapy, yet little is known regarding the effects of drug pressure on parasite genes associated with drug resistance. The aims of this study were to determine the prevalence of polymorphisms in the SP resistance-associated genes pvdhfr, pvdhps and chloroquine resistance-associated gene pvmdr1 in P. vivax isolates collected from across the country. Methods In 2011, 801 microscopically confirmed malaria-parasite positive filter paper blood samples were collected at 14 sites representing four provinces and the capital city of Islamabad. Species-specific polymerase chain reaction (PCR) was used to identify human Plasmodium species infection. PCR-positive P. vivax isolates were subjected to sequencing of pvdhfr, pvdhps and pvmdr1 and to real-time PCR analysis to assess pvmdr1 copy number variation. Results Of the 801 samples, 536 were determined to be P. vivax, 128 were P. falciparum, 43 were mixed vivax/falciparum infections and 94 were PCR-negative for Plasmodium infection. Of PCR-positive P. vivax samples, 372 were selected for sequence analysis. Seventy-six of the isolates (23%) were double mutant at positions S58R and S117N in pvdhfr. Additionally, two mutations at positions N50I and S93H were observed in 55 (15%) and 24 (7%) of samples, respectively. Three 18 base pair insertion-deletions (indels) were observed in pvdhfr, with two insertions at different nucleotide positions in 36 isolates and deletions in 10. Ninety-two percent of samples contained the pvdhps (S382/A383G/K512/A553/V585) SAKAV wild type haplotype. For pvmdr1, all isolates were wild type at position Y976F and 335 (98%) carried the mutation at codon F1076L. All

  12. 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

  13. 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. PMID:23572632

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

    PubMed Central

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

    2015-01-01

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

  15. 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

  16. Validation of a chloroquine-induced cell death mechanism for clinical use against malaria

    PubMed Central

    Ch'ng, J-H; Lee, Y-Q; Gun, S Y; Chia, W-N; Chang, Z-W; Wong, L-K; Batty, K T; Russell, B; Nosten, F; Renia, L; Tan, K S-W

    2014-01-01

    An alternative antimalarial pathway of an ‘outdated' drug, chloroquine (CQ), may facilitate its return to the shrinking list of effective antimalarials. Conventionally, CQ is believed to interfere with hemozoin formation at nanomolar concentrations, but resistant parasites are able to efflux this drug from the digestive vacuole (DV). However, we show that the DV membrane of both resistant and sensitive laboratory and field parasites is compromised after exposure to micromolar concentrations of CQ, leading to an extrusion of DV proteases. Furthermore, only a short period of exposure is required to compromise the viability of late-stage parasites. To study the feasibility of this strategy, mice malaria models were used to demonstrate that high doses of CQ also triggered DV permeabilization in vivo and reduced reinvasion efficiency. We suggest that a time-release oral formulation of CQ may sustain elevated blood CQ levels sufficiently to clear even CQ-resistant parasites. PMID:24967967

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

    PubMed Central

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

    2009-01-01

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

  18. Efficacy of Chloroquine for the Treatment of Uncomplicated Plasmodium falciparum Malaria in Honduras

    PubMed Central

    Torres, Rosa Elena Mejia; 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

    2013-01-01

    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. PMID:23458957

  19. Inhibition of Autophagy by Chloroquine Enhances the Antitumor Efficacy of Sorafenib in Glioblastoma.

    PubMed

    Liu, Xiangyu; Sun, Kangjian; Wang, Handong; Dai, Yuyuan

    2016-10-01

    Glioblastoma multiforme (GBM) is the most aggressive and common brain tumor in adults. Sorafenib, a multi-kinase inhibitor, has been shown to inhibit cell proliferation and induce apoptosis through inhibition of STAT3 signaling in glioblastoma cells and in intracranial gliomas. However, sorafenib also induces cell autophagy. Due to the dual roles of autophagy in tumor cell survival and death, the therapeutic effect of sorafenib on glioblastoma is uncertain. Here, we combined sorafenib treatment in GBM cells (U373 and LN229) and tumors with the autophagy inhibitor chloroquine. We found that blockage of autophagy further inhibited cell proliferation and migration and induced cell apoptosis in vitro and in vivo. These findings suggest the possibility of combination treatment with sorafenib and autophagy inhibitors for GBM. PMID:26971793

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

    PubMed

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

    2015-03-17

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

  1. 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

  2. Chloroquine-induced bilateral anterior shoulder dislocation: a unique aetiology for a rare clinical problem.

    PubMed

    Martin, Alexander Nicholas; Tsekes, Dimitris; White, William James; Rossouw, Dan

    2016-01-01

    Bilateral anterior shoulder dislocation is a rare clinical entity with few case reports and limited series published in the literature. Bilateral shoulder dislocations are rare and of them, most are posterior. We present a highly unusual case of bilateral, atraumatic, anterior shoulder dislocation with concomitant comminuted greater tuberosity fracture on the right side, secondary to seizure, in a patient without known epilepsy, induced by oral chloroquine medication. We demonstrate the treatment approach that led to a satisfactory clinical outcome, evidenced by radiological union, clinical assessment and Patient Reported Outcome Measure data, following non-operative management of both shoulders. The unusual mechanism for anterior shoulder dislocation, the asymmetric dislocation pattern and peculiar precipitant for the causative seizure all provide interesting learning points from this case. PMID:27005796

  3. Molecular Mechanisms for Drug Hypersensitivity Induced by the Malaria Parasite's Chloroquine Resistance Transporter.

    PubMed

    Richards, Sashika N; Nash, Megan N; Baker, Eileen S; Webster, Michael W; Lehane, Adele M; Shafik, Sarah H; Martin, Rowena E

    2016-07-01

    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

  4. Glutathione Transport: A New Role for PfCRT in Chloroquine Resistance

    PubMed Central

    Patzewitz, Eva-Maria; Salcedo-Sora, J. Enrique; Wong, Eleanor H.; Sethia, Sonal; Stocks, Paul A.; Maughan, Spencer C.; Murray, James A.H.; Krishna, Sanjeev; Bray, Patrick G.

    2013-01-01

    Abstract Aims: Chloroquine (CQ) kills Plasmodium falciparum by binding heme, preventing its detoxification to hemozoin in the digestive vacuole (DV) of the parasite. CQ resistance (CQR) is associated with mutations in the DV membrane protein P. falciparum chloroquine resistance transporter (PfCRT), mediating the leakage of CQ from the DV. However, additional factors are thought to contribute to the resistance phenotype. This study tested the hypothesis that there is a link between glutathione (GSH) and CQR. Results: Using isogenic parasite lines carrying wild-type or mutant pfcrt, we reveal lower levels of GSH in the mutant lines and enhanced sensitivity to the GSH synthesis inhibitor l-buthionine sulfoximine, without any alteration in cytosolic de novo GSH synthesis. Incubation with N-acetylcysteine resulted in increased GSH levels in all parasites, but only reduced susceptibility to CQ in PfCRT mutant-expressing lines. In support of a heme destruction mechanism involving GSH in CQR parasites, we also found lower hemozoin levels and reduced CQ binding in the CQR PfCRT-mutant lines. We further demonstrate via expression in Xenopus laevis oocytes that the mutant alleles of Pfcrt in CQR parasites selectively transport GSH. Innovation: We propose a mechanism whereby mutant pfcrt allows enhanced transport of GSH into the parasite's DV. The elevated levels of GSH in the DV reduce the level of free heme available for CQ binding, which mediates the lower susceptibility to CQ in the PfCRT mutant parasites. Conclusion: PfCRT has a dual role in CQR, facilitating both efflux of harmful CQ from the DV and influx of beneficial GSH into the DV. Antioxid. Redox Signal. 19, 683–695. PMID:23256874

  5. 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

  6. 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

  7. [Molecular epidemiology of imported malaria in Italy: the use of genetic markers and in vitro sensitivity test in a study of chloroquine resistance in Plasmodium falciparum].

    PubMed

    Menegon, Michela; Sannella, Anna Rosa; Severini, Carlo; Paglia, Maria Grazia; Matteelli, Alberto; Caramello, Pietro; Severini, Francesco; Taramelli, Donatella; Majori, Giancarlo

    2006-01-01

    The emergence of Plasmodium falciparum drug-resistance, especially chloroquine resistance, represents one of the main obstacles to the control of malaria. Several studies have shown that in P. falciparum the mechanism of chloroquine resistance is linked to specific point mutations in the pfcrt gene of the parasite. In the present study we have analyzed 120 Italian imported malaria cases to evaluate the prevalence of 76T and 220S mutantions in the pfcrt gene. Moreover, the correlation between the presence of pfcrt point mutations and in vitro chloroquine resistance has been evaluated on 25 plasmodial isolates. The results showed a high prevalence of the pfcrt point mutations in isolates analyzed and a significant association between point mutations and in vitro chloroquine resistance. Molecular screening on imported malaria cases can be a useful tool to be employed in surveillance activity and also in monitoring the development and spread of drug resistance in endemic areas. PMID:17033142

  8. Similar Efficacy and Tolerability of Double-Dose Chloroquine and Artemether-Lumefantrine for Treatment of Plasmodium falciparum Infection in Guinea-Bissau: A Randomized Trial

    PubMed Central

    Kofoed, Poul-Erik; Rodrigues, Amabelia; Blessborn, Daniel; Thoft-Nielsen, Rikke; Björkman, Anders; Rombo, Lars

    2011-01-01

    Background. In 2008, Guinea-Bissau introduced artemether-lumefantrine for treatment of uncomplicated malaria. Previously, 3 times the standard dose of chloroquine, that was probably efficacious against Plasmodium falciparum with the resistance-associated chloroquine-resistance transporter (pfcrt) 76T allele, was routinely used. The present study compared the efficacy and tolerability of a double standard dose of chloroquine with the efficacy and tolerability of artemether-lumefantrine. Methods. In a randomized open-label clinical trial, artemether-lumefantrine or chloroquine (50 mg/kg) were given as 6 divided doses over 3 days to children aged 6 months - 15 years who had uncomplicated P. falciparum monoinfection. Drug concentrations were measured on day 7. P. falciparum multidrug resistance gene N86Y and pfcrt K76T alleles were identified. Results. The polymerase chain reaction–adjusted day 28 and 42 treatment efficacies were 162 (97%) of 168 and 155 (97%) of 161, respectively, for artemether-lumefantrine and 150 (95%) of 158 and 138 (94%) of 148, respectively, for chloroquine. When parasites with resistance-associated pfcrt 76T were treated, the day 28 efficacy of chloroquine was 87%. No severe drug-related adverse events were detected. Symptom resolution was similar with both treatments. Conclusions. Both treatments achieved the World Health Organization–recommended efficacy for antimalarials that will be adopted as policy. High-dose chloroquine treatment regimes should be further evaluated with the aim of assessing chloroquine as a potential partner drug to artemisinin derivatives. Clinical trials registration. NCT00426439 PMID:21148503

  9. The effect of chloroquine prophylaxis on yellow fever vaccine antibody response: comparison of plaque reduction neutralization test and enzyme-linked immunosorbent assay.

    PubMed

    Barry, M; Patterson, J E; Tirrell, S; Cullen, M R; Shope, R E

    1991-01-01

    Weekly oral chloroquine prophylaxis for malaria has been associated with impaired antibody response to intradermal rabies vaccination. Experimental data indicate that chloroquine may inhibit yellow fever virus in vitro, yet there has been no clinical evidence to suggest that antibody response to yellow fever vaccine is impaired by concomitant oral administration of chloroquine. A prospective trial was undertaken to evaluate the antibody response to yellow fever 17D vaccine (Connaught Laboratories) of volunteers who were randomized to taking either chloroquine or no drug. Of fifty subjects, 28 were randomized to taking chloroquine, 22 were randomized to taking no drug. Yellow fever 17D vaccine was administered on day 0 and blood sampled on days 0, 14, 35 and 210. Chloroquine was administered weekly for four weeks. There was no significant difference in peak antibody titer by plaque reduction neutralization testing (PRNT) between the group that took chloroquine (mean log peak of reciprocal titer 1.43 +/- SD 0.60) with vaccine subcutaneously compared to vaccine-only group (mean log peak of reciprocal titer = 1.21 +/- 0.55). All fifty subjects seroconverted to yellow fever vaccine by day 210. ELISA testing was also performed on all subjects. The two tests showed good correlation (Spearman r = 0.675), although ELISA readings were positive by day 14 in significantly more subjects (p = .01). We conclude that routine anti-malarial doses of chloroquine do not affect antibody response to yellow fever 17D vaccine. ELISA testing, a less complex and less time-consuming test, correlates well with PRNT and is proposed for additional trials to measure yellow fever 17D vaccine response in flavivirus non-immune subjects. PMID:1996743

  10. Muscarinic interactions of bisindolylmaleimide analogues.

    PubMed

    Lazareno, S; Popham, A; Birdsall, N J

    1998-11-01

    We have used radioligand binding studies to determine the affinities of seven bisindolylmaleimide analogues, six of which are selective inhibitors of protein kinase C, at human muscarinic M1-M4 receptors. The compounds were most potent at M1 receptors, and Ro-31-8220 was the most potent analogue, with a Kd of 0.6 microM at M1 receptors. The weakest compounds, bisindolylmaleimide IV and bisindolylmaleimide V, had Kd values of 100 microM. If it is necessary to use protein kinase C inhibitors at concentrations of 10 microM or more in studies involving muscarinic receptors then bisindolylmaleimide IV may be the most appropriate inhibitor to use. PMID:9851596

  11. 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.

  12. 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.

  13. 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

  14. Gametocytocidal and sporontocidal effects of primaquine and of sulfadiazine with pyrimethamine in a chloroquine-resistant strain of Plasmodium falciparum*

    PubMed Central

    Rieckmann, Karl H.; McNamara, James V.; Frischer, Henri; Stockert, Thomas A.; Carson, Paul E.; Powell, Robin D.

    1968-01-01

    Studies with 3 volunteers were conducted to determine the effects of a combination of sulfadiazine and pyrimethamine and the effects of primaquine upon mature gametocytes of a strain of chloroquine-resistant Plasmodium falciparum—the Malayan (Camp.) strain. One volunteer was treated with sulfadiazine and pyrimethamine; two other volunteers each received a single dose of 45 mg of primaquine base. The combination of sulfadiazine and pyrimethamine, although active against blood schizonts, did not exert a marked sporontocidal effect against the Malayan (Camp.) strain. In sharp contrast, primaquine, although not effective as a blood schizontocide, exerted a marked gametocytocidal and sporontocidal effect against this strain. The findings emphasize the need for further studies of the sporontocidal and gametocytocidal effects of drugs, particularly primaquine, against chloroquine-resistant strains of P. falciparum and suggest that primaquine may come to play an important role in preventing the transmission of such strains. PMID:4876731

  15. 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

  16. In vivo response of Plasmodium falciparum to chloroquine in pregnant and non-pregnant women in Siaya District, Kenya*

    PubMed Central

    Steketee, R. W.; Brandling-Bennett, A. D.; Kaseje, D. C. O.; Schwartz, I. K.; Churchill, F. C.

    1987-01-01

    Chemoprophylaxis using chloroquine (CQ) in suppressive doses has been recommended to protect pregnant women in malarious areas from the adverse effects of malaria during pregnancy. In a malaria-endemic area of western Kenya with CQ-resistant Plasmodium falciparum, we determined the prevalence and density of falciparum infection in gravid and nulligravid women and compared the in-vivo parasite response to CQ using two regimens: 25 mg/kg body weight (CQ25) divided over a period of three days (for high-density parasitaemias) and 5 mg/kg body weight (CQ5) weekly for 4 weeks (for low-density parasitaemias). P. falciparum infections were present in 102 (42%) of 244 pregnant women. A greater proportion of primigravidae were parasitaemic (68%) than nulligravidae (50%, P=0.02) or multigravidae (33%, P <10-6). Primigravidae showed a higher geometric mean parasite density. In the CQ25 treatment group, failure to clear parasites by day 7 was more common in primigravidae than nulligravidae (P=0.008) or multigravidae (P=0.15). In the CQ5 treatment group, primigravidae were more likely to show increasing parasite density than nulligravidae or multigravidae. In this area of Kenya, virtually all women in their first pregnancy are exposed to malaria and are at greatest risk for malaria infection; compared with other women, they show higher parasite densities and are least likely to respond to chloroquine treatment in areas of chloroquine resistance. Malaria control strategies might be targeted to this group of women, but we are pessimistic about the efficacy of weekly CQ5 where there is chloroquine resistance. PMID:3325186

  17. 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

  18. Decreased sensitivity of artesunate and chloroquine of Plasmodium falciparum infecting hemoglobin H and/or hemoglobin constant spring erythrocytes.

    PubMed Central

    Yuthavong, Y; Butthep, P; Bunyaratvej, A; Fucharoen, S

    1989-01-01

    Plasmodium falciparum infecting hemoglobin (Hb) H and/or Hb Constant Spring erythrocytes in vitro was relatively more resistant than that infecting normal erythrocytes to artesunate and chloroquine, while the sensitivity to pyrimethamine was unchanged. The 50% inhibitory concentrations (IC50) for artesunate in HbH (alpha-thal 1/alpha-thal 2), HbH (alpha-thal 1/Hb Constant Spring), and homozygous Hb Constant Spring erythrocytes were 4.5 +/- 2.8, 8.5 +/- 3.2, and 2.6 +/- 1.6 nM compared with 0.82 +/- 0.35 nM in normal erythrocytes (P less than 0.002 for all three cases). The IC50 for chloroquine were 97 +/- 46, 162 +/- 67, and 93 +/- 36 nM, respectively, in the variant erythrocytes, compared with 48 +/- 13 nM in normal erythrocytes (P less than 0.002, 0.002, and 0.02, respectively). The differences in sensitivity to artesunate and chloroquine of the parasite infecting HbH erythrocytes are probably related to their oxidative mode of action and relatively high amounts of antioxidant enzymes in the host erythrocytes. This novel example of dependence on the host of the malarial parasite drug sensitivity may have implications for chemotherapy of malaria in patients with genetically variant erythrocytes. PMID:2643631

  19. 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

  20. 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

  1. 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

  2. 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

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

    PubMed

    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; Khan, Shahid M

    2015-06-01

    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

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

    PubMed Central

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

    2015-01-01

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

  5. 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

  6. 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

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

    PubMed Central

    Wittes, Robert

    1987-01-01

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

  8. 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

  9. 3-Iodo-4-aminoquinoline derivative sensitises resistant strains of Plasmodium falciparum to chloroquine.

    PubMed

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

    2016-06-01

    Chloroquine (CQ), the first cost-effective synthetic antimalarial, is rendered ineffective in malaria-endemic regions owing to the rise and spread of CQ-resistant Plasmodium falciparum. In this report, we show that a halogen derivative of CQ, namely 3-iodo-CQ, inhibits the proliferation of CQ-sensitive and -resistant P. falciparum in a verapamil-insensitive manner. Similar to CQ, the antimalarial activity of 3-iodo-CQ is likely due to its inhibition of β-haematin formation. Interestingly, the presence of non-inhibitory concentrations of 3-iodo-CQ potentiated the antiproliferative activity of CQ against CQ-resistant strains or P. falciparum transfectants expressing wild-type or mutant P. falciparum CQ resistance transporter (PfCRT) (C2(GC03) or C4(Dd2), respectively). These findings demonstrate that halogenation of the third position of 4-aminoquinoline, with a simple one-step reaction from CQ, generates a novel derivative that is active against CQ-sensitive and -resistant P. falciparum, possibly by inhibiting the activity of mutant PfCRT. PMID:27211211

  10. 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

  11. Chloroquine and beyond: exploring anti-rheumatic drugs to reduce immune hyperactivation in HIV/AIDS.

    PubMed

    Savarino, Andrea; Shytaj, Iart Luca

    2015-01-01

    The restoration of the immune system prompted by antiretroviral therapy (ART) has allowed drastically reducing the mortality and morbidity of HIV infection. However, one main source of clinical concern is the persistence of immune hyperactivation in individuals under ART. Chronically enhanced levels of T-cell activation are associated with several deleterious effects which lead to faster disease progression and slower CD4(+) T-cell recovery during ART. In this article, we discuss the rationale, and review the results, of the use of antimalarial quinolines, such as chloroquine and its derivative hydroxychloroquine, to counteract immune activation in HIV infection. Despite the promising results of several pilot trials, the most recent clinical data indicate that antimalarial quinolines are unlikely to exert a marked beneficial effect on immune activation. Alternative approaches will likely be required to reproducibly decrease immune activation in the setting of HIV infection. If the quinoline-based strategies should nevertheless be pursued in future studies, particular care must be devoted to the dosage selection, in order to maximize the chances to obtain effective in vivo drug concentrations. PMID:26084487

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

    PubMed

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

    2016-03-01

    Anti-malarial drugs specifically hydroxychloroquine (HCQ) or chloroquine (CQ) are very effective in treating and preventing the symptoms of systemic lupus erythematosus and other connective tissue diseases. These medications have shown to improve joint and muscle pain and arthritis, skin rashes, fatique, fever and also to control systemic signs of lupus as pericarditis or pleuritis. Shortterm and long-term treatment reduce cholesterol and have anti-platelet effect with decreasing risk of cardiovascular disease. The lupus patients on anti-malarials have also lower risk of cumulative organ damage due to reduce the amount of steroids. They may help to decrease lupus flares, mortality and are the key to controlling lupus long term outcome. Some lupus patients should be on anti-malarials for the rest of their life. For this reason, the key question is weather these drugs are absolutely safe and can be long term used in all lupus patients as a background therapy? Potential non-specific side effects occur very rare and are usually minor and last for short period. The major concerns are retinal deposits damage which could be potential reversible especially during hydroxychloroquine treatment. Nevertheless, ophthalmologist examination is still needed before starting to take HCQ or CQ and at to follow-up visits every 6-12 months. In conclusion it seems that anti-malarials are safe and have more clinical benefits than risks and from rheumatologist point of view should be more widely use in all lupus patients. PMID:27088206

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

    PubMed

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

    2016-02-01

    Chloroquine (CQ) and hydroxychloroquine (HCQ) are widely used to treat malaria and inflammatory diseases, long-term usage of which often causes severe side effects, especially retinopathy. Solute carrier transporters (SLCs) are important proteins responsible for the cellular uptake of endogenous and exogenous substances. Inhibitors competing with transporter substrates for SLCs often results in unfavorable toxicities and unsatisfactory therapeutic outcomes. We investigated the inhibitory effect of CQ and HCQ on substrate uptake mediated through a range of important SLC transporters in overexpressing human embryonic kidney (HEK293) cells. Our data revealed that both CQ and HCQ potently inhibit the uptake activity of organic anion transporting polypeptide 1A2 (OATP1A2). We recently reported OATP1A2 to be expressed in human retinal pigment epithelium (RPE), where it mediates cellular uptake of all-trans-retinol (atROL), a key step in the classical visual cycle. In this study, we demonstrate that CQ and HCQ could markedly impair atROL uptake in OATP1A2-expressing HEK293 cells and more importantly, in primary human RPE cells. Our study shows that CQ and HCQ are novel inhibitors of OATP1A2 and significantly impair OATP1A2-mediated substrate uptake, particularly transport of atROL into the RPE. This effect may compromise the function of the classic visual cycle leading to vision impairment and contribute to the retinopathy observed clinically in patients using CQ or HCQ. PMID:26429523

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

    PubMed

    Andayi, Warren A; Egan, Timothy J; Gut, Jiri; Rosenthal, Philip J; Chibale, Kelly

    2013-07-11

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

  15. Sensory neuron-specific GPCRs Mrgprs are itch receptors mediating chloroquine-induced pruritus

    PubMed Central

    Liu, Qin; Tang, Zongxiang; Surdenikova, Lenka; Kim, Seungil; Patel, Kush N.; Kim, Andrew; Ru, Fei; Guan, Yun; Weng, Hao-Jui; Geng, Yixun; Undem, Bradley J.; Kollarik, Marian; Chen, Zhou-Feng; Anderson, David J.; Dong, Xinzhong

    2010-01-01

    SUMMARY The cellular and molecular mechanisms mediating histamine-independent itch in primary sensory neurons are largely unknown. Itch induced by chloroquine (CQ) is a common side-effect of this widely used anti-malarial drug. Here we show that Mrgprs, a family of G protein-coupled receptors expressed exclusively in peripheral sensory neurons, function as itch receptors. Mice lacking a cluster of Mrgpr genes display significant deficits in itch induced by CQ but not histamine. CQ directly excites sensory neurons in an Mrgpr-dependent manner. CQ specifically activates mouse MrgprA3 and human MrgprX1. Loss- and gain-of-function studies demonstrate that MrgprA3 is required for CQ responsiveness in mice. Furthermore, MrgprA3-expressing neurons respond to histamine and co-express Gastrin-Releasing Peptide, a peptide involved in itch sensation, and MrgprC11. Activation of these neurons with MrgprC11-specific agonist BAM8-22 induces itch in wild-type but not mutant mice. Therefore, Mrgprs may provide molecular access to itch-selective neurons and constitute novel targets for itch therapeutics. PMID:20004959

  16. Sensory neuron-specific GPCR Mrgprs are itch receptors mediating chloroquine-induced pruritus.

    PubMed

    Liu, Qin; Tang, Zongxiang; Surdenikova, Lenka; Kim, Seungil; Patel, Kush N; Kim, Andrew; Ru, Fei; Guan, Yun; Weng, Hao-Jui; Geng, Yixun; Undem, Bradley J; Kollarik, Marian; Chen, Zhou-Feng; Anderson, David J; Dong, Xinzhong

    2009-12-24

    The cellular and molecular mechanisms mediating histamine-independent itch in primary sensory neurons are largely unknown. Itch induced by chloroquine (CQ) is a common side effect of this widely used antimalarial drug. Here, we show that Mrgprs, a family of G protein-coupled receptors expressed exclusively in peripheral sensory neurons, function as itch receptors. Mice lacking a cluster of Mrgpr genes display significant deficits in itch induced by CQ but not histamine. CQ directly excites sensory neurons in an Mrgpr-dependent manner. CQ specifically activates mouse MrgprA3 and human MrgprX1. Loss- and gain-of-function studies demonstrate that MrgprA3 is required for CQ responsiveness in mice. Furthermore, MrgprA3-expressing neurons respond to histamine and coexpress gastrin-releasing peptide, a peptide involved in itch sensation, and MrgprC11. Activation of these neurons with the MrgprC11-specific agonist BAM8-22 induces itch in wild-type but not mutant mice. Therefore, Mrgprs may provide molecular access to itch-selective neurons and constitute novel targets for itch therapeutics. PMID:20004959

  17. 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

  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. Inhibition of autophagy of fetal rabbit gonoducts by puromycin, tunicamycin and chloroquin in organ culture.

    PubMed

    Djehiche, B; Segalen, J; Chambon, Y

    1996-02-01

    At the end of ambisexual stage, mullerian or wolffian ducts are programmed to die. Cell degeneration is initialized by an appearance of lysosomes, subsequently involved in invading autophagic vacuoles. In an organ culture assay, performed for 6 days, treatments by puromycin, tunicamycin and chloroquine, known to act on synthesis, transport and activation of lysosomal enzymes, were applied to inhibit the duct regression. Four situations were studied: female genital tract of 17 day post coitum (d.p.c.) cultured with differentiated testis of 19 d.p.c.; male genital ducts of 17 d.p.c. cultured without testis; female and male genital tracts of 17 d.p.c. cultured alone as controls. The stabilization of the mullerian duct cultured with testis and of the wolffian duct cultured without testis was obtained. Ultrastructuraly, the lysosomes were scarce or absent and no autophagic vacuoles were observed. In preventing the formation of lysosomes, it was possible to avoid the duct cell autophagy and to comfirm the existence of a wolffian lysosomal system spontaneously active when testosterone is absent, while a mullerian one spontaneously inactive when AMH is absent. PMID:8907731

  20. Double Mutation in the pfmdr1 Gene Is Associated with Emergence of Chloroquine-Resistant Plasmodium falciparum Malaria in Eastern India

    PubMed Central

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

    2014-01-01

    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). PMID:25070111

  1. High-dose chloroquine is metabolically cardiotoxic by inducing lysosomes and mitochondria dysfunction in a rat model of pressure overload hypertrophy

    PubMed Central

    Chaanine, Antoine H; Gordon, Ronald E; Nonnenmacher, Mathieu; Kohlbrenner, Erik; Benard, Ludovic; Hajjar, Roger J

    2015-01-01

    Autophagy, macroautophagy and chaperone-mediated autophagy (CMA), are upregulated in pressure overload (PO) hypertrophy. In this study, we targeted this process at its induction using 3 methyladenine and at the lysosomal level using chloroquine and evaluated the effects of these modulations on cardiac function and myocyte ultrastructure. Sprague–Dawley rats weighing 200 g were subjected to ascending aortic banding. After 1 week of PO, animals were randomized to receive 3 methyladenine versus chloroquine, intraperitoneally, for 2 weeks at a dose of 40 and 50 mg/kg/day, respectively. Saline injection was used as control. Chloroquine treatment, in PO, resulted in regression in cardiac hypertrophy but with significant impairments in cardiac relaxation and contractility. Ultrastructurally, chloroquine accentuated mitochondrial fragmentation and cristae destruction with a plethora of autophagosomes containing collapsed mitochondria and lysosomal lamellar bodies. In contrast, 3 methyladenine improved cardiac function and attenuated mitochondrial fragmentation and autophagososme formation. Markers of macroautophagy and CMA were significantly decreased in the chloroquine group; whereas 3 methyladenine treatment significantly attenuated macroautophagy with a compensatory increase in CMA. Furthermore, chloroquine accentuated PO induced oxidative stress through the further decrease in the expression of manganese superoxide dismutase; whereas, 3 MA had a completely opposite effect. Taken together, these data suggest that high-dose chloroquine, in addition to its effect on the autophagy-lysosome pathway, significantly impairs mitochondrial antioxidant buffering capacity and accentuates oxidative stress and mitochondrial dysfunction in PO hypertrophy; highlighting, the cautious administration of this drug in high oxidative stress conditions, such as pathological hypertrophy or heart failure. PMID:26152691

  2. 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)

  3. Ecstasy analogues found in cacti.

    PubMed

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

    2008-06-01

    Human interest in psychoactive phenethylamines is known from the use of mescaline-containing cacti and designer drugs such as Ecstasy. From the alkaloid composition of cacti we hypothesized that substances resembling Ecstasy might occur naturally. In this article we show that lophophine, homopiperonylamine and lobivine are new minor constituents of two cactus species, Lophophora williamsii (peyote) and Trichocereus pachanoi (San Pedro). This is the first report of putatively psychoactive phenethylamines besides mescaline in these cacti. A search for further biosynthetic analogues may provide new insights into the structure-activity relationships of mescaline. An intriguing question is whether the new natural compounds can be called "designer drugs." PMID:18720674

  4. 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.

  5. Synthesis and α1-adrenoceptor antagonist activity of tamsulosin analogues.

    PubMed

    Sagratini, Gianni; Angeli, Piero; Buccioni, Michela; Gulini, Ugo; Marucci, Gabriella; Melchiorre, Carlo; Poggesi, Elena; Giardinà, Dario

    2010-12-01

    Tamsulosin (-)-1 is the most utilized α(1)-adrenoceptor antagonist in the benign prostatic hyperplasia therapy owing to its uroselective antagonism and capability in relieving both obstructive and irritative lower urinary tract symptoms. Here we report the synthesis and pharmacological study of the homochiral (-)-1 analogues (-)-2-(-)-5, bearing definite modifications in the 2-substituted phenoxyethylamino group in order to evaluate their influence on the affinity profile for α(1)-adrenoceptor subtypes. The benzyl analogue (-)-3, displaying a preferential antagonist profile for α1A-than α1D-and α1B-adrenoceptors, and a 12-fold higher potency at α1A-adrenoceptors with respect to the α1B subtype, may have improved uroselectivity compared to (-)-1. PMID:20934789

  6. 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.

  7. 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

  8. Effects of long-term chloroquine administration on the natural history of aortic aneurysms in mice.

    PubMed

    Ramadan, Azza; Wheatcroft, Mark D; Quan, Adrian; Singh, Krishna K; Lovren, Fina; Dhingra, Natasha; Teoh, Hwee; Al-Omran, Mohammed; Leong-Poi, Howard; Verma, Subodh

    2015-08-01

    Autophagy regulates cellular homeostasis and integrates the cellular pro-survival machinery. We investigated the role of autophagy in the natural history of murine abdominal aortic aneurysms (AAA). ApoE(-/-) mice were implanted with saline- or angiotensin II (Ang-II)-filled miniosmotic pumps then treated with either the autophagy inhibitor chloroquine (CQ; 50 mg·(kg body mass)(-1)·day(-1), by intraperitoneal injection) or saline. Ang-II-elicited aneurysmal expansion of the suprarenal aorta coupled with thrombus formation were apparent 8 weeks later. CQ had no impact on the incidence (50% for Ang-II compared with 46.2% for Ang-II + CQ; P = NS) and categorical distribution of aneurysms. The markedly reduced survival rate observed with Ang-II (57.1% for Ang-II compared with 100% for saline; P < 0.05) was unaffected by CQ (61.5% for Ang-II + CQ; P = NS compared with Ang-II). CQ did not affect the mean maximum suprarenal aortic diameter (1.91 ± 0.19 mm for Ang-II compared with 1.97 ± 0.21 mm for Ang-II + CQ; P = NS). Elastin fragmentation, collagen accumulation, and smooth muscle attrition, which were higher in Ang-II-treated mice, were unaffected by CQ treatment. Long-term CQ administration does not affect the natural history and prognosis of experimental AAA, suggesting that global loss of autophagy is unlikely to be a causal factor in the development of aortic aneurysms. Manipulation of autophagy as a mechanism to reduce AAA may need re-evaluation. PMID:26099030

  9. 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

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

    PubMed

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

    2015-04-01

    Malignant melanoma is associated with a 5-year survival rate of less than 20% once metastasized. Malignant melanoma cells exhibit increased levels of autophagy, a process of intracellular digestion that allows cells to survive various stresses including chemotherapies, resulting in reduced patient survival. Autophagy can be inhibited by chemicals like chloroquine (CQ), which prevents fusion of autophagosomes to lysosomes, resulting in autophagosome accumulation in most systems. Here, we describe how tested CQ to see whether it could sensitize B16F10 metastatic mouse melanoma cells to the anticancer activities of the natural compounds ursolic acid (UA) and resveratrol (RES). CQ with UA or RES strongly and synergistically reduced the viability of B16F10 mouse melanoma and A375 human melanoma cells. Surprisingly, flow cytometry of acridine orange-stained cells showed that UA or RES in combination with CQ significantly reduced autophagosome levels. Western blotting analysis revealed that CQ plus UA or RES paradoxically increased LC3II, indicative of autophagosome accumulation. In addition, CQ plus RES synergistically decreased the levels of both autophagy initiator beclin-1 and autophagy supporter p62. These results indicate that CQ with UA or RES strongly and synergistically reduces the viability of B16F10 and A375 melanoma cells. However, studies on B16F10 cells have shown that the synergistic effect was not mediated by inhibition of autophagy induced by UA or RES. These compounds are well-tolerated in humans, and CQ has shown promise as an adjuvant therapy. These combinations may be valuable treatment strategies for melanoma. PMID:25647735

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

    PubMed

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

    2016-05-30

    Rhodococcus equi preferentially infects macrophages causing pyogranulomatous pneumonia in young foals. Both the vapA and rhbC genes are up-regulated in an iron (Fe)-deprived environment, such as that found within macrophages. Chloroquine (CQ) is a drug widely used against malaria that suppresses the intracellular availability of Fe in eukaryotic cells. The main objective of this study was to evaluate the ability of CQ to inhibit replication of virulent R. equi within murine (J774A.1) and foal alveolar macrophages (AMs) and to verify whether the mechanism of inhibition could be Fe-deprivation-dependent. CQ effect on R. equi extracellular survival and toxicity to J774A.1 were evaluated. R. equi survival within J774A.1 and foal AMs was evaluated under CQ (10 and 20μM), bovine saturated transferrin (bHTF), and bovine unsaturated transferrin (bATF) exposure. To explore the action mechanism of CQ, the superoxide anion production, the lysozyme activity, as well as the relative mRNA expression of vapA and rhbC were examined. CQ at≤20μM had no effect on R. equi extracellular multiplication and J774A.1 viability. Exposure to CQ significantly and markedly reduced survival of R. equi within J774A.1 and foal AMs. Treatment with bHTF did not reverse CQ effect on R. equi. Exposure to CQ did not affected superoxide anion production or lysozyme activity, however vapA and rhbC expression was significantly increased. Our results reinforce the hypothesis that intracellular availability of Fe is required for R. equi survival, and our initial hypothesis that CQ can limit replication of R. equi in J774A.1 and foal AMs, most likely by Fe starvation. PMID:27139025

  12. Chloroquine neither eliminates liver stage parasites nor delays their development in a murine Chemoprophylaxis Vaccination model.

    PubMed

    Sahu, Tejram; Lambert, Lynn; Herrod, Jessica; Conteh, Solomon; Orr-Gonzalez, Sachy; Carter, Dariyen; Duffy, Patrick E

    2015-01-01

    Chemoprophylaxis Vaccination (CVac) confers long lasting sterile protection against homologous parasite strains in humans, and involves inoculation of infectious sporozoites (SPZ) under drug cover. CVac using the drug chloroquine (CQ) induces pre-erythrocytic immunity in humans that includes antibody to SPZ and T-cell responses to liver stage (LS) parasites. The mechanism by which CVac with CQ induces strong protective immunity is not understood as untreated infections do not confer protection. CQ kills blood stage parasites, but its effect on LS parasites is poorly studied. Here we hypothesized that CQ may prolong or perturb LS development of Plasmodium, as a potential explanation for enhanced pre-erythrocytic immune responses. Balb/c mice with or without CQ prophylaxis were infected with sporozoite forms of a luciferase-expressing rodent parasite, Plasmodium yoelii-Luc (Py-Luc). Mice that received primaquine, a drug that kills LS parasites, served as a positive control of drug effect. Parasite burden in liver was measured both by bioluminescence and by qRT-PCR quantification of parasite transcript. Time to appearance of parasites in the blood was monitored by microscopic analysis of Giemsa-stained thick and thin blood smears. The parasite load in livers of CQ-treated and untreated mice did not significantly differ at any of the time points studied. Parasites appeared in the blood smears of both CQ-treated and untreated mice 3 days after infection. Taken together, our findings confirm that CQ neither eliminates LS parasites nor delays their development. Further investigations into the mechanism of CQ-induced protection after CVac are required, and may give insights relevant to drug and vaccine development. PMID:25914686

  13. Chloroquine neither eliminates liver stage parasites nor delays their development in a murine Chemoprophylaxis Vaccination model

    PubMed Central

    Sahu, Tejram; Lambert, Lynn; Herrod, Jessica; Conteh, Solomon; Orr-Gonzalez, Sachy; Carter, Dariyen; Duffy, Patrick E.

    2015-01-01

    Chemoprophylaxis Vaccination (CVac) confers long lasting sterile protection against homologous parasite strains in humans, and involves inoculation of infectious sporozoites (SPZ) under drug cover. CVac using the drug chloroquine (CQ) induces pre-erythrocytic immunity in humans that includes antibody to SPZ and T-cell responses to liver stage (LS) parasites. The mechanism by which CVac with CQ induces strong protective immunity is not understood as untreated infections do not confer protection. CQ kills blood stage parasites, but its effect on LS parasites is poorly studied. Here we hypothesized that CQ may prolong or perturb LS development of Plasmodium, as a potential explanation for enhanced pre-erythrocytic immune responses. Balb/c mice with or without CQ prophylaxis were infected with sporozoite forms of a luciferase-expressing rodent parasite, Plasmodium yoelii-Luc (Py-Luc). Mice that received primaquine, a drug that kills LS parasites, served as a positive control of drug effect. Parasite burden in liver was measured both by bioluminescence and by qRT-PCR quantification of parasite transcript. Time to appearance of parasites in the blood was monitored by microscopic analysis of Giemsa-stained thick and thin blood smears. The parasite load in livers of CQ-treated and untreated mice did not significantly differ at any of the time points studied. Parasites appeared in the blood smears of both CQ-treated and untreated mice 3 days after infection. Taken together, our findings confirm that CQ neither eliminates LS parasites nor delays their development. Further investigations into the mechanism of CQ-induced protection after CVac are required, and may give insights relevant to drug and vaccine development. PMID:25914686

  14. 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

  15. 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

  16. Fully analogue photonic reservoir computer.

    PubMed

    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. An analogue study of intrusions.

    PubMed

    Laposa, Judith M; Alden, Lynn E

    2006-07-01

    According to cognitive theorists, intrusive trauma memories have their origin in how information during the event is processed. Two studies investigated functional cognitive strategies during medical crises that might protect against intrusions. In Study 1, interviews with health-care professionals were used to identify cognitive strategies judged to be effective in controlling emotions and dealing with medical crises. Study 2 systematically manipulated the use of those strategies in a trauma analogue film paradigm. Experimental participants reported fewer intrusions, and less fear and avoidance of film-related stimuli during the subsequent week than controls. The manipulation did not affect anxiety during the film or memory disorganization. Implications for cognitive theories of intrusion development are discussed. PMID:16125135

  18. 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

  19. 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. PMID:26001972

  20. Laboratory study of cometary analogues

    NASA Astrophysics Data System (ADS)

    Colangeli, L.; Brucato, J.; Mennella, V.; Palumbo, P.

    In situ exploration (e.g., GIOTTO mission) and astronomical observations (e.g., ISO) of comets have provided fundamental information about the structure, chemistry and physical properties of materials present in such primordial bodies of the Solar System. Moreover, it is known that cosmic materials evolve, depending on the efficiency of active processes (e.g., thermal annealing, UV irradiation, ion bombardment, gassolid interactions) in different space environments. Thus, the properties of cometary constituents must be considered in a wider perspective, including cosmic dust formation around cold stars and evolution in the interstellar medium until the formation of proto-planetary nebulae. In this scenario, laboratory experiments provide important hints to clarify the status of cometary compounds. The laboratory work is aimed at both reproducing material properties and at simulating their evolution based on the most effective mechanisms active in space. Several techniques are used to synthesise "analogues" of cometary compounds with controlled chemical and physical characteristics. The study of optical properties, complemented by other analytical techniques, is applied to investigate the products of synthesis in the experiments. The monitoring of the effects produced by processing methods, similar to those active in space, provides information both on the reactivity of materials and on the efficiency of treatments. Such an approach is able to provide quantitative information on chemical and structural modifications produced on organic and refractory materials. The comparison of laboratory results with data coming from space observations and in situ measurements provides a powerful tool to understand the real nature of comets and to place constraints on formation and evolution pathways. The laboratory experiments on analogues gain even more relevance as a sort of training in the future perspective of analysing cometary samples returned to Earth by space missions (e

  1. 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.

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

    PubMed

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

    2014-01-01

    Chloroquine, an antimalarial drug, can also be used in the regulation of the immune system, e.g. it is used in the treatment of autoimmune diseases. In this study we investigated the effects of chloroquine and its hydroxy-derivative on nitric oxide (NO) production in two different cell types: (i) immortalized mouse macrophage cell line RAW 264.7 and (ii) mouse bone marrow-derived macrophages (BMDM). The cells were treated with different concentrations (1-100 μM) of chloroquine or hydroxychloroquine and stimulated with lipopolysaccharide for 24 h to induce NO production. Measurement of nitrites by the Griess reaction was used to evaluate the production of NO. Expression of inducible NO synthase was evaluated with Western blot and ATPcytotoxicity test was used to measure the viability of the cells. Our results showed that both chloroquine and its hydroxy-derivative inhibited NO production in both cell types. However, based on the results of LD50 these inhibitory effects of both derivatives were due to their cytotoxicity. The LD50 values for chloroquine were 24.77 μM (RAW 264.7) and 24.86 μM (BMDM), the LD50 for hydroxychloroquine were 13.28 μM (RAW 264.7) and 13.98 μM (BMDM). In conclusion, hydroxychloroquine was more cytotoxic than its parent molecule. Comparing the two cell types tested, our data suggest that there are no differences in cytotoxicity of chloroquine or hydroxychloroquine for primary cells (BMDM) or immortalized cell line (RAW 264.7). PMID:25369339

  3. Plant volatile analogues strengthen attractiveness to insect.

    PubMed

    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

  4. 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

  5. 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].

  6. 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

  7. 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. PMID:25783783

  8. 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

  9. Treatment of uncomplicated falciparum malaria in southern Vietnam: can chloroquine or sulfadoxine-pyrimethamine be reintroduced in combination with artesunate?

    PubMed

    Nguyen, Mai Huong; Davis, Timothy M E; Cox-Singh, Janet; Hewitt, Sean; Tran, Quoc Toan; Tran, Bach Kim; Nguyen, Thi Hanh; Vo, Nhu Phuong; Doan, Hanh Nhan; Le, Dinh Cong

    2003-12-01

    The effectiveness of chloroquine or sulfadoxine-pyrimethamine administered with artesunate for treating uncomplicated falciparum malaria was assessed in 2 Vietnamese provinces where the sensitivity of parasites in vitro to conventional therapies had increased with the removal of drug pressure. In the province of Dac Lac, where potential malaria exposure begins at birth, 57 subjects (mean age, 9.6 years) were randomized to receive artesunate-chloroquine (group 1) or artesunate-sulfadoxine-pyrimethamine (group 2). In the province of Binh Phuoc, 66 nonimmune workers and their relatives (mean age, 24.2 years) were similarly randomized. By day 28 of follow-up, >96% of Dac Lac patients and <52% of Binh Phuoc patients in group 1 and group 2 had an in vivo response that demonstrated sensitivity to therapy. PCR-confirmed cure rates paralleled in vivo results among patients in Binh Phuoc, but PCR results identified 9 (15.7%) of the Dac Lac patients as having experienced asymptomatic, submicroscopic recrudescences. In Dac Lac, pfcrt K76T was near fixation, but infection with parasites with this mutation predicted recrudescence among group 1 patients in Binh Phuoc. Common pfdhfr mutations did not predict outcome in group 2. The successful reintroduction of conventional therapies in combination with artesunate depends on epidemiological and/or parasitological factors. PMID:14614668

  10. 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

  11. Chloroquine Is Grossly Under Dosed in Young Children with Malaria: Implications for Drug Resistance

    PubMed Central

    Ursing, Johan; Eksborg, Staffan; Rombo, Lars; Bergqvist, Yngve; Blessborn, Daniel; Rodrigues, Amabelia; Kofoed, Poul-Erik

    2014-01-01

    Background Plasmodium falciparum malaria is treated with 25 mg/kg of chloroquine (CQ) irrespective of age. Theoretically, CQ should be dosed according to body surface area (BSA). The effect of dosing CQ according to BSA has not been determined but doubling the dose per kg doubled the efficacy of CQ in children aged <15 years infected with P. falciparum carrying CQ resistance causing genes typical for Africa. The study aim was to determine the effect of age on CQ concentrations. Methods and Findings Day 7 whole blood CQ concentrations were determined in 150 and 302 children treated with 25 and 50 mg/kg, respectively, in previously conducted clinical trials. CQ concentrations normalised for the dose taken in mg/kg of CQ decreased with decreasing age (p<0.001). CQ concentrations normalised for dose taken in mg/m2 were unaffected by age. The median CQ concentration in children aged <2 years taking 50 mg/kg and in children aged 10–14 years taking 25 mg/kg were 825 (95% confidence interval [CI] 662–988) and 758 (95% CI 640–876) nmol/l, respectively (p = 0.67). The median CQ concentration in children aged 10–14 taking 50 mg/kg and children aged 0–2 taking 25 mg/kg were 1521 and 549 nmol/l. Adverse events were not age/concentration dependent. Conclusions CQ is under-dosed in children and should ideally be dosed according to BSA. Children aged <2 years need approximately double the dose per kg to attain CQ concentrations found in children aged 10–14 years. Clinical trials assessing the efficacy of CQ in Africa are typically performed in children aged <5 years. Thus the efficacy of CQ is typically assessed in children in whom CQ is under dosed. Approximately 3 fold higher drug concentrations can probably be safely given to the youngest children. As CQ resistance is concentration dependent an alternative dosing of CQ may overcome resistance in Africa. PMID:24466245

  12. Interaction between rifampicin, amodiaquine and artemether in mice infected with chloroquine resistant Plasmodium berghei

    PubMed Central

    2014-01-01

    Background Artemisinin-based combination therapy (ACT) remains the most effective chemotherapeutic strategy in the management of malaria. However, reports of reduced susceptibility of Plasmodium falciparum to the ACT justify the need for continued search for alternative anti-malarial drugs. The use of antibiotics with anti-malarial properties represents a potentially valuable chemotherapeutic option for the management of drug resistant infections. Thus, the intrinsic anti-malarial activity of the combination of clinical doses of rifampicin with amodiaquine and artemether was evaluated in an animal model using Plasmodium berghei. Methods A modification of the suppressive tests in vivo was employed. The anti-malarial activity of standard doses of amodiaquine (AQ) with or without artemether (ART) and combined with varying doses of rifampicin (RIF 15 mg/kg or RIF 30 mg/kg body weight) was evaluated in 40 mice sub-divided into eight groups and inoculated intraperitoneally with 1 × 107 red blood cells infected with chloroquine-resistant P. berghei ANKA strain. There were two control groups of animals, one group received amodiaquine alone while the other group received saline. Parasiticidal activity and survival of the animals were assessed over 21 days. Results Parasitaemia in the control animals peaked at 38% on day 9 and all animals died by day 10. The combination of amodiaquine with rifampicin 15 mg/kg body weight was the most effective of all the combinations and more efficacious than amodiaquine alone. The order of superiority of anti-malarial efficacy of the combinations was as follows; AQ + RIF 15 > AQ > AQ + ART + RIF 30 > AQ + ART + RIF 15 > AQ + RIF 30. Conclusion The combination of the clinical dose of rifampicin (15 mg/kg) with amodiaquine represents a potentially valuable treatment option in management of drug resistant malaria. In addition, the role of pharmacokinetic interaction in multiple drug therapy

  13. 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.

  14. 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

  15. 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

  16. 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.

  17. Synthesis, cytotoxicity and inhibition of NO production of ivangustin enantiomer analogues.

    PubMed

    Qin, Xiang-Yang; Chen, Bing-Yang; Fu, Jian-Jun; Shan, Lei; Lei, Xiao-Guang; Zhang, Wei-Dong

    2015-09-18

    The eight novel ivangustin enantiomer analogues possessing α-methylene-γ-butyrolactone moiety have been synthesized using (4S6R, 4S6S)-4-tert-butyldimethylsilyloxy-6-methylcyclohex-2-en-1-one (1) as starting material. These transformations were mainly carried out by aldol condensation reaction and one-pot annelation procedure. The stereochemistry of these synthesized analogues was determined by NOE analysis. Their cytoxicity was evaluated against the human cancer cell lines HCT-116 (colon), HL-60 (leukemia), QGY-7701 (liver), SMMC-7721 (liver), A549 (lung), MCF-7 (breast). The results showed that these analogues were more selective against the cell lines HL-60 and QGY-7701. Analogue 17 exhibited potent cytotoxicity and high selectivity toward HL-60 cell line with IC50 value of 1.02 μM, which suggested that it might be a promising anti-cancer lead compound. The inhibitory activities against NO production and the cytotoxicities in RAW 264.7 macrophages were determined at the same time. All of the analogues significantly inhibited the NO production with IC50 value in the range of 3.44-6.99 μM. Analogues 17, 22, 23 and 7 showed higher cytotoxicities, indicated their inhibitory activities against NO production may be influenced by the cytotoxicities. PMID:26280922

  18. 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.

  19. Heterocyclic chalcone analogues as potential anticancer agents.

    PubMed

    Sharma, Vikas; Kumar, Vipin; Kumar, Pradeep

    2013-03-01

    Chalcones, aromatic ketones and enones acting as the precursor for flavonoids such as Quercetin, are known for their anticancer effects. Although, parent chalcones consist of two aromatic rings joined by a three-carbon α,β-unsaturated carbonyl system, various synthetic compounds possessing heterocyclic rings like pyrazole, indole etc. are well known and proved to be effective anticancer agents. In addition to their use as anticancer agents in cancer cell lines, heterocyclic analogues are reported to be effective even against resistant cell lines. In this connection, we hereby highlight the potential of various heterocyclic chalcone analogues as anticancer agents with a brief summary about therapeutic potential of chalcones, mechanism of anticancer action of various chalcone analogues, and current and future prospects related to the chalcones-derived anticancer research. Furthermore, some key points regarding chalcone analogues have been reviewed by analyzing their medicinal properties. PMID:22721390

  20. Synthesis and SAR of vinca alkaloid analogues.

    PubMed

    Voss, Matthew E; Ralph, Jeffery M; Xie, Dejian; Manning, David D; Chen, Xinchao; Frank, Anthony J; Leyhane, Andrew J; Liu, Lei; Stevens, Jason M; Budde, Cheryl; Surman, Matthew D; Friedrich, Thomas; Peace, Denise; Scott, Ian L; Wolf, Mark; Johnson, Randall

    2009-02-15

    Versatile intermediates 12'-iodovinblastine, 12'-iodovincristine and 11'-iodovinorelbine were utilized as substrates for transition metal based chemistry which led to the preparation of novel analogues of the vinca alkaloids. The synthesis of key iodo intermediates, their transformation into final products, and the SAR based upon HeLa and MCF-7 cell toxicity assays is presented. Selected analogues 27 and 36 show promising anticancer activity in the P388 murine leukemia model. PMID:19147348

  1. 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

  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. 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

  4. Aggregated enhanced Raman scattering in Fe(III)PPIX solutions: the effects of concentration and chloroquine on excitonic interactions.

    PubMed

    Webster, Grant T; McNaughton, Don; Wood, Bayden R

    2009-05-14

    Resonance Raman spectra of hematin and hemin solutions are reported for 413 and 514 nm excitation wavelengths. Enhancement of A1g modes (1569 and 1370 cm(-1)) and B1g modes (1124 and 755 cm(-1)) as a function of increased concentration are observed when irradiating with 514 nm laser excitation but not 413 nm. This can be rationalized by considering an excitonic coupling mechanism. As the concentration of hematin increases there is an increased probability of supramolecular interactions between iron(III) protoporphyrin IX (Fe(III)PPIX) units occurring. The Fe(III)PPIX concentration reaches a saturation point in solution and excitonic coupling reaches a maximum causing the enhancement profile to plateau when applying 514 nm excitation. In contrast, when using 413 nm excitation there were no changes in band intensity with increased concentration showing that excitonic coupling through supramolecular interactions for aggregated solutions is wavelength dependent. Electronic absorption spectra show that as the concentration of Fe(III)PPIX increases in solution the Soret band is slightly blue shifted and the Q-band significantly broadens supporting the excitonic hypothesis. Understanding the mechanism that accounts for the Raman photophysical behavior of hemes at high concentrations provided an indirect method to monitor antimalarial drug interactions. A second aim was to investigate chloroquine binding to Fe(III)PPIX-OH/H2O monomers, pi-pi dimers and micro-oxo dimers formed in highly concentrated solutions approaching those of the digestive vacuole of the P. falciparum malaria parasite using excitonic Raman enhancement. It was hypothesized that the Raman excitonic enhancement mechanism could be impeded in heme aggregated solutions by the addition of chloroquine. This would result in a reduction in heme bands associated with the A1g modes including nu4. Resonance Raman spectra recorded using 514 nm excitation show that chloroquine (CQ) acts as a molecular spacer and binds

  5. Attributions about Perpetrators and Victims of Interpersonal Abuse: Results from an Analogue Study

    ERIC Educational Resources Information Center

    Langhinrichsen-Rohling, Jennifer; Shlien-Dellinger, Rania K.; Huss, Matthew T.; Kramer, Vertrie L.

    2004-01-01

    This analogue study (written vignettes and videotapes) examines the influence of victim-perpetrator relationship (spouse or acquaintance), sex of perceiver, and type of abuse (psychological vs. physical) on attributions about victims and perpetrators of domestic abuse. College student participants (73 men, 108 women) were randomly assigned to…

  6. Glucagonlike Peptide 2 Analogue Teduglutide

    PubMed Central

    Chaturvedi, Lakshmi S.; Basson, Marc D.

    2015-01-01

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

  7. 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

  8. Resonance Raman spectroscopy can detect structural changes in haemozoin (malaria pigment) following incubation with chloroquine in infected erythrocytes.

    PubMed

    Webster, Grant T; Tilley, Leann; Deed, Samantha; McNaughton, Don; Wood, Bayden R

    2008-04-01

    Resonance Raman spectroscopy was applied to monitor the effects of chloroquine (CQ) treatment on cultures of Plasmodium falciparum trophozoites. A number of bands assigned to A(1g) and B(1g) modes characteristic of the haemozoin aggregate are reduced in intensity in the CQ-treated cells, however, no bands from the CQ are observed. The intensity changes are attributed to intermolecular drug binding of the CQ in a sandwich type complex between ferriprotoporphyrin IX (FePPIX) dimer units. It is postulated that the CQ binds via pi-pi interactions between adjacent and orientated porphyrins thereby disrupting the haemozoin aggregate and reducing excitonic interactions between adjacent haems. The results show the potential of Raman microscopy as a screening tool for FePPIX:drug interactions in live cells. PMID:18325340

  9. Convergent syntheses of LeX analogues

    PubMed Central

    Wang, An; Hendel, Jenifer

    2010-01-01

    Summary The synthesis of three Lex derivatives from one common protected trisaccharide is reported. These analogues will be used respectively for competitive binding experiments, conjugation to carrier proteins and immobilization on gold. An N-acetylglucosamine monosaccharide acceptor was first glycosylated at O-4 with a galactosyl imidate. This coupling was performed at 40 °C under excess of BF3·OEt2 activation and proceeded best if the acceptor carried a 6-chlorohexyl rather than a 6-azidohexyl aglycon. The 6-chlorohexyl disaccharide was then converted to an acceptor and submitted to fucosylation yielding the corresponding protected 6-chlorohexyl Lex trisaccharide. This protected trisaccharide was used as a precursor to the 6-azidohexyl, 6-acetylthiohexyl and 6-benzylthiohexyl trisaccharide analogues which were obtained in excellent yields (70–95%). In turn, we describe the deprotection of these intermediates in one single step using dissolving metal conditions. Under these conditions, the 6-chlorohexyl and 6-azidohexyl intermediates led respectively to the n-hexyl and 6-aminohexyl trisaccharide targets. Unexpectedly, the 6-acetylthiohexyl analogue underwent desulfurization and gave the n-hexyl glycoside product, whereas the 6-benzylthiohexyl analogue gave the desired disulfide trisaccharide dimer. This study constitutes a particularly efficient and convergent preparation of these three Lex analogues. PMID:20485599

  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. 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

  12. Selectivity of celite-immobilized patatin (lipid acyl hydrolase) from potato (Solanum tuberosum L.) tubers in esterification reactions As influenced by water activity and glycerol analogues as alcohol acceptors.

    PubMed

    Pinsirodom, P; Parkin, K L

    2000-02-01

    Lipid acyl hydrolase (LAH; patatin) was purified from potato tubers by ammonium sulfate fractionation followed by anion-exchange and affinity chromatography. The major protein band of 40-43 kDa on SDS-PAGE appeared to be patatin, and it stained positive for lipase activity on native PAGE. Selectivity of a Celite-immobilized potato LAH in esterification reactions with n-acyl fatty acids (FA; C4, C6, C8, C10, C12, C14, C16, and C18) and alcohol acceptors (n-propanol, 2-propanol, 1,3-propanediol, and glycerol; 1,2-propanediol was not sufficiently reactive) was studied in isooctane. Immobilized LAH was highly selective for medium chain FAs (C8/C10) with a secondary optimum for chain lengths of C14/16. Water activity (a(w)) influenced activity and FA selectivity of the enzyme. Initial rates of ester synthesis were greatest at a(w) of 0.90 for all alcohol acceptors except for glycerol, where greatest initial rates were observed at a(w) of 0.19. Immobilized LAH preparations exhibited a bell-shape pH profile with optimum activity at pH 6-7 for ester synthesis, and no effect of pH on FA selectivity was observed. PMID:10691609

  13. Inhibition of plant and mammalian diamine oxidase by substrate analogues.

    PubMed

    Biegański, T; Osińska, Z; Masliński, C

    1982-04-01

    Imidazoles, aliphatic substrate analogues and the natural dipeptides, carnosine and anserine, were investigated as inhibitors of diamine oxidase from the pig kidney, human pregnancy plasma and pea seedlings. Imidazole, methylimidazoles, N-acetylimidazole, histamine and N tau-methylhistamine are relatively potent inhibitors of mammalian diamine oxidase showing no influence on plant enzymes. Anserine and carnosine are inhibitors of pig kidney and pea seedling enzymes. Ki values are 2 microM and 10 microM respectively. Investigated natural derivatives of putrescine and cadaverine have no influence on diamine oxidase of different origin. In conclusion, we present some evidence to suggest that mammalian diamine oxidase, despite a high reaction rate with putrescine, is better adapted to histamine oxidation, whereas for plant enzymes the diamines are preferred substrates. PMID:6805264

  14. 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. PMID:15878670

  15. Synthesis of alpha-substituted fosmidomycin analogues as highly potent Plasmodium falciparum growth inhibitors.

    PubMed

    Haemers, Timothy; Wiesner, Jochen; Van Poecke, Sara; Goeman, Jan; Henschker, Dajana; Beck, Edwald; Jomaa, Hassan; Van Calenbergh, Serge

    2006-04-01

    In view of the promising antimalarial activity of fosmidomycin or its N-acetyl homologue FR900098, the objective of this work was to investigate the influence of aromatic substituents in the alpha-position of the phosphonate moiety. The envisaged analogues were prepared using a linear route involving a 3-aryl-3-phosphoryl propanal intermediate. The activities of all compounds were evaluated on Eschericia coli 1-deoxy-d-xylulose 5-phosphate reductoisomerase and against two Plasmodium falciparum strains. Compared with fosmidomycin, several analogues displayed enhanced activity towards the P. falciparum strains. Compound 1e with a 3,4-dichlorophenyl substitution in the alpha-position of fosmidomycin emerged as the most potent analogue of this series. It is approximately three times more potent in inhibiting the growth of P. falciparum than FR900098, the most potent representative of this class reported so far. PMID:16439126

  16. 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.

  17. Classical Simulated Annealing Using Quantum Analogues

    NASA Astrophysics Data System (ADS)

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

    2016-06-01

    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.

  18. Chloroquine enhances replication of influenza A virus A/WSN/33 (H1N1) in dose-, time-, and MOI-dependent manners in human lung epithelial cells A549.

    PubMed

    Wu, Liqi; Dai, Jianping; Zhao, Xiangfeng; Chen, Youying; Wang, Gefei; Li, Kangsheng

    2015-07-01

    Anti-malaria drug, chloroquine, has been reported to be effective against influenza A virus (IAV) in vitro and used in in-vivo experiments and clinical trial for prevention or treatment of influenza. In this study, it has been shown by immunofluorescence, hemagglutination, and plaque assays that chloroquine enhanced A/WSN/33 (H1N1) replication with pronounced cytopathic effect in dose-, time-, and MOI-dependent manners in human lung epithelial cells A549. Time-of-addition assay showed that inhibitory effect on virus replication by chloroquine pre-treatment was indistinctive, and virus productions were enhanced when the drug was applied after viral adsorption. The effectiveness of chloroquine as an anti-influenza drug is questioned, and caution in its use is recommended. PMID:25715935

  19. Modelling future no-analogue climate distributions: A world-wide phytoclimatic niche-based survey

    NASA Astrophysics Data System (ADS)

    García-López, Javier M.; Allué, Carmen

    2013-02-01

    By the end of the 21st century in some zones the accelerating climate change affecting this planet will create factorial combinations unknown at this time, which will give rise to climates unlike the present ones. This study presents a numerical and cartographic evaluation of these no-analogue climatic zones, whose consequences for existing ecosystems are quite unpredictable, using a method based on the convex hull in a climate hyperspace and 12 future climate projections for 2080. The percentage of the world surface that will foreseeably be occupied by no-analogue climates by 2080 ranges between 3.5% and 17.5%. The bulk of the no-analogue surface area will foreseeably be located in the Northern hemisphere (> 80%), with more elevated risk in tropical and subtropical latitudes between 10 degrees latitude South and 30 degrees latitude North, preferentially in Africa, South America, the Arabian Peninsula, the Indian Peninsula, the North-West of the Gulf of Mexico, Eastern China and Polynesia. Mean temperatures would appear to be the variables most influencing the process. This affects 32 of the 34 hotspots defined for the planet, especially tropical forests in South America and Asia. 6.8% of these conservation-critical surfaces are predicted as no-analogue areas. Population density is greater in the areas that will probably develop no-analogue climates in the future than in those that will not.

  20. Structural and Spectroscopic Characterizations of Amide-AlCl3-Based Ionic Liquid Analogues.

    PubMed

    Hu, Pengcheng; Zhang, Rui; Meng, Xianghai; Liu, Haiyan; Xu, Chunming; Liu, Zhichang

    2016-03-01

    Several amide-AlCl3-based ionic liquid (IL) analogues were synthesized through a one-step method using three different structure amides as donor molecules. The effects of the steric and inductive effects of the methyl group substituted on the N atom on the asymmetric splitting of AlCl3 and the coordination site of the amide were investigated by (27)Al NMR, Raman, in situ IR, and UV-vis spectra for these IL analogues. Bidentate coordination through both the O and N atoms was dominant in the N-methylacetamide-AlCl3- and N,N-dimethylacetamide-AlCl3-based IL analogues because of the inductive effect of the methyl group. By contrast, the acetamide-AlCl3-based IL analogue presented mainly in the form of monodentate coordination via the O atom. Compared with monodentate coordination, bidentate coordination was favorable to the asymmetric splitting of AlCl3 with the same amide-AlCl3 molar ratio. Under the influence of the steric and inductive effects of the methyl group, the ionic species percentages in these IL analogues ranked in the following order: N-methylacetamide > N,N-dimethylacetamide > acetamide. PMID:26848508

  1. 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

  2. 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

  3. D-luciferin analogues: a multicolor toolbox for bioluminescence imaging.

    PubMed

    Sun, Yuan-Qiang; Liu, Jing; Wang, Pi; Zhang, Jingyu; Guo, Wei

    2012-08-20

    Colorful mixture: Three types of luciferin analogues, that is, alkylaminoluciferins, aminoselenoluciferin, and luciferins with a benzimidazole scaffold, have been reported. These analogues show excellent bioluminescent properties and great potential in bioluminescence imaging. PMID:22807027

  4. Synthesis and Cytoxicity of Sempervirine and Analogues.

    PubMed

    Pan, Xiaohong; Yang, Chunying; Cleveland, John L; Bannister, Thomas D

    2016-03-01

    Sempervirine and analogues were synthesized using a route featuring Sonogashira and Larock Pd-catalyzed reactions. Structure-activity relationships were investigated using three human cancer cell lines. 10-Fluorosempervirine is the most potently cytotoxic member of the family yet described. PMID:26828413

  5. Solanapyrone analogues from a Hawaiian fungicolous fungus

    Technology Transfer Automated Retrieval System (TEKTRAN)

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

  6. New cytotoxic analogues of annonaceous acetogenins.

    PubMed

    Rodier, S; Le Huerou, Y; Renoux, B; Doyon, J; Renard, P; Pierré, A; Gesson, J P; Grée, R

    2001-01-01

    A series of new acetogenin analogues incorporating a central catechol moiety instead of the tetrahydrofuran ring(s) have been prepared and tested against L1210 leukemia cells. Although less potent than bullatacinone, which has the same terminal lactone, these compounds display interesting cell cycle effects. PMID:11962508

  7. 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.

  8. Synthesis of lipid II phosphonate analogues.

    PubMed

    Borbás, Anikó; Herczegh, Pál

    2011-09-01

    Simple analogues of lipid II were synthesized from 3,4,6-tri-O-acetyl-2-acetamido-2-deoxy-1-thio-β-D-glucopyranose using conjugate addition onto ethylidene bisphosphonate and subsequent Wadsworth-Horner-Emmons reaction with long chain aliphatic aldehydes. PMID:21600568

  9. The arsonomethyl analogue of 3-phosphoglycerate.

    PubMed Central

    Adams, S R; Sparkes, M J; Dixon, H B

    1983-01-01

    4-Arsono-2-hydroxybutanoic acid, the analogue of 3-phosphoglycerate in which -CH2-AsO3H2 replaces -O-PO3H2, was synthesized. It proved to be a substrate for phosphoglycerate kinase. Its Michaelis constant was only slightly higher than that of the natural substrate, but its catalytic constant was about 1300 times smaller. PMID:6615422

  10. 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

  11. New experimental protocols for tensile testing of abdominal aortic analogues.

    PubMed

    Bailly, L; Deplano, V; Lemercier, A; Boiron, O; Meyer, C

    2014-06-01

    This work proposes an in vitro tensile testing protocol that is able to characterize abdominal aortic (AA) analogues under physiologically inspired mechanical loadings. Kinematic parameters are defined in agreement with in vivo measurements of aortic dynamics. A specific focus is given to the choice of the applied loading rates, deriving from the knowledge of aortic Peterson modulus and blood pressure variations from diastolic to systolic instants. The influence of physiological elongation rates has been tested on both porcine AAs and a thermoplastic polyurethane (TPU) material used to elaborate AA analogues. The diastolic and systolic elongation rates estimates vary between orders of magnitude O(10(-2)) and O(10(-1))s(-1). Negligible differences are obtained when comparing stress-elongation responses between both physiological elongation rates. In contrast, a noticeable stiffening of the TPU mechanical response is observed compared to that obtained under the common low traction rate of O(10(-3))s(-1). This work shows how relevant physiological elongation rates can be evaluated as a function of age, gender and pathological context. PMID:24613685

  12. [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

  13. 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

  14. 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

  15. 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

  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. PMID:25199554

  17. 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. PMID:26094944

  18. X-ray microanalysis of Plasmodium falciparum and infected red blood cells: effects of qinghaosu and chloroquine on potassium, sodium, and phosphorus composition

    SciTech Connect

    Lee, P.; Ye, Z.; Van Dyke, K.; Kirk, R.G.

    1988-08-01

    Cryosections of human red blood cells infected by Plasmodium falciparum were analyzed by energy dispersive x-ray microanalysis to determine the elemental composition of the parasites and their red cell hosts separately. The effects of two antimalarial drugs, qinghaosu and chloroquine, on potassium, sodium, and phosphorus concentrations were studied. Malarial infection causes a decrease in potassium concentration and an increase in sodium concentration in the host red cells. The drastic change in the cation composition, however, occurs only in red cells infected by late stage parasites (late trophozoite and schizont). Red cells infected by early stage parasites (ring stage) show only small changes in sodium concentration. Furthermore, the noninfected red cells in parasitized cultures show no difference in composition from those of normal red cells. Treatment of the parasitized cultures with qinghaosu (10(-6) M) or chloroquine (10(-6) M) for 8 hr causes phosphorus concentration of both early and late parasites to decrease. An 8 hr treatment with qinghaosu also produces a reduction in potassium and an increase in sodium concentrations in early and late parasites. In contrast, 8 hr treatment with chloroquine only causes a change in the sodium and potassium concentrations of the late stage parasites and does not affect the early stage parasites.

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

    PubMed Central

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

    2009-01-01

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

  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. Are transporter genes other than the chloroquine resistance locus (pfcrt) and multidrug resistance gene (pfmdr) associated with antimalarial drug resistance?

    PubMed

    Anderson, Timothy J C; Nair, Shalini; Qin, Huang; Singlam, Sittaporn; Brockman, Alan; Paiphun, Lucy; Nosten, François

    2005-06-01

    Mu et al. (Mu, J., M. T. Ferdig, X. Feng, D. A. Joy, J. Duan, T. Furuya, G. Subramanian, L. Aravind, R. A. Cooper, J. C. Wootton, M. Xiong, and X. Z. Su, Mol. Microbiol. 49:977-989, 2003) recently reported exciting associations between nine new candidate transporter genes and in vitro resistance to chloroquine (CQ) and quinine (QN), with six of these loci showing association with CQ or QN in a southeast Asian population sample. We replicated and extended this work by examining polymorphisms in these genes and in vitro resistance to eight drugs in parasites collected from the Thailand-Burma border. To minimize problems of multiple testing, we used a two-phase study design, while to minimize problems caused by population structure, we analyzed parasite isolates collected from a single clinic. We first examined associations between genotype and drug response in 108 unique single-clone parasite isolates. We found strong associations between single nucleotide polymorphisms in pfmdr and mefloquine (MFQ), artesunate (AS), and lumefantrine (LUM) response. We also observed associations between an ABC transporter (G7) and response to QN and AS and between another ABC transporter (G49) and response to dihydro-artemisinin (DHA). We reexamined significant associations in an independent sample of 199 unique single-clone infections from the same location. The significant associations with pfmdr-1042 detected in the first survey remained. However, with the exception of the G7-artesunate association, all other associations observed with the nine new candidate transporters disappeared. We also examined linkage disequilibrium (LD) between markers and phenotypic correlations between drug responses. We found minimal LD between genes. Furthermore, we found no correlation between chloroquine and quinine responses, although we did find expected strong correlations between MFQ, QN, AS, DHA, and LUM. To conclude, we found no evidence for an association between 8/9 candidate genes and

  2. Randomised controlled trial of weekly chloroquine to re-establish normal erythron iron flux and haemoglobin recovery in postmalarial anaemia

    PubMed Central

    Cox, Sharon E; Nweneka, Chidi V; Doherty, Conor P; Fulford, Anthony J; Moore, Sophie E; Prentice, Andrew M

    2013-01-01

    Objective To determine if low-dose weekly chloroquine (CQ) therapy improves recovery from malaria-associated anaemia. Design Proof of concept randomised clinical trial. Setting West Kiang District, Lower River Region, The Gambia. Participants Children resident in participating communities, aged 12–72 months, with uncomplicated malaria identified using active case detection over two consecutive malaria transmission seasons. Interventions In 2007, eligible children were randomised to chloroquine-sulfadoxine/pyrimethamine (CQ-SP) or co-artemether (ACT) antimalarial therapy, and after parasite clearance on day 3 were subsequently re-randomised (double-blind) to weekly low-dose CQ (5 mg/kg) or placebo. In 2008, all eligible children were treated with ACT and subsequently randomised to CQ or placebo. Outcome measures The primary outcome was a change in haemoglobin from baseline (day 3 of antimalarial treatment) to day 90 in the CQ and placebo treatment arms. Secondary outcomes were changes in urinary neopterin as a marker of macrophage activation, markers of erythropoietic response and prevalence of submicroscopic parasitaemia. Change in haemoglobin in the placebo arm by initial antimalarial treatment was also assessed. Results In 2007, 101 children with uncomplicated malaria were randomised to antimalarial treatment with CQ-SP or ACT and 65 were subsequently randomised to weekly CQ or placebo. In 2008, all children received ACT antimalarial treatment and 31 were subsequently randomised to receive weekly CQ or placebo. Follow-up to day 90 was 96%. There was no effect of weekly CQ vs placebo on change in haemoglobin at day 90 (CQ+10.04 g/L (95% CI 6.66 to 13.42) vs placebo +7.61 g/L (95% CI 2.88 to 12.35)). There was no effect on the secondary outcomes assessed, or effect of initial antimalarial therapy on haemoglobin recovery. Higher day 90 haemoglobin correlated independently with older age, not being stunted, higher haemoglobin at day 0 and adequate iron

  3. [Insulin analogues: modifications in the structure, molecular and metabolic consequences].

    PubMed

    de Luis, D A; Romero, E

    2013-01-01

    Recombinant DNA technology has provided insulin analogues for the treatment of diabetes mellitus, with an efficacy and safety that has improved the treatment of this disease. We briefly review the principal characteristics of the insulin analogues currently available. Both rapid-acting (lispro, aspart and glulisine) and long acting (glargine and determir) insulin analogues are included in this review. We describe the pharmacology of each insulin analogue, their differences with the human insulin, the administration, indication, efficacy and safety. In addition we discussed the main controversies of the use of these insulin analogues. In particular, those related with the risk of cancer and retinopathy, and their use in pregnant women. PMID:23517895

  4. Design and synthesis of new fluconazole analogues.

    PubMed

    Pore, Vandana S; Agalave, Sandip G; Singh, Pratiksha; Shukla, Praveen K; Kumar, Vikash; Siddiqi, Mohammad I

    2015-06-21

    We have synthesized new fluconazole analogues containing two different 1,2,3-triazole units in the side chain. The synthesis of new amide analogues using a variety of acids is also described. All the compounds showed very good antifungal activity. A hemolysis study of the most active compounds 6e and 13j showed that both compounds did not cause any hemolysis at the dilutions tested. These compounds did not exhibit any toxicity to L929 cells at MIC and lower concentrations. In the docking study, the overall binding mode of 6e and 13j appeared to be reasonable and provided a good insight into the structural basis of inhibition of Candida albicans Cyp51 by these compounds. PMID:25975803

  5. How to teach an old dog new tricks: autophagy-independent action of chloroquine on the tumor vasculature.

    PubMed

    Maes, Hannelore; Kuchnio, Anna; Carmeliet, Peter; Agostinis, Patrizia

    2014-01-01

    Chloroquine (CQ) is exploited in clinical trials as an autophagy blocker to potentiate anticancer therapy, but it is unknown if it solely acts by inhibiting cancer cell-autonomous autophagy. Our recent study shows that besides blocking cancer cell growth, CQ also affects endothelial cells (ECs) and promotes tumor vessel normalization. This vessel normalizing effect of CQ reduces tumor hypoxia, cancer cell intravasation, and metastasis, while improving the delivery and response to chemotherapy. By compromising autophagy in melanoma cells or using mice with a conditional knockout of ATG5 in ECs, we found that the favorable effects of CQ on the tumor vasculature do not rely on autophagy. CQ-induced vessel normalization relies mainly on altered endolysosomal trafficking and sustained NOTCH1 signaling in ECs. Remarkably these CQ-mediated effects are abrogated when tumors are grown in mice harboring EC-specific deletion of NOTCH1. The autophagy-independent vessel normalization by CQ leading to improved delivery and tumor response to chemotherapy further advocates its clinical use in combination with anticancer treatments. PMID:25484095

  6. The effect of AZT and chloroquine on the activities of ricin and a saporin-transferrin chimeric toxin.

    PubMed

    Lizzi, A R; D'Alessandro, A M; Zeolla, N; Brisdelli, F; D'Andrea, G; Pitari, G; Oratore, A; Bozzi, A; Ippoliti, R

    2005-08-15

    This study deals with the combination of chloroquine (CQ, an anti-malaric drug) and 3'-azido-3'-deoxythymidine (AZT, anti-human immuno-deficiency virus (HIV) drug) with a chimeric toxin (TS) obtained by chemical linking of saporin (a ribosome inactivating protein from the plant Saponaria officinalis) and human transferrin, in the intoxication of the human chronic myeloid leukaemia cells (K562). Our data demonstrate that AZT, at concentrations comparable to those reached in the blood of HIV-infected patients under pharmacological treatment with this drug, can increase the toxicity of TS in cooperation with CQ inducing an increased effect on protein synthesis in K562 cells ( approximately 50% inhibition of protein synthesis for TS alone, and TS with AZT and approximately 70% with both AZT and CQ). Furthermore, pre-treatment of cells with AZT alone can induce an increase of apoptosis in K562 cells intoxicated with TS. By comparing data obtained with the model toxin ricin, we get indications that the two toxins partially differ in their intracellular routes, also suggesting that chimeric constructs containing ricin-like toxins (i.e. immunotoxins) could be coupled with the use of common and cheap drugs for the treatment of cancer in HIV-infected patients. PMID:15982641

  7. 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

  8. Phenotypic reversal of the btn1 defects in yeast by chloroquine: a yeast model for Batten disease.

    PubMed

    Pearce, D A; Carr, C J; Das, B; Sherman, F

    1999-09-28

    BTN1 of Saccharomyces cerevisiae encodes an ortholog of CLN3, the human Batten disease gene. We have reported previously that deletion of BTN1, btn1-Delta, resulted in a pH-dependent resistance to D-(-)-threo-2-amino-1-[p-nitrophenyl]-1,3-propanediol (ANP). This phenotype was caused by btn1-Delta strains having an elevated ability to acidify growth medium through an elevated activity of the plasma membrane H(+)-ATPase, resulting from a decreased vacuolar pH during early growth. We have determined that growing btn1-Delta strains in the presence of chloroquine reverses the resistance to ANP, decreases the rate of medium acidification, decreases the activity of plasma membrane H(+)-ATPase, and elevates vacuolar pH. However, an additional effect of this phenotypic reversal is that activity of plasma membrane H(+)-ATPase is decreased further and vacuolar pH is increased further as btn1-Delta strains continue to grow. This phenotypic reversal of btn1-Delta can be considered for developing a therapy for Batten disease. PMID:10500178

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

    PubMed Central

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

    2015-01-01

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

  10. Methylene blue for malaria in Africa: results from a dose-finding study in combination with chloroquine

    PubMed Central

    Meissner, Peter E; Mandi, Germain; Coulibaly, Boubacar; Witte, Steffen; Tapsoba, Théophile; Mansmann, Ulrich; Rengelshausen, Jens; Schiek, Wolfgang; Jahn, Albrecht; Walter-Sack, Ingeborg; Mikus, Gerd; Burhenne, Jürgen; Riedel, Klaus-Dieter; Schirmer, R Heiner; Kouyaté, Bocar; Müller, Olaf

    2006-01-01

    The development of safe, effective and affordable drug combinations against malaria in Africa is a public health priority. Methylene blue (MB) has a similar mode of action as chloroquine (CQ) and has moreover been shown to selectively inhibit the Plasmodium falciparum glutathione reductase. In 2004, an uncontrolled dose-finding study on the combination MB-CQ was performed in 435 young children with uncomplicated falciparum malaria in Burkina Faso (CQ monotherapy had a > 50% clinical failure rate in this area in 2003). Three serious adverse events (SAE) occurred of which one was probably attributable to the study medication. In the per protocol safety analysis, there were no dose specific effects. The overall clinical and parasitological failure rates by day 14 were 10% [95% CI (7.5%, 14.0%)] and 24% [95% CI (19.4%, 28.3%)], respectively. MB appears to have efficacy against malaria, but the combination of CQ-MB is clearly not effective in the treatment of malaria in Africa. PMID:17026773

  11. Efficient synthesis of esermethole and its analogues.

    PubMed

    Zhou, Yongyun; Zhao, Yuanhong; Dai, Xiaoyong; Liu, Jianping; Li, Liang; Zhang, Hongbin

    2011-06-01

    In this work, a general and flexible synthetic route towards the synthesis of pyrroloindoline alkaloids was developed. This new strategy features with a palladium mediated sequential arylation-allylation of o-bromoanilides and leads to the construction of oxindoles bearing a full carbon quaternary center. The cheap triphenylphosphine was proved to be a highly effective ligand for this one pot transformation. On the basis of this new method, esermethole and its analogues were synthesized. PMID:21472186

  12. 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

  13. Synthesis and cytotoxic activity of acetogenin analogues.

    PubMed

    Rodier, S; Le Huérou, Y; Renoux, B; Doyon, J; Renard, P; Pierré, A; Gesson, J P; Grée, R

    2000-06-19

    A set of 16 new simplified analogues of acetogenins has been designed based on: (i) the replacement of the bis THF moiety of these natural products by an ethylene glycol bis ether unit; (ii) the introduction of different lipophilic side chains (alkyl, aryl, dialkylamino, O-cholesteryl); (iii) the presence of the same terminal isolactone. In vitro cytotoxic activity against L1210 leukemia is reported. PMID:10890167

  14. 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.

  15. 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

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

    NASA Astrophysics Data System (ADS)

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

    2014-07-01

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

  17. 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.

  18. 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

  19. [The effect of gamma-L-glutamylhistamine analogues on the severity of experimental anaphylactic reaction, hormonal status and liver cytochrome P450 system].

    PubMed

    Nebol'sin, V E; Zheltukhina, G A; Krzhechkovskaia, V V; Kovaleva, V L; Evstigneeva, R P

    2001-01-01

    The influence of gamma-L-glutamylhistamine analogues on the hexenal-induced sleeping, glucocorticoid hormone content in blood plasma and severity of experimental anaphylactic reaction was studied. It was observed that gamma-L-glutamylhistamine analogues caused decrease in the sleeping time and severity of experimental anaphylactic reaction, the elevation of glucocorticoids content in blood plasma. The present results indicate that substances have the wide spectrum of biological activity which depends on the length of the N-acyl radical. PMID:11558312

  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. Three Efficient Methods for Preparation of Coelenterazine Analogues.

    PubMed

    Shakhmin, Anton; Hall, Mary P; Walker, Joel R; Machleidt, Thomas; Binkowski, Brock F; Wood, Keith V; Kirkland, Thomas A

    2016-07-18

    The growing popularity of bioluminescent assays has highlighted the need for coelenterazine analogues possessing properties tuned for specific applications. However, the structural diversity of known coelenterazine analogues has been limited by current syntheses. Known routes for the preparation of coelenterazine analogues employ harsh reaction conditions that limit access to many substituents and functional groups. Novel synthetic routes reported here establish simple and robust methods for synthesis and investigation of structurally diverse marine luciferase substrates. Specifically, these new routes allow synthesis of coelenterazine analogues containing various heterocyclic motifs and substituted aromatic groups with diverse electronic substituents at the R(2) position. Interesting analogues described herein were characterized by their physicochemical properties, bioluminescent half-life, light output, polarity and cytotoxicity. Some of the analogues represent leads that can be utilized in the development of improved bioluminescent systems. PMID:27305599

  2. 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

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

    PubMed Central

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

    2015-01-01

    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

  4. 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

  5. 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

  6. 4-Aminoquinolines Active against Chloroquine-Resistant Plasmodium falciparum: Basis of Antiparasite Activity and Quantitative Structure-Activity Relationship Analyses▿

    PubMed Central

    Hocart, Simon J.; Liu, Huayin; Deng, Haiyan; De, Dibyendu; Krogstad, Frances M.; Krogstad, Donald J.

    2011-01-01

    Chloroquine (CQ) is a safe and economical 4-aminoquinoline (AQ) antimalarial. However, its value has been severely compromised by the increasing prevalence of CQ resistance. This study examined 108 AQs, including 68 newly synthesized compounds. Of these 108 AQs, 32 (30%) were active only against CQ-susceptible Plasmodium falciparum strains and 59 (55%) were active against both CQ-susceptible and CQ-resistant P. falciparum strains (50% inhibitory concentrations [IC50s], ≤25 nM). All AQs active against both CQ-susceptible and CQ-resistant P. falciparum strains shared four structural features: (i) an AQ ring without alkyl substitution, (ii) a halogen at position 7 (Cl, Br, or I but not F), (iii) a protonatable nitrogen at position 1, and (iv) a second protonatable nitrogen at the end of the side chain distal from the point of attachment to the AQ ring via the nitrogen at position 4. For activity against CQ-resistant parasites, side chain lengths of ≤3 or ≥10 carbons were necessary but not sufficient; they were identified as essential factors by visual comparison of 2-dimensional (2-D) structures in relation to the antiparasite activities of the AQs and were confirmed by computer-based 3-D comparisons and differential contour plots of activity against P. falciparum. The advantage of the method reported here (refinement of quantitative structure-activity relationship [QSAR] descriptors by random assignment of compounds to multiple training and test sets) is that it retains QSAR descriptors according to their abilities to predict the activities of unknown test compounds rather than according to how well they fit the activities of the compounds in the training sets. PMID:21383099

  7. 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

  8. 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

  9. 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.

  10. 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.

  11. Phonon analogue of topological nodal semimetals

    NASA Astrophysics Data System (ADS)

    Po, Hoi Chun; Bahri, Yasaman; Vishwanath, Ashvin

    2015-03-01

    Recently, Kane and Lubensky proposed a mapping between bosonic phonon problems on isostatic lattices to chiral fermion systems based on factorization of the dynamical matrix [Nat. Phys. 10, 39 (2014)]. The existence of topologically protected zero modes in such mechanical problems is related to their presence in the fermionic system and is dictated by a local index theorem. Here we adopt the proposed mapping to construct a two-dimensional mechanical analogue of a fermionic topological nodal semimetal that hosts a robust bulk node in its linearized phonon spectrum. Such topologically protected soft modes with tunable wavevector may be useful in designing mechanical structures with fault-tolerant properties.

  12. 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

  13. Analogue factoring algorithm based on polychromatic interference

    NASA Astrophysics Data System (ADS)

    Tamma, Vincenzo; Garuccio, Augusto; Shih, Yanhua

    2010-08-01

    We present a novel factorization algorithm which can be computed using an analogue computer based on a polychromatic source with a given wavelength bandwidth, a multi-path interferometer and a spectrometer. The core of this algorithm stands on the measurement of the periodicity of a "factoring" function given by an exponential sum at continuous argument by recording a sequence of interferograms associated with suitable units of displacement in the inteferometer. A remarking rescaling property of such interferograms allows, in principle, the prime number decomposition of several large integers. The information about factors is encoded in the location of the inteferogram maxima.

  14. 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

  15. 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.

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

    PubMed Central

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

    2012-01-01

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

  17. 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

  18. 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

  19. The electrical properties of Mars analogue dust

    NASA Astrophysics Data System (ADS)

    Merrison, J.; Jensen, J.; Kinch, K.; Mugford, R.; Nørnberg, P.

    2004-03-01

    Dust is a major environmental factor on the surface and in the atmosphere of Mars. Knowing the electrical charge state of this dust would be of both scientific interest and important for the safety of instruments on the Martian surface. In this study the first measurements have been performed of dust electrification using suspended Mars analogue material. This has been achieved by attracting suspended dust onto electrodes placed inside a Mars simulation wind tunnel. The Mars analogue used was from Salten Skov in Denmark, this contained a high concentration of ferric oxide precipitate. Once suspended, this dust was found to consist of almost equal quantities of negatively (46±6%) and positively (44±15%) charged grains. These grains were estimated to typically carry a net charge of around 10 5e, this is sufficient to dominate the processes of adhesion and cohesion of this suspended dust. Evidence is presented for electrostatic aggregation of the dust while in suspension. Development of a simple instrument for measuring electrical charging of the suspended dust on Mars will be discussed.

  20. 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.

  1. 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

  2. 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

  3. [GnRH analogues containing SV-40 virus T-antigen nuclear localization sequence].

    PubMed

    Burov, S V; Iablokova, T V; Dorosh, M Iu; Kriviziuk, E V; Efremov, A M; Orlov, S V

    2010-01-01

    To improve the efficiency of anticancer drugs due to their delivery to intracellular targets a set of GnRH analogues containing nuclear localization signal (NLS) of SV-40 virus large T-antigen have been synthesized. NLS was attached to the parent molecule via ε-amino group of D-Lysine in position 1 or 6 of peptide sequence using orthogonal protection strategy. The biological activity studies revealed that incorporation of NLS moiety significantly increases cytotoxic activity of palmitoyl-containing GnRH analogues in vitro. The influence of tested peptides on tumor cells does not accompanied by the destruction of cell membrane, as confirmed in experiments with normal fibroblasts, used as a control. PMID:21063449

  4. Functional Analysis: The Use of Analogues in Applied Settings.

    ERIC Educational Resources Information Center

    Stichter, Janine Peck

    2001-01-01

    This article suggests possible applications of experimental analyses using analogues to empirically verify results of functional assessments in classrooms for students with autism and related disabilities. Analogue assessments involve creating conditions in which antecedents and consequences are held constant and specific variables suspected to…

  5. 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

  6. 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

    Bastiaens, Guido J H; van Meer, Maurits P A; Scholzen, Anja; Obiero, Joshua M; Vatanshenassan, Mansoureh; van Grinsven, Tim; Sim, B Kim Lee; 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

    2016-03-01

    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 × 10(4) 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 × 10(5) PfSPZ-CVac was safe, but induced only minimal immune responses and no sterile protection against Pf CHMI. PMID:26711509

  7. 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

  8. Randomized Dose-Ranging Controlled Trial of AQ-13, a Candidate Antimalarial, and Chloroquine in Healthy Volunteers

    PubMed Central

    Mzayek, Fawaz; Deng, Haiyan; Mather, Frances J; Wasilevich, Elizabeth C; Liu, Huayin; Hadi, Christiane M; Chansolme, David H; Murphy, Holly A; Melek, Bekir H; Tenaglia, Alan N; Mushatt, David M; Dreisbach, Albert W; Lertora, Juan J. L; Krogstad, Donald J

    2007-01-01

    Objectives: To determine: (1) the pharmacokinetics and safety of an investigational aminoquinoline active against multidrug–resistant malaria parasites (AQ-13), including its effects on the QT interval, and (2) whether it has pharmacokinetic and safety profiles similar to chloroquine (CQ) in humans. Design: Phase I double-blind, randomized controlled trials to compare AQ-13 and CQ in healthy volunteers. Randomizations were performed at each step after completion of the previous dose. Setting: Tulane–Louisiana State University–Charity Hospital General Clinical Research Center in New Orleans. Participants: 126 healthy adults 21–45 years of age. Interventions: 10, 100, 300, 600, and 1,500 mg oral doses of CQ base in comparison with equivalent doses of AQ-13. Outcome Measures: Clinical and laboratory adverse events (AEs), pharmacokinetic parameters, and QT prolongation. Results: No hematologic, hepatic, renal, or other organ toxicity was observed with AQ-13 or CQ at any dose tested. Headache, lightheadedness/dizziness, and gastrointestinal (GI) tract–related symptoms were the most common AEs. Although symptoms were more frequent with AQ-13, the numbers of volunteers who experienced symptoms with AQ-13 and CQ were similar (for AQ-13 and CQ, respectively: headache, 17/63 and 10/63, p = 0.2; lightheadedness/dizziness, 11/63 and 8/63, p = 0.6; GI symptoms, 14/63 and 13/63; p = 0.9). Both AQ-13 and CQ exhibited linear pharmacokinetics. However, AQ-13 was cleared more rapidly than CQ (respectively, median oral clearance 14.0–14.7 l/h versus 9.5–11.3 l/h; p ≤ 0.03). QTc prolongation was greater with CQ than AQ-13 (CQ: mean increase of 28 ms; 95% confidence interval [CI], 18 to 38 ms, versus AQ-13: mean increase of 10 ms; 95% CI, 2 to 17 ms; p = 0.01). There were no arrhythmias or other cardiac AEs with either AQ-13 or CQ. Conclusions: These studies revealed minimal differences in toxicity between AQ-13 and CQ, and similar linear pharmacokinetics. PMID:17213921

  9. 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

  10. Development of new mitomycin C and porfiromycin analogues.

    PubMed

    Iyengar, B S; Lin, H J; Cheng, L; Remers, W A; Bradner, W T

    1981-08-01

    New mitomycin C and porfiromycin analogues were prepared by treating mitomycin A and N-methylmitomycin A with a variety of amines, including aziridines, allylamines, propargylamines, chloroalkylamines, hydroxyalkylamines, glycine derivatives, aralkylamines, and heterocyclic amines. All analogues were evaluated against P-388 murine leukemia and selected ones were examined for their leukopenic properties. Certain analogues were found to be superior to mitomycin C in potency, efficacy, and therapeutic ratio in the P-388 assay. The most active substituents at the mitosane 7 position included aziridine, 2-methylaziridine, propargylamine, furfurylamine, methyl glycinate, and 3-aminopyridine. Mitomycin A and the 7-aziridino, 7-(2-methylaziridino), and 3-aminopyridine analogues were less leukopenic than mitomycin C. Certain other analogues, including propargylamino and methyl glycinate, were highly leukopenic. The three compounds tested against B-16 melanoma in mice were significantly more effective than mitomycin C in this assay. Previously established structure--activity relationships were found inadequate to account for all of the new data. PMID:7328599

  11. Synthesis and biological activity of tetralone abscisic acid analogues.

    PubMed

    Nyangulu, James M; Nelson, Ken M; Rose, Patricia A; Gai, Yuanzhu; Loewen, Mary; Lougheed, Brenda; Quail, J Wilson; Cutler, Adrian J; Abrams, Suzanne R

    2006-04-01

    Bicyclic analogues of the plant hormone abscisic acid (ABA) were designed to incorporate the structural elements and functional groups of the parent molecule that are required for biological activity. The resulting tetralone analogues were predicted to have enhanced biological activity in plants, in part because oxidized products would not cyclize to forms corresponding to the inactive catabolite phaseic acid. The tetralone analogues were synthesized in seven steps from 1-tetralone and a range of analogues were accessible through a second route starting with 2-methyl-1-naphthol. Tetralone ABA 8 was found to have greater activity than ABA in two bioassays. The absolute configuration of (+)-8 was established by X-ray crystallography of a RAMP hydrazone derivative. The hydroxymethyl compounds 10 and 11, analogues for studying the roles of 8- and 9-hydroxy ABA 3 and 6, were also synthesized and found to be active. PMID:16557330

  12. Derivatisable Cyanobactin Analogues: A Semisynthetic Approach

    PubMed Central

    Oueis, Emilia; Adamson, Catherine; Mann, Greg; Ludewig, Hannes; Redpath, Philip; Migaud, Marie

    2015-01-01

    Abstract Many natural cyclic peptides have potent and potentially useful biological activities. Their use as therapeutic starting points is often limited by the quantities available, the lack of known biological targets and the practical limits on diversification to fine‐tune their properties. We report the use of enzymes from the cyanobactin family to heterocyclise and macrocyclise chemically synthesised substrates so as to allow larger‐scale syntheses and better control over derivatisation. We have made cyclic peptides containing orthogonal reactive groups, azide or dehydroalanine, that allow chemical diversification, including the use of fluorescent labels that can help in target identification. We show that the enzymes are compatible and efficient with such unnatural substrates. The combination of chemical synthesis and enzymatic transformation could help renew interest in investigating natural cyclic peptides with biological activity, as well as their unnatural analogues, as therapeutics. PMID:26507241

  13. 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

  14. 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.

  15. Evolving a polymerase for hydrophobic base analogues.

    PubMed

    Loakes, David; Gallego, José; Pinheiro, Vitor B; Kool, Eric T; Holliger, Philipp

    2009-10-21

    Hydrophobic base analogues (HBAs) have shown great promise for the expansion of the chemical and coding potential of nucleic acids but are generally poor polymerase substrates. While extensive synthetic efforts have yielded examples of HBAs with favorable substrate properties, their discovery has remained challenging. Here we describe a complementary strategy for improving HBA substrate properties by directed evolution of a dedicated polymerase using compartmentalized self-replication (CSR) with the archetypal HBA 5-nitroindole (d5NI) and its derivative 5-nitroindole-3-carboxamide (d5NIC) as selection substrates. Starting from a repertoire of chimeric polymerases generated by molecular breeding of DNA polymerase genes from the genus Thermus, we isolated a polymerase (5D4) with a generically enhanced ability to utilize HBAs. The selected polymerase. 5D4 was able to form and extend d5NI and d5NIC (d5NI(C)) self-pairs as well as d5NI(C) heteropairs with all four bases with efficiencies approaching, or exceeding, those of the cognate Watson-Crick pairs, despite significant distortions caused by the intercalation of the d5NI(C) heterocycles into the opposing strand base stack, as shown by nuclear magnetic resonance spectroscopy (NMR). Unlike Taq polymerase, 5D4 was also able to extend HBA pairs such as Pyrene: varphi (abasic site), d5NI: varphi, and isocarbostyril (ICS): 7-azaindole (7AI), allowed bypass of a chemically diverse spectrum of HBAs, and enabled PCR amplification with primers comprising multiple d5NI(C)-substitutions, while maintaining high levels of catalytic activity and fidelity. The selected polymerase 5D4 promises to expand the range of nucleobase analogues amenable to replication and should find numerous applications, including the synthesis and replication of nucleic acid polymers with expanded chemical and functional diversity. PMID:19778048

  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. Biological targets for isatin and its analogues: Implications for therapy

    PubMed Central

    Medvedev, Alexei; Buneeva, Olga; Glover, Vivette

    2007-01-01

    Isatin and its metabolites are constituents of many natural substances. They are also components of many synthetic compounds exhibiting a wide range of effects, including antiviral activity, antitumor and antiangiogenic activity, antibacterial, antitubercular, antifungal, antiaptotic, anticonvulsant and anxyolytic activities. Isatin itself is an endogenous oxidized indole with a wide spectrum of behavioral and metabolic effects. It has a distinct and discontinuous distribution in the brain, peripheral tissues and body fluids and isatin binding sites are widely distributed also. Its output is increased during stress. Its most potent known in vitro actions are as an antagonist of atrial natriuretic peptide (ANP) function and NO signaling. As we understand more about its function and sites of action we may be able to develop new pharmacological agents to mimic or counteract its activity. We consider here the most promising biological targets for various isatin analogues and/or metabolites, which are employed for the development of various groups of therapeutics. It is also possible that the level of endogenous isatin may influence the in vivo pharmacological activity of compounds possessing the isatin moiety. PMID:19707325

  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. Antithyroid drugs and their analogues: synthesis, structure, and mechanism of action.

    PubMed

    Manna, Debasish; Roy, Gouriprasanna; Mugesh, Govindasamy

    2013-11-19

    Thyroid hormones are essential for the development and differentiation of all cells of the human body. They regulate protein, fat, and carbohydrate metabolism. In this Account, we discuss the synthesis, structure, and mechanism of action of thyroid hormones and their analogues. The prohormone thyroxine (T4) is synthesized on thyroglobulin by thyroid peroxidase (TPO), a heme enzyme that uses iodide and hydrogen peroxide to perform iodination and phenolic coupling reactions. The monodeiodination of T4 to 3,3',5-triiodothyronine (T3) by selenium-containing deiodinases (ID-1, ID-2) is a key step in the activation of thyroid hormones. The type 3 deiodinase (ID-3) catalyzes the deactivation of thyroid hormone in a process that removes iodine selectively from the tyrosyl ring of T4 to produce 3,3',5'-triiodothyronine (rT3). Several physiological and pathological stimuli influence thyroid hormone synthesis. The overproduction of thyroid hormones leads to hyperthyroidism, which is treated by antithyroid drugs that either inhibit the thyroid hormone biosynthesis and/or decrease the conversion of T4 to T3. Antithyroid drugs are thiourea-based compounds, which include propylthiouracil (PTU), methimazole (MMI), and carbimazole (CBZ). The thyroid gland actively concentrates these heterocyclic compounds against a concentration gradient. Recently, the selenium analogues of PTU, MMI, and CBZ attracted significant attention because the selenium moiety in these compounds has a higher nucleophilicity than that of the sulfur moiety. Researchers have developed new methods for the synthesis of the selenium compounds. Several experimental and theoretical investigations revealed that the selone (C═Se) in the selenium analogues is more polarized than the thione (C═S) in the sulfur compounds, and the selones exist predominantly in their zwitterionic forms. Although the thionamide-based antithyroid drugs have been used for almost 70 years, the mechanism of their action is not completely

  20. 25OHD analogues and vacuum blood collection tubes dramatically affect the accuracy of automated immunoassays.

    PubMed

    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

  1. 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

  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. PMID:26478954

  3. 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,

  4. The preparation of zaragozic acid A analogues by directed biosynthesis.

    PubMed

    Chen, T S; Petuch, B; MacConnell, J; White, R; Dezeny, G; Arison, B; Bergstrom, J D; Colwell, L; Huang, L; Monaghan, R L

    1994-11-01

    Zaragozic acid A analogues are produced by an unidentified sterile fungus when it is exogenously supplied with 2-thiophenecarboxylic acid, 3-thiophenecarboxylic acid, 2-furoic acid, 2-fluorobenzoic acid, 3-fluorobenzoic acid, or 4-fluorobenzoic acid. The analogues carry 2-thiophenyl, 3-thiophenyl, 2-furyl, o-fluorophenyl, m-fluorophenyl, or p-fluorophenyl group, respectively, at C-6' of the C-1 alkyl side chain replacing the phenyl group of natural zaragozic acid A. All the new analogues of zaragozic acid A possess picomolar inhibitory activity against squalene synthase in vitro. PMID:8002393

  5. Recent developments in naturally derived antimalarials: cryptolepine analogues.

    PubMed

    Wright, Colin W

    2007-06-01

    Increasing resistance of Plasmodium falciparum to commonly used antimalarial drugs has made the need for new agents increasingly urgent. In this paper, the potential of cryptolepine, an alkaloid from the West African shrub Cryptolepis sanguinolenta, as a lead towards new antimalarial agents is discussed. Several cryptolepine analogues have been synthesized that have promising in-vitro and in-vivo antimalarial activity. Studies on the antimalarial modes of action of these analogues indicate that they may have different or additional modes of action to the parent compound. Elucidation of the mode of action may facilitate the development of more potent antimalarial cryptolepine analogues. PMID:17637183

  6. 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

  7. Analogue modelling of salt diapirism induced by differential loading

    NASA Astrophysics Data System (ADS)

    Warsitzka, Michael; Kley, Jonas; Kukowski, Nina; Jähne, Fabian

    2010-05-01

    the adjoining areas. This leads to further generation of diapirs in a purely "halokinetic" way. The potential to form these "secondary diapirs" (Parker and McDowell, 1955) basically depends on the thickness of the silicone layer and on the sedimentation rate. The deformation paths and the strains in the experiments can be well observed with the PIV, which offers a new application in the analogue modelling of salt diapirism. Our experiments contribute new insights in the discussion of diapir formation. They show that sedimentary processes can initiate diapirism without any tectonic influence if the salt movement starts early after its deposition. Additionally, the model results provide a validation of the theory of "salt-stock families" in the Northwest German Basin (Sannemann, 1965) in the light of new analogue modelling techniques. References Parker, T.J., McDowell, A.N. (1955): Model studies of salt-dome tectonics, Bulletin of the American Association of Petroleum Geologists, vol. 39, no. 12, p. 2384-2471 Sannemann, D. (1965): Salt-stock families in Northwestern Germany, Bulletin of the American Association of Petroleum Geologists, vol. 49. p. 261-270. Trusheim, F. (1960): Mechanism of salt migration in Northern Germany, Bulletin of the American Association of Petroleum Geologists, vol. 44, no. 9, p. 1519-1540. Vendeville, B.C. and Jackson, M. P. A. (1992): The rise of diapirs during thin-skinned extension, Marine and Petroleum Geology, vol. 9, no. 4, p. 331-353.

  8. 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

  9. 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

  10. 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

  11. 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

  12. 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

  13. Synthesis of a stable and orally bioavailable englerin analogue.

    PubMed

    Fash, David M; Peer, Cody J; Li, Zhenwu; Talisman, Ian J; Hayavi, Sima; Sulzmaier, Florian J; Ramos, Joe W; Sourbier, Carole; Neckers, Leonard; Figg, W Douglas; Beutler, John A; Chain, William J

    2016-06-01

    Synthesis of analogues of englerin A with a reduced propensity for hydrolysis of the glycolate moiety led to a compound which possessed the renal cancer cell selectivity of the parent and was orally bioavailable in mice. PMID:27107948

  14. Efficient total syntheses and biological activities of two teixobactin analogues.

    PubMed

    Parmar, Anish; Iyer, Abhishek; Vincent, Charlotte S; Van Lysebetten, Dorien; Prior, Stephen H; Madder, Annemieke; Taylor, Edward J; Singh, Ishwar

    2016-04-26

    The discovery of the new antibiotic teixobactin has been timely in the race for unearthing novel antibiotics wherein the emergence of drug resistant bacteria poses a serious threat worldwide. Herein, we present the total syntheses and biological activities of two teixobactin analogues. This approach is simple, efficient and has several advantages: it uses commercially available building blocks (except AllocHN-d-Thr-OH), has a single purification step and a good recovery (22%). By using this approach we have synthesised two teixobactin analogues and established that the d-amino acids are critical for the antimicrobial activity of these analogues. With continuing high expectations from teixobactin, this work can be regarded as a stepping stone towards an in depth study of teixobactin, its analogues and the quest for synthesising similar molecules. PMID:26984316

  15. Defining Analytical Strategies for Mars Sample Return with Analogue Missions

    NASA Astrophysics Data System (ADS)

    Osinski, G. R.; Sapers, H. M.; Francis, R.; Pontefract, A.; Tornabene, L. L.; Haltigin, T.

    2016-05-01

    The characterization of biosignatures in MSR samples will require integrated, cross-platform laboratory analyses carefully correlated and calibrated with Rover-based technologies. Analogue missions provide context for implementation and assessment.

  16. 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

  17. Practical enantiospecific syntheses of lysobisphosphatidic acid and its analogues.

    PubMed

    Jiang, Guowei; Xu, Yong; Prestwich, Glenn D

    2006-02-01

    We describe a versatile, efficient, and practical method for the preparation of enantiomerically pure lysobisphosphatidic acid (LBPA), bisether analogues, and phosphorothioate analogues of LBPA from solketal. Phosphorylation of a protected sn-2-O-oleoyl glycerol with 2-cyanoethyl bis(N,N-diisopropylamino)phosphite, followed by oxidation and deprotection, generated the enantiomers of 2,2'-LBPA. The corresponding phosphorothioate analogues were obtained by oxidation with sulfur. The (R,R) and (S,S) enantiomers of both LBPA and phosphorothioate LBPA were synthesized from (S)- and (R)-solketal, respectively. The ether analogue of (S,S)-lysobisphosphatidic acid (LBPA) and its enantiomer were synthesized from the same enantiomer (S)-solketal by simply changing the sequence of deprotection steps. PMID:16438504

  18. 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

  19. Structural analogues of diosgenyl saponins: synthesis and anticancer activity.

    PubMed

    Kaskiw, Matthew J; Tassotto, Mary Lynn; Mok, Mac; Tokar, Stacey L; Pycko, Roxanne; Th'ng, John; Jiang, Zi-Hua

    2009-11-15

    Saponins display various biological activities including anti-tumor activity. Recently intensive research has been focused on developing saponins for tumor therapies. The diosgenyl saponin dioscin is one of the most common steroidal saponins and exhibits potent anticancer activity in several human cancer cells through apoptosis-inducing pathways. In this paper, we describe the synthesis of several diosgenyl saponin analogues containing either a 2-amino-2-deoxy-beta-d-glucopyranosyl residue or an alpha-l-rhamnopyranosyl-(1-->4)-2-amino-2-deoxy-beta-d-glucopyranosyl residue with different acyl substituents on the amino group. The cytotoxic activity of these compounds was evaluated in MCF-7 breast cancer cells and HeLa cervical cancer cells. Structure-activity relationship studies show that the disaccharide saponin analogues are in general less active than their corresponding monosaccharide analogues. The incorporation of an aromatic nitro functionality into these saponin analogues does not exhibit significant effect on their cytotoxic activity. PMID:19819703

  20. 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

  1. 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.

  2. Amphiphilic Tobramycin Analogues as Antibacterial and Antifungal Agents

    PubMed Central

    Shrestha, Sanjib K.; Fosso, Marina Y.; Green, Keith D.

    2015-01-01

    In this study, we investigated the in vitro antifungal activities, cytotoxicities, and membrane-disruptive actions of amphiphilic tobramycin (TOB) analogues. The antifungal activities were established by determination of MIC values and in time-kill studies. Cytotoxicity was evaluated in mammalian cell lines. The fungal membrane-disruptive action of these analogues was studied by using the membrane-impermeable dye propidium iodide. TOB analogues bearing a linear alkyl chain at their 6″-position in a thioether linkage exhibited chain length-dependent antifungal activities. Analogues with C12 and C14 chains showed promising antifungal activities against tested fungal strains, with MIC values ranging from 1.95 to 62.5 mg/liter and 1.95 to 7.8 mg/liter, respectively. However, C4, C6, and C8 TOB analogues and TOB itself exhibited little to no antifungal activity. Fifty percent inhibitory concentrations (IC50s) for the most potent TOB analogues (C12 and C14) against A549 and Beas 2B cells were 4- to 64-fold and 32- to 64-fold higher, respectively, than their antifungal MIC values against various fungi. Unlike conventional aminoglycoside antibiotics, TOB analogues with alkyl chain lengths of C12 and C14 appear to inhibit fungi by inducing apoptosis and disrupting the fungal membrane as a novel mechanism of action. Amphiphilic TOB analogues showed broad-spectrum antifungal activities with minimal mammalian cell cytotoxicity. This study provides novel lead compounds for the development of antifungal drugs. PMID:26033722

  3. Analysis of gene mutations involved in chloroquine resistance in Plasmodium falciparum parasites isolated from patients in the southwest of Saudi Arabia

    PubMed Central

    Bin Dajem, Saad M.; Al-Qahtani, Ahmed

    2010-01-01

    BACKGROUND AND OBJECTIVES: Chloroquine has been the drug of choice for the treatment of malaria for many decades. We aimed to examine the molecular basis of chloroquine resistance among Plasmodium falciparum isolates from the southwestern region of Saudi Arabia by analyzing the K76T and N86Y mutations in the PfCRT and PfMDR1 genes, respectively. PATIENTS AND METHODS: P falciparum-infected blood spot samples (n=121) were collected on filter papers. DNA was extracted and fragments from the above genes were amplified using nested PCR. The amplicons were digested by ApoI enzyme and sequenced. RESULTS: Of the 121 samples, 95 and 112 samples could be amplified for PfCRT K76T and PfMDR1 N86Y mutations, respectively. All of the samples amplified for the PfCRT K76T mutation were undigestible by ApoI, suggesting the presence of the K76T mutation. For the PfMDR1 N86Y mutation, 65/109 samples (59.6%) were digestible when treated with ApoI in a pattern, suggestive of the presence of the investigated wild allele (N86). However, 44/109 samples (40.4%) were digestible by ApoI, suggesting the presence of the mutated allele (Y) at position 86. DNA sequencing confirmed these results. CONCLUSION: Surprisingly, all isolates exhibited the mutated allele at codon 76 (K76T) of PfCRT. However, the mutated mutant allele at codon 86 (N86Y) of PfMDR1 was found in 40.4% of the samples studied. To our knowledge, this is the first study that has investigated the existence of the mutation in the PfMDR1 gene in the country. This study will contribute to the development of new strategies for therapeutic intervention against malaria in Saudi Arabia. PMID:20427933

  4. 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

  5. Analogue gravitational phenomena in Bose-Einstein condensates

    NASA Astrophysics Data System (ADS)

    Finazzi, Stefano

    2012-08-01

    Analogue gravity is based on the simple observation that perturbations propagating in several physical systems can be described by a quantum field theory in a curved spacetime. While phenomena like Hawking radiation are hardly detectable in astrophysical black holes, these effects may be experimentally tested in analogue systems. In this Thesis, focusing on Bose-Einstein condensates, we present our recent results about analogue models of gravity from three main perspectives: as laboratory tests of quantum field theory in curved spacetime, for the techniques that they provide to address various issues in general relativity, and as toy models of quantum gravity. The robustness of Hawking-like particle creation is investigated in flows with a single black hole horizon. Furthermore, we find that condensates with two (white and black) horizons develop a dynamical instability known in general relativity as black hole laser effect. Using techniques borrowed from analogue gravity, we also show that warp drives, which are general relativistic spacetimes allowing faster-than-light travel, are unstable. Finally, the cosmological constant issue is investigated from an analogue gravity perspective and relativistic Bose-Einstein condensates are proposed as new analogue systems with novel interesting properties.

  6. 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

  7. 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

  8. Hydrophobic surfactant proteins and their analogues.

    PubMed

    Walther, Frans J; Waring, Alan J; Sherman, Mark A; Zasadzinski, Joseph A; Gordon, Larry M

    2007-01-01

    Lung surfactant is a complex mixture of phospholipids and four surfactant-associated proteins (SP-A, SP-B, SP-C and SP-D). Its major function in the lung alveolus is to reduce surface tension at the air-water interface in the terminal airways by the formation of a surface-active film enriched in surfactant lipids, hence preventing cellular collapse during respiration. Surfactant therapy using bovine or porcine lung surfactant extracts, which contain only polar lipids and native SP-B and SP-C, has dramatically improved the therapeutic outcomes of preterm infants with respiratory distress syndrome (RDS). One important goal of surfactant researchers is to replace animal-derived therapies with fully synthetic preparations based on SP-B and SP-C, produced by recombinant technology or peptide synthesis, and reconstituted with selected synthetic lipids. Here, we review recent research developments with peptide analogues of SP-B and SP-C, designed using either the known primary sequence and three-dimensional (3D) structure of the native proteins or, alternatively, the known 3D structures of closely homologous proteins. Such SP-B and SP-C mimics offer the possibility of studying the mechanisms of action of the respective native proteins, and may allow the design of optimized surfactant formulations for specific pulmonary diseases (e.g., acute lung injury (ALI) or acute respiratory distress syndrome (ARDS)). These synthetic surfactant preparations may also be a cost-saving therapeutic approach, with better quality control than may be obtained with animal-based treatments. PMID:17575474

  9. Vascular disrupting activity of combretastatin analogues.

    PubMed

    Porcù, Elena; Salvador, Alessia; Primac, Irina; Mitola, Stefania; Ronca, Roberto; Ravelli, Cosetta; Bortolozzi, Roberta; Vedaldi, Daniela; Romagnoli, Romeo; Basso, Giuseppe; Viola, Giampietro

    2016-08-01

    Tubulin binding agents (TBAs) are drugs commonly used in cancer therapy as antimitotics. In the last years it has been described that TBAs, like combretastatin A-4 (CA-4), present also vascular disrupting activity and among its derivatives we identified three analogues endowed with potent microtubule depolymerizing activity, higher than that of the lead compound. In this paper we have investigated the anti-vascular activity of these derivatives. We tested the anti-angiogenic effects in human umbilical endothelial cells (HUVEC) and in vivo in chick chorioallantoic membrane assay (CAM), and in a syngeneic tumor mouse model. The three molecules, compound 1: 1-(3,4,5-trimethoxyphenyl)-5-(4-ethoxyphenyl)-1H-1,2,4-triazole; compound 2: (1-(3,4,5-trimethoxyphenyl)-5-(4-ethoxyphenyl)-1H-tetrazole, compound-3 (4-amino-2-p-tolylaminothiazol-5-yl)-(3,4,5-trimethoxyphenyl)-methanone) showed a moderate effect on the growth of HUVEC cells at concentrations below 200nM. At lower concentrations (5-20nM), in particular compound 2, they induced inhibition of capillary tube formation, inhibition of endothelial cell migration and affected endothelial cell morphology as demonstrated by the alteration of the microfilaments network. Moreover, they also increased permeability of HUVEC cells in a time dependent manner. In addition, compounds 1 and 3, as well as the reference compound CA-4, inhibited VEGF-induced phosphorylation of VE-cadherin and in addition compound 3 prevented the VEGF-induced phosphorylation of FAK. In CAM assay, both compounds 2 and 3 efficiently counteracted the strong angiogenic response induced by bFGF, even at the lowest concentration used (1pmol/egg). Moreover in a syngenic mouse model, compounds 1-3 after a single i.p. injection (30mg/kg), showed a stronger reduction of microvascular density. Altogether our results identified these derivatives as potential new vascular disrupting agents candidates. PMID:27235861

  10. Somatostatin Analogues for Receptor Targeted Photodynamic Therapy

    PubMed Central

    Kaščáková, Slávka; Hofland, Leo J.; De Bruijn, Henriette S.; Ye, Yunpeng; Achilefu, Samuel; van der Wansem, Katy; van der Ploeg-van den Heuvel, Angelique; van Koetsveld, Peter M.; Brugts, Michael P.; van der Lelij, Aart-Jan; Sterenborg, Henricus J. C. M.; ten Hagen, Timo L. M.; Robinson, Dominic J.; van Hagen, Martin P.

    2014-01-01

    Photodynamic therapy (PDT) is an established treatment modality, used mainly for anticancer therapy that relies on the interaction of photosensitizer, light and oxygen. For the treatment of pathologies in certain anatomical sites, improved targeting of the photosensitizer is necessary to prevent damage to healthy tissue. We report on a novel dual approach of targeted PDT (vascular and cellular targeting) utilizing the expression of neuropeptide somatostatin receptor (sst2) on tumor and neovascular-endothelial cells. We synthesized two conjugates containing the somatostatin analogue [Tyr3]-octreotate and Chlorin e6 (Ce6): Ce6-K3-[Tyr3]-octreotate (1) and Ce6-[Tyr3]-octreotate-K3-[Tyr3]-octreotate (2). Investigation of the uptake and photodynamic activity of conjugates in-vitro in human erythroleukemic K562 cells showed that conjugation of [Tyr3]-octreotate with Ce6 in conjugate 1 enhances uptake (by a factor 2) in cells over-expressing sst2 compared to wild-type cells. Co-treatment with excess free Octreotide abrogated the phototoxicity of conjugate 1 indicative of a specific sst2-mediated effect. In contrast conjugate 2 showed no receptor-mediated effect due to its high hydrophobicity. When compared with un-conjugated Ce6, the PDT activity of conjugate 1 was lower. However, it showed higher photostability which may compensate for its lower phototoxicity. Intra-vital fluorescence pharmacokinetic studies of conjugate 1 in rat skin-fold observation chambers transplanted with sst2+ AR42J acinar pancreas tumors showed significantly different uptake profiles compared to free Ce6. Co-treatment with free Octreotide significantly reduced conjugate uptake in tumor tissue (by a factor 4) as well as in the chamber neo-vasculature. These results show that conjugate 1 might have potential as an in-vivo sst2 targeting photosensitizer conjugate. PMID:25111655

  11. 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

  12. Structural insights into the interactions of xpt riboswitch with novel guanine analogues: a molecular dynamics simulation study.

    PubMed

    Jain, Swapan S; Sonavane, Uddhavesh B; Uppuladinne, Mallikarjunachari V N; McLaughlin, Emily C; Wang, Weiqing; Black, Sheneil; Joshi, Rajendra R

    2015-01-01

    Ligand recognition in purine riboswitches is a complex process requiring different levels of conformational changes. Recent efforts in the area of purine riboswitch research have focused on ligand analogue binding studies. In the case of the guanine xanthine phosphoribosyl transferase (xpt) riboswitch, synthetic analogues that resemble guanine have the potential to tightly bind and subsequently influence the genetic expression of xpt mRNA in prokaryotes. We have carried out 25 ns Molecular Dynamics (MD) simulation studies of the aptamer domain of the xpt G-riboswitch in four different states: guanine riboswitch in free form, riboswitch bound with its cognate ligand guanine, and with two guanine analogues SJ1 and SJ2. Our work reveals novel interactions of SJ1 and SJ2 ligands with the binding core residues of the riboswitch. The ligands proposed in this work bind to the riboswitch with greater overall stability and lower root mean square deviations and fluctuations compared to guanine ligand. Reporter gene assay data demonstrate that the ligand analogues, upon binding to the RNA, lower the genetic expression of the guanine riboswitch. Our work has important implications for future ligand design and binding studies in the exciting field of riboswitches. PMID:24404773

  13. 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.

  14. 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. PMID:26872656

  15. Phosphonate analogues of carboxypeptidase A substrates are potent transition-state analogue inhibitors.

    PubMed

    Hanson, J E; Kaplan, A P; Bartlett, P A

    1989-07-25

    Analogues of tri- and tetrapeptide substrates of carboxypeptidase A in which the scissile peptide linkage is replaced with a phosphonate moiety (-PO2--O-) were synthesized and evaluated as inhibitors of the enzyme. The inhibitors terminated with either L-lactate or L-phenyllactate [designated (O) Ala and (O) Phe, respectively] in the P1' position. Transition-state analogy was shown for a series of 14 tri- and tetrapeptide derivatives containing the structure RCO-AlaP-(O)Ala [RCO-AP(O)A, AP indicates the phosphonic acid analogue of alanine] by the correlation of the Ki values for the inhibitors and the Km/kcat values for the corresponding amide substrates. This correlation supports a transition state for the enzymatic reaction that resembles the tetrahedral intermediate formed upon addition of water to the scissile carbonyl group. The inhibitors containing (O) Phe at the P1' position proved to be the most potent reversible inhibitors of carboxypeptidase A reported to date: the dissociation constants of ZAFP(O)F, ZAAP(O)F, and ZFAP(O)F are 4, 3, and 1 pM, respectively. Because of the high affinity of these inhibitors, their dissociation constants could not be determined by steady-state methods. Instead, the course of the association and dissociation processes was monitored for each inhibitor as its equilibrium with the enzyme was established in both the forward and reverse directions. A phosphonamidate analogue, ZAAPF, in which the peptide linkage is replaced with a -PO2-NH- moiety, was prepared and shown to hydrolyze rapidly at neutral pH (t1/2 = 20 min at pH 7.5). This inhibitor is bound an order of magnitude less tightly than the corresponding phosphonate, ZAAP(O)F, a result that contrasts with the 840-fold higher affinity of phosphonamidates for thermolysin [Bartlett, P. A., & Marlowe, C. K. (1987) Science 235, 569-571], a zinc peptidase with a similar arrangement of active-site catalytic residues. PMID:2790000

  16. 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

  17. 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

  18. 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

  19. Review of insulin and its analogues in diabetes mellitus.

    PubMed

    Mane, Krishnappa; Chaluvaraju, Kc; Niranjan, Ms; Zaranappa, Tr; Manjuthej, Tr

    2012-03-01

    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

  20. 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).

  1. 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

  2. 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

  3. 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. PMID:15501549

  4. 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.

  5. Membrane-permeable Triphosphate Prodrugs of Nucleoside Analogues.

    PubMed

    Gollnest, Tristan; Dinis de Oliveira, Thiago; Rath, Anna; Hauber, Ilona; Schols, Dominique; Balzarini, Jan; Meier, Chris

    2016-04-18

    The metabolic conversion of nucleoside analogues into their triphosphates often proceeds insufficiently. Rate-limitations can be at the mono-, but also at the di- and triphosphorylation steps. We developed a nucleoside triphosphate (NTP) delivery system (TriPPPro-approach). In this approach, NTPs are masked by two bioreversible units at the γ-phosphate. Using a procedure involving H-phosphonate chemistry, a series of derivatives bearing approved, as well as potentially antivirally active, nucleoside analogues was synthesized. The enzyme-triggered delivery of NTPs was demonstrated by pig liver esterase, in human T-lymphocyte cell extracts and by a polymerase chain reaction using a prodrug of thymidine triphosphate. The TriPPPro-compounds of some HIV-inactive nucleoside analogues showed marked anti-HIV activity. For cellular uptake studies, a fluorescent TriPPPro-compound was prepared that delivered the triphosphorylated metabolite to intact CEM cells. PMID:27008042

  6. The metabolic and mitogenic properties of basal insulin analogues

    PubMed Central

    2013-01-01

    Context Retrospective, observational studies have reported an association between diabetes treatment with insulin and a higher incidence of cancer. Objective Overview the literature for in vitro and in vivo studies of the metabolic and mitogenic properties of basal insulin analogues and assess the implications for clinical use. Methods Relevant studies were identified through PubMed and congress abstract database searches; data on metabolic and mitogenic signalling in relation to insulin treatment of diabetes are included in this review. Results The balance of evidence shows that although some analogues have demonstrated mitogenic potency in some in vitro studies in cancer cell lines, these findings do not translate to the in vivo setting in animals or to the clinical setting in humans. Conclusions The current consensus is that there is no clinical or in vivo evidence to indicate that any commercially available insulin analogue has carcinogenic effects. Large-scale, prospective clinical and observational studies will further establish any potential link. PMID:23373726

  7. 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. PMID:27311894

  8. 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). PMID:27005578

  9. Analogue peptides for the immunotherapy of human acute myeloid leukemia.

    PubMed

    Hofmann, Susanne; Mead, Andrew; Malinovskis, Aleksandrs; Hardwick, Nicola R; Guinn, Barbara-Ann

    2015-11-01

    The use of peptide vaccines, enhanced by adjuvants, has shown some efficacy in clinical trials. However, responses are often short-lived and rarely induce notable memory responses. The reason is that self-antigens have already been presented to the immune system as the tumor develops, leading to tolerance or some degree of host tumor cell destruction. To try to break tolerance against self-antigens, one of the methods employed has been to modify peptides at the anchor residues to enhance their ability to bind major histocompatibility complex molecules, extending their exposure to the T-cell receptor. These modified or analogue peptides have been investigated as stimulators of the immune system in patients with different cancers with variable but sometimes notable success. In this review we describe the background and recent developments in the use of analogue peptides for the immunotherapy of acute myeloid leukemia describing knowledge useful for the application of analogue peptide treatments for other malignancies. PMID:26438084

  10. Nicorandil analogues containing NO-donor furoxans and related furazans.

    PubMed

    Boschi, D; Cena, C; Di Stilo, A; Fruttero, R; Gasco, A

    2000-07-01

    The synthesis and in vitro vasodilating properties of hybrid compounds in which furoxan (1,2,5-oxadiazole 2-oxide) moieties, endowed with different NO-donor properties, were substituted for the nitroxy function of Nicorandil are reported. The corresponding cyanoguanidine analogues are also considered. This approach has led to a series of vasorelaxing compounds devoid of affinity for K(ATP) channels, whose activity is prevalently due to their ability to activate sGC, at the concentrations of the experiments. Related furazan (1,2,5-oxadiazole) derivatives, unable to release nitric oxide were also prepared and studied for control. The amide analogues of Nicorandil display feeble vasorelaxing action not involving the activation of K+ channels, while in the guanidine analogues, this mechanism seems to underlie this action. PMID:10976520

  11. 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.

  12. Relative benefits of linear analogue and advanced digital hearing aids.

    PubMed

    Wood, Sally A; Lutman, Mark E

    2004-03-01

    Speech recognition performance and self-reported benefit from linear analogue and advanced (digital) hearing aids were compared in 100 first-time hearing aid users with mild-to-moderate sensorineural hearing loss fitted monaurally with a behind-the-ear (BTE) hearing aid in a single-blind randomized crossover trial. Subjects used each aid for 5 weeks in turn, with aid order balanced across subjects. Three alternative models of digital hearing aid were assigned to subjects according to a balanced design. Aid type was disguised to keep subjects blind within practical limitations. Aided speech recognition performance in noise was measured at speech levels of 65 and 75dB at a speech-to-noise ratio (SNR) of +2dB for closed sets of single words. Self-rated benefit was measured using the Abbreviated Profile of Hearing Aid Benefit (APHAB) and the Glasgow Hearing Aid Benefit Profile (GHABP). Quality of life, hearing aid use and user preferences were also assessed. Speech recognition scores with the digital aids were significantly better at 75dB than with the analogue aids Self-reported benefit (APHAB, GHABP) and improvement in quality of life were generally not significantly different between analogue and digital aids, although aversiveness measured with the APHAB was significantly lower with digital aids, and satisfaction measured with the GHABP was greater. The digital aids were preferred significantly more often than the analogue aids, with 61 subjects choosing their digital aid, 26 choosing the analogue aid, and nine being equivocal. Overall, this study shows advantages for advanced digital over simple linear analogue aids in terms of both objective and subjective outcomes, although average differences are not large. PMID:15198378

  13. 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

  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. 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.

  16. Halogenase Engineering for the Generation of New Natural Product Analogues.

    PubMed

    Brown, Stephanie; O'Connor, Sarah E

    2015-10-12

    Halogenases catalyze the incorporation of halogen atoms into organic molecules. Given the importance that halogenation has on the biological activity of small molecules, these enzymes have been subjected to intense engineering efforts to make them more suitable for biotechnology applications. The ability to biohalogenate complex molecules provides, in principle, the opportunity for rapid generation of a series of analogues with new or improved properties. Here we discuss the potential and limitations of using halogenases as biocatalysts, including recent advances in engineering halogenases to generate halogenated natural product analogues. PMID:26256103

  17. 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

  18. 12-Amino-andrographolide analogues: synthesis and cytotoxic activity.

    PubMed

    Kasemsuk, Sakkasem; Sirion, Uthaiwan; Suksen, Kanoknetr; Piyachaturawat, Pawinee; Suksamrarn, Apichart; Saeeng, Rungnapha

    2013-12-01

    Andrographolide, a diterpenoid lactone of the plant Andrographis paniculata, has been shown to be cytotoxic against various cancer cells in vitro. In the present study, a series of β-amino-γ-butyrolactone analogues has been synthesized from naturally occurring andrographolide via one pot tandem aza-conjugate addition-elimination reaction. By using economic procedure without any base or catalyst at room temperature, the products obtained were in fair to excellent yields with high stereoselectivity. The cytotoxicity of all new amino analogues were evaluated against six cancer cell lines and revealed their potential for being developed as promising anti-cancer agents. PMID:23709127

  19. Concise synthesis of ether analogues of lysobisphosphatidic acid.

    PubMed

    Jiang, Guowei; Xu, Yong; Falguières, Thomas; Gruenberg, Jean; Prestwich, Glenn D

    2005-09-01

    We describe a versatile, efficient method for the preparation of ether analogues of (S,S)-lysobisphosphatidic acid (LBPA) and its enantiomer from (S)-solketal. Phosphorylation of a protected sn-2-O-octadecenyl glyceryl ether with 2-cyanoethyl bis-N,N-diisopropylamino phosphine and subsequent deprotection generated the bisether LBPA analogues. By simply changing the sequence of deprotection steps, we obtained the (R,R)- and (S,S)-enantiomers of 2,2'-bisether LBPA. An ELISA assay with anti-LBPA monoclonal antibodies showed that the bisether LBPAs were recognized with the same affinity as the natural 2,2'-bisoleolyl LBPA. [reaction: see text] PMID:16119911

  20. Synthesis of Conformationally Locked Versions of Puromycin Analogues

    PubMed Central

    Saneyoshi, Hisao; Michel, Benoît Y.; Choi, Yongseok; Strazewski, Peter; Marquez, Victor E.

    2009-01-01

    Conformationally locked North and South versions of puromycin analogues built on a bicyclo[3.1.0]hexane pseudosugar template were synthesized. The final assembly of the products was accomplished by the Staudinger-Vilarrasa coupling of the corresponding North (2 and 3) and South (6 and 7) 3′-azidopurine carbanucleosides with the Fmoc-protected 1-hydroxybenzotriazole ester of 4-methoxy-L-tyrosine. North azides 2 and 3 were reported earlier. The 3′-azido intermediates 6 and 7 that are necessary for the synthesis of the South puromycin analogues are described herein for the first time. PMID:18991379

  1. 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

  2. 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

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

    PubMed Central

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

    2015-01-01

    A series of novel bis-tetrahydropyran 1,4-triazole analogues based on the acetogenin framework display low micromolar trypanocidal activities towards both bloodstream and insect forms of Trypanosoma brucei, the causative agent of African sleeping sickness. A divergent synthetic strategy was adopted for the synthesis of the key tetrahydropyran intermediates to enable rapid access to diastereochemical variation either side of the 1,4-triazole core. The resulting diastereomeric analogues displayed varying degrees of trypanocidal activity and selectivity in structure activity relationship studies. PMID:25145275

  4. 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.

  5. 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

  6. The zinc ionophore clioquinol reverses autophagy arrest in chloroquine-treated ARPE-19 cells and in APP/mutant presenilin-1-transfected Chinese hamster ovary cells.

    PubMed

    Seo, Bo-Ra; Lee, Sook-Jeong; Cho, Kyung Sook; Yoon, Young Hee; Koh, Jae-Young

    2015-12-01

    Arrested autophagy may contribute to the pathogenesis of Alzheimer's disease. Because we found that chloroquine (CQ) causes arrested autophagy but clioquinol (ClioQ), a zinc ionophore, activates autophagic flux, in the present study, we examined whether ClioQ can overcome arrested autophagy induced by CQ or mutant presenilin-1 (mPS1). CQ induced vacuole formation and cell death in adult retinal pigment epithelial (ARPE-19) cells, but co-treatment with ClioQ attenuated CQ-associated toxicity in a zinc-dependent manner. Increases in lysosome dilation and blockage of autophagic flux by CQ were also markedly attenuated by ClioQ treatment. Interestingly, CQ increased lysosomal pH in amyloid precursor protein (APP)/mPS1-expressing Chinese hamster ovary 7WΔE9 (CHO-7WΔE9) cell line, and ClioQ partially re-acidified lysosomes. Furthermore, accumulation of amyloid-β (Aβ) oligomers in CHO-7WΔE9 cells was markedly attenuated by ClioQ. Moreover, intracellular accumulation of exogenously applied fluorescein isothiocyanate-conjugated Aβ(1-42) was also increased by CQ but was returned to control levels by ClioQ. These results suggest that modulation of lysosomal functions by manipulating lysosomal zinc levels may be a useful strategy for clearing intracellular Aβ oligomers. PMID:26453000

  7. Chloroquine enhances TRAIL-mediated apoptosis through up-regulation of DR5 by stabilization of mRNA and protein in cancer cells

    PubMed Central

    Park, Eun Jung; Min, Kyoung-jin; Choi, Kyeong Sook; Kubatka, Peter; Kruzliak, Peter; Kim, Dong Eun; Kwon, Taeg Kyu

    2016-01-01

    Chloroquine (CQ), an anti-malarial drug, has immune-modulating activity and lysosomotropic activity. In this study, we investigated CQ sensitizes TRAIL-mediated apoptosis in human renal cancer Caki cells. Combination of CQ and TRAIL significantly induces apoptosis in human renal cancer Caki cells and various human cancer cells, but not in normal mouse kidney cells (TMCK-1) and human mesangial cells (MC). CQ up-regulates DR5 mRNA and protein expression in a dose- and time- dependent manner. Interestingly, CQ regulates DR5 expression through the increased stability in the mRNA and protein of DR5, rather than through the increased transcriptional activity of DR5. Moreover, we found that CQ decreased the expression of Cbl, an E3 ligase of DR5, and knock-down of Cbl markedly enhanced DR5 up-regulation. Other lysosomal inhibitors, including monensin and nigericin, also up-regulated DR5 and sensitized TRAIL-mediated apoptosis. Therefore, this study demonstrates that lysosomal inhibition by CQ may sensitize TRAIL-mediated apoptosis in human renal cancer Caki cells via DR5 up-regulation. PMID:26964637

  8. New use of an old drug: chloroquine reduces viral and ALT levels in HCV non-responders (a randomized, triple-blind, placebo-controlled pilot trial).

    PubMed

    Peymani, Payam; Yeganeh, Behzad; Sabour, Siamak; Geramizadeh, Bita; Fattahi, Mohammad Reza; Keyvani, Hossein; Azarpira, Negar; Coombs, Kevin M; Ghavami, Saied; Lankarani, Kamran B

    2016-06-01

    Hepatitis C virus (HCV) infection induces autophagy, but the virus assimilates the autophagic response into its own life cycle. Chloroquine (CQ) is an autophagy inhibitor that is clinically used to treat malaria. The aims of this pilot clinical trial were to evaluate the therapeutic potential and short-term safety of CQ in patients with chronic HCV genotype 1, who were unresponsive to a combination of pegylated interferon alpha and ribavirin. Ten non-responders to previous antiviral treatment(s) were randomized to receive either CQ (150 mg daily for 8 weeks) or placebo, and were followed for 4 weeks after CQ therapy. HCV RNA load and plasma alanine transaminase (ALT) levels were measured at baseline, week 4 (initial response), week 8 (end-of-treatment response), and at the end of 12 weeks. A significant decrease in HCV RNA after the treatments (week 8) was observed in all patients in the CQ group (P = 0.04). However, HCV RNA levels increased within 4 weeks after discontinuation of CQ treatment although they were still lower than baseline. In addition, the ALT normalized during treatment in the CQ group. However, this response was also lost after treatment cessation. This study provides preliminary evidence that CQ is possibly a safe treatment option for HCV non-responders. PMID:26998724

  9. Feasibility of amlodipine besylate, chloroquine phosphate, dapsone, phenytoin, pyridoxine hydrochloride, sulfadiazine, sulfasalazine, tetracycline hydrochloride, trimethoprim and zonisamide in SyrSpend(®) SF PH4 oral suspensions.

    PubMed

    Ferreira, Anderson O; Polonini, Hudson C; Silva, Sharlene L; Patrício, Fernando B; Brandão, Marcos Antônio F; Raposo, Nádia R B

    2016-01-25

    The objective of this study was to evaluate the feasibility of 10 commonly used active pharmaceutical ingredients (APIs) compounded in oral suspensions using an internationally used suspending vehicle (SyrSpend(®) SF PH4 liquid): (i) amlodipine, (as besylate) 1.0mg/mL; (ii) chloroquine phosphate,15.0 mg/mL; (iii) dapsone, 2.0 mg/mL; (iv) phenytoin, 15.0 mg/mL; (v) pyridoxine hydrochloride, 50.0 mg/mL; (vi) sulfadiazine, 100.0 mg/mL; (vii) sulfasalazine, 100.0 mg/mL; (viii) tetracycline hydrochloride, 25.0 mg/mL; (ix) trimethoprim, 10.0 mg/mL; and (x) zonisamide, 10.0 mg/mL. All suspensions were stored both at controlled refrigeration (2-8 °C) and controlled room temperature (20-25 °C). Feasibility was assessed by measuring the percent recovery at varying time points throughout a 90-day period. API quantification was performed by high-performance liquid chromatography (HPLC-UV), via a stability-indicating method. Given the percentage of recovery of the APIs within the suspensions, the expiration date of the final products (API+vehicle) was at least 90 days for all suspensions with regard to both the controlled temperatures. This suggests that the vehicle is stable for compounding APIs from different pharmacological classes. PMID:26540625

  10. Inhibition of autophagy by chloroquine induces apoptosis in primary effusion lymphoma in vitro and in vivo through induction of endoplasmic reticulum stress.

    PubMed

    Masud Alam, Md; Kariya, Ryusho; Kawaguchi, Azusa; Matsuda, Kouki; Kudo, Eriko; Okada, Seiji

    2016-10-01

    Autophagy plays a crucial role in cancer cell survival and the inhibition of autophagy is attracting attention as an emerging strategy for the treatment of cancer. Chloroquine (CQ) is an anti-malarial drug, and is also known as an inhibitor of autophagy. Recently, it has been found that CQ induces cancer cell death through the inhibition of autophagy; however, the underlying mechanism is not entirely understood. In this study, we identified the role of CQ-induced cancer cell death using Primary Effusion Lymphoma (PEL) cells. We found that a CQ treatment induced caspase-dependent apoptosis in vitro. CQ also suppressed PEL cell growth in a PEL xenograft mouse model. We showed that CQ activated endoplasmic reticulum (ER) stress signal pathways and induced CHOP, which is an inducer of apoptosis. CQ-induced cell death was significantly decreased by salbrinal, an ER stress inhibitor, indicating that CQ-induced apoptosis in PEL cells depended on ER stress. We show here for the first time that the inhibition of autophagy induces ER stress-mediated apoptosis in PEL cells. Thus, the inhibition of autophagy is a novel strategy for cancer chemotherapy. PMID:27484211

  11. Prospects of intermittent preventive treatment of adults against malaria in areas of seasonal and unstable malaria transmission, and a possible role for chloroquine.

    PubMed

    Giha, Hayder A

    2010-04-01

    Chloroquine (CQ) is outmoded as an antimalarial drug in most of the malarial world because of the high resistance rate of parasites. The parasite resistance to CQ is attributed to pfcrt/pfmdr1 gene mutations. Recent studies showed that parasites with mutations of pfcrt/pfmdr1 genes are less virulent, and that those with dhfr/dhps mutations are more susceptible to host immune clearance; the former and latter mutations are linked. In the era of artemisinin-based combination therapy, the frequency of pfcrt/pfmdr1 wild variants is expected to rise. In areas of unstable malaria transmission, the unpredictable severe epidemics of malaria and epidemics of severe malaria could result in high mortality rate among the semi-immune population. With this in mind, the use of CQ for intermittent preventive treatment of adults (IPTa) is suggested as a feasible control measure to reduce malaria mortality in adults and older children without reducing uncomplicated malaria morbidity. The above is discussed in a multidisciplinary approach validating the deployment of molecular techniques in malaria control and showing a possible role for CQ as a rescue drug after being abandoned. PMID:20307217

  12. [Drug resistance of Plasmodium falciparum in Congo. I. In vivo study with 10 and 25 mg/kg of chloroquine (235 tests)].

    PubMed

    Carme, B; Benthein, F; Moudzeo, H; Bitsi, A; Madzou, G

    1986-01-01

    An evaluation of chloroquine resistance in P. falciparum was conducted in four different areas of the People's Republic of the Congo during the months of October and November 1985. Using the simplified seven day in vivo test protocol, 235 tests were completed in 92 children aged three months to five years seen at the Maternal Child Health Clinics (54 children were treated by a single dose at 10 mg/kg and 38 children were treated by the three day dose of 25 mg/kg) and 143 school children aged six to 12 years (70 treated by 10 mg/kg and 73 treated by 25 mg/kg). In three of the zones (Brazzaville, the forest mountains of the Mayombe and Chaillu), a high level of resistance was found in the percentage of children with asexual forms of P. falciparum parasites (1 000 leucocytes) in the blood smears. After 7 days, the percentage of positive results in children treated by 10 mg/kg was found to be 65.5% and 29.3% for children treated by 25 mg/kg. Failure rates, independent of parasite density, were less in school aged children. A significant number of observations seems to be Type II resistance. The situation is more favorable in the fourth area of Likouala, a region of flooded forests in the north of the country. PMID:3542258

  13. Treatment of malaria in north-eastern and south-eastern Nigeria: a population study of mefloquine, sulphadoxine, pyrimethamine combination (MSP) vs chloroquine (CQ).

    PubMed

    Ekanem, O J; Ezedinachi, E N; Molta, N B; Watila, I M; Chukwuani, C M; Meremikwu, M M; Akpede, G; Ojar, E A

    2000-01-01

    In a population-based study involving 4019 patients in 20 peripheral health facilities in Nigeria, the outcome of presumptive malaria treatment with MSP was compared to that of CQ. The study was conducted between January 1995 and January 1996. Patients aged 6 months or more with a clinical diagnosis of malaria based on history of fever and axillary temperature > 37.5 degrees C were either treated with MSP (250 mg mefloquine, 500 mg sulphadoxine, and 25 mg pyrimethamine per tablet) or CQ (150 mg chloroquine base per tablet). The clinical cure rate was assessed by the disappearance of clinical signs and symptoms over a 7-day period. Tolerability was assessed by the incidence of adverse events (adverse drug reaction and intercurrent illness). The result shows that the clinical care rate of suspected malaria was 97.6% with MSP and 85.6% with CQ. The incidence of adverse event was 9.5% with MSP and 9.2% with CQ. The withdrawal rate was 2.0% with MSP and 5.0% with CQ; 3.5% of the patients in the CQ group withdrew due to adverse events compared to 0.47% with MSP. In conclusion it was observed that in addition to superior efficacy of MSP over CQ, fever clearance rate with MSP was comparable to that of CQ. The study also demonstrated that two tablets maximum dose of MSP is safe and effective in a large population of Nigeria malaria patients. PMID:11391844

  14. 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

  15. Thymidine analogues to assess microperfusion in human tumors

    SciTech Connect

    Janssen, Hilde L.; Ljungkvist, Anna S.; Rijken, Paul F.; Sprong, Debbie; Bussink, Jan; Kogel, Albert J. van der; Haustermans, Karin M.; Begg, Adrian C. . E-mail: a.begg@nki.nl

    2005-07-15

    Purpose: To validate the use of the thymidine analogues as local perfusion markers in human tumors (no labeling indicates no perfusion) by comparison with the well-characterized perfusion marker Hoechst 33342. Methods and Materials: Human tumor xenografts from gliomas and head-and-neck cancers were injected with iododeoxyuridine (IdUrd) or bromodeoxyuridine (BrdUrd) and the fluorescent dye Hoechst 33342. In frozen sections, each blood vessel was scored for the presence of IdUrd/BrdUrd labeling and Hoechst in surrounding cells. The percentage of analogue-negative vessels was compared with the fraction of Hoechst-negative vessels. Collocalization of the two markers was also scored. Results: We found considerable intertumor variation in the fraction of perfused vessels, measured by analogue labeling, both in the human tumor xenografts and in a series of tumor biopsies from head-and-neck cancer patients. There was a significant correlation between the Hoechst-negative and IdUrd/BrdUrd-negative vessels in the xenografts (r 85, p = 0.0004), despite some mismatches on a per-vessel basis. Conclusions: Thymidine analogues can be successfully used to rank tumors according to their fraction of perfused vessels. Whether this fraction correlates with the extent of acute hypoxia needs further confirmation.

  16. Synthesis, reactivity and biological activity of 5-alkoxymethyluracil analogues

    PubMed Central

    Brulikova, Lucie

    2011-01-01

    Summary This review article summarizes the results of a long-term investigation of 5-alkoxymethyluracil analogues and is aimed, in particular, at methods of syntheses. Most of the presented compounds were synthesized in order to evaluate their biological activity, therefore, a brief survey of biological activity, especially antiviral, cytotoxic and antibacterial, is also reported. PMID:21804865

  17. 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…

  18. Charged Analogues of Henning Knutsen Type Solutions in General Relativity

    NASA Astrophysics Data System (ADS)

    Gupta, Y. K.; Kumar, Sachin; Pratibha

    2011-11-01

    In the present article, we have found charged analogues of Henning Knutsen's interior solutions which join smoothly to the Reissner-Nordstrom metric at the pressure free interface. The solutions are singularity free and analyzed numerically with respect to pressure, energy-density and charge-density in details. The solutions so obtained also present the generalization of A.L. Mehra's solutions.

  19. 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

  20. ON A p-ADIC ANALOGUE OF TATE HEIGHT

    NASA Astrophysics Data System (ADS)

    Berzin'sh, A. A.

    1983-04-01

    This paper is devoted to the study of the Tate height of an elliptic curve and its p-adic analogue. The main result is a series of explicit formulas for computing the local archimedean part of the Tate height. These results are used to obtain a new method for constructing the p-adic Tate height. Bibliography: 5 titles.

  1. 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

  2. A new analogue of fatty alcohol from Tamarix hampeana L.

    PubMed

    Aykac, Ahmet; Akgül, Yurdanur

    2010-01-01

    New analogues of a long-chain secondary alcohol (1) and laserine (2) were isolated from the flowers of Tamarix hampeana L. The isolated compounds were identified using 1D and 2D NMR, LCMS/APCI, and chemical methods. Laserine was isolated for the first time from T. hampeana L. PMID:20013470

  3. 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

  4. Synthesis of monophytanyl ether analogues of lysophosphatidic and lysophosphatidyl glycerol.

    PubMed

    Kates, M; Hancock, A J

    1976-10-01

    The chemical synthesis of 3-O-phytanyl-sn-glycero-1-phosphoric acid (monophytanyl ether analogue of lysophosphatidic acid) was effected by condensation of 1-iodo-2-O-benzyl-3-O-phytanyl-sn-glycerol with silver di-p-nitrobenzyl phosphate in anhydrous toluene followed by catalytic hydrogenolysis of the resulting phosphotriester to remove the benzyl and p-nitrobenzyl groups. Synthesis of 3-O-phytanyl-sn-glycero-1-phosphoryl-1'-sn-glycerol (monophytanyl ether analogue of lysophosphatidyl glycerol) was carried out by conversion of the above phosphotriester to the monosilver salt of the suitably blocked lysophosphatidic acid which was condensed with 1-iodo-2-O-t-butyl-3-O-benzyl-sn-glycerol. Removal of the protecting aromatic and t-butyl groups from the resulting blocked triester intermediate gave the desired phytanyl ether analogue of lysophosphatidyl glycerol. Both lyso analogues were isolated as analytically and chromatographically pure potassium salts. Their physical properties and behavior towards acid hydrolysis are described. PMID:991376

  5. 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

  6. Synthesis of glycophostones: cyclic phosphonate analogues of biologically relevant sugars

    PubMed

    Hanessian; Rogel

    2000-05-01

    Analogues of L-fucose, N-acetyl-D-glucosamine, N-acetyl-D-mannosamine, and N-acetyl neuraminic acid in which the anomeric carbon atom was replaced by a phosphonyl group (phostones or cyclic phosphonates) were synthesized by stereocontrolled methods relying on the Abramov reaction. PMID:10808439

  7. 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…

  8. q-bosons and the q-analogue quantized field

    NASA Technical Reports Server (NTRS)

    Nelson, Charles A.

    1995-01-01

    The q-analogue coherent states are used to identify physical signatures for the presence of a 1-analogue quantized radiation field in the q-CS classical limits where the absolute value of z is large. In this quantum-optics-like limit, the fractional uncertainties of most physical quantities (momentum, position, amplitude, phase) which characterize the quantum field are O(1). They only vanish as O(1/absolute value of z) when q = 1. However, for the number operator, N, and the N-Hamiltonian for a free q-boson gas, H(sub N) = h(omega)(N + 1/2), the fractional uncertainties do still approach zero. A signature for q-boson counting statistics is that (Delta N)(exp 2)/ (N) approaches 0 as the absolute value of z approaches infinity. Except for its O(1) fractional uncertainty, the q-generalization of the Hermitian phase operator of Pegg and Barnett, phi(sub q), still exhibits normal classical behavior. The standard number-phase uncertainty-relation, Delta(N) Delta phi(sub q) = 1/2, and the approximate commutation relation, (N, phi(sub q)) = i, still hold for the single-mode q-analogue quantized field. So, N and phi(sub q) are almost canonically conjugate operators in the q-CS classical limit. The q-analogue CS's minimize this uncertainty relation for moderate (absolute value of z)(exp 2).

  9. Trehalose Analogues: Latest Insights in Properties and Biocatalytic Production.

    PubMed

    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

  10. Topographic modelling of caldera analogues using Structure from Motion - Multiview stereo-photogrammetry

    NASA Astrophysics Data System (ADS)

    Ulusoy, İnan; Aydın, Eda; Evren Çubukçu, H.

    2016-04-01

    Analogue caldera models have long been used in volcanology to investigate structural evolution of volcanoes during tumescence and collapse periods. Influence of tectonic forces on volcanic features are also in the scope of those experiments. As well as interior modelling of the caldera experiments, topographic modelling is essential for digital monitoring and quantification purposes. Topographic modelling of those sandbox models is possible using laser scanning techniques. Particle tracking using still images is another way to demonstrate and quantify the structure and movement during the experiment. The quantum leap in the digital photography and computation tools and ease of access to both, provides the use of a new modelling technique in various scales and applications in Geology. Although the roots are older, Structure from Motion - Multiview stereo-photogrammetry (SfM-MVS) is a relatively new technique for surface modelling via several high resolution photographs. We have used SfM-MVS to digitally model the elevation of the tumescence and collapse cycles in analogue caldera experiments. Several sandbox experiments have been modelled using SfM-MVS technique stage by stage during tumescence and collapse periods. It has been possible to evaluate the structural evolution of the collapse models. Additionally, using particle tracking via still images acquired during the experiments, we have modelled the superficial evolution of the caldera structure. SfM-MVS is an effective low budget method for modelling in decimetric scale down to millimetre/micrometre precision.

  11. Synthesis, Physiochemical Properties, Photochemical Probe, and Antimicrobial Effects of Novel Norfloxacin Analogues

    PubMed Central

    Bakhotmah, Dina A.; Abdul-Rahman, Reda M.; Makki, Mohammad S.; El-Zahabi, Mohamed A.; Suliman, Mansor

    2011-01-01

    The emerging resistance to antimicrobial drugs demands the synthesis of new remedies for microbial infections. Attempts have been made to prepare new compounds by modifications in the quinolone structure. An important method for the synthesis of new quinolone is using Vilsmeier approach but has its own limitations. The present work aimed to synthesize novel norfloxacin analogues using modified Vilsmeier approach and conduct preliminary investigations for the evaluation of their physicochemical properties, photochemical probe, and antimicrobial effects. In an effort to synthesize norfloxacin analogues, only 7-bromo-6-N-benzyl piperazinyl-4-oxoquinoline-3-carboxylic acid was isolated using Vilsmeier approach at high temperature, where N, N′-bis-(4-fluoro-3-nitrophenyl)-oxalamide and N, N′-bis-(3-chloro-4-fluorophenyl)-malonamide were obtained at low temperature. Correlation results showed that lipophilicity, molecular mass, and electronic factors might influence the activity. The synthesized compounds were evaluated for their antimicrobial effects against important pathogens, for their potential use in the inhibition of vitiligo. PMID:24052816

  12. Non-robust numerical simulations of analogue extension experiments

    NASA Astrophysics Data System (ADS)

    Naliboff, John; Buiter, Susanne

    2016-04-01

    Numerical and analogue models of lithospheric deformation provide significant insight into the tectonic processes that lead to specific structural and geophysical observations. As these two types of models contain distinct assumptions and tradeoffs, investigations drawing conclusions from both can reveal robust links between first-order processes and observations. Recent studies have focused on detailed comparisons between numerical and analogue experiments in both compressional and extensional tectonics, sometimes involving multiple lithospheric deformation codes and analogue setups. While such comparisons often show good agreement on first-order deformation styles, results frequently diverge on second-order structures, such as shear zone dip angles or spacing, and in certain cases even on first-order structures. Here, we present finite-element experiments that are designed to directly reproduce analogue "sandbox" extension experiments at the cm-scale. We use material properties and boundary conditions that are directly taken from analogue experiments and use a Drucker-Prager failure model to simulate shear zone formation in sand. We find that our numerical experiments are highly sensitive to numerous numerical parameters. For example, changes to the numerical resolution, velocity convergence parameters and elemental viscosity averaging commonly produce significant changes in first- and second-order structures accommodating deformation. The sensitivity of the numerical simulations to small parameter changes likely reflects a number of factors, including, but not limited to, high angles of internal friction assigned to sand, complex, unknown interactions between the brittle sand (used as an upper crust equivalent) and viscous silicone (lower crust), highly non-linear strain weakening processes and poor constraints on the cohesion of sand. Our numerical-analogue comparison is hampered by (a) an incomplete knowledge of the fine details of sand failure and sand

  13. Metric optimisation for analogue forecasting by simulated annealing

    NASA Astrophysics Data System (ADS)

    Bliefernicht, J.; Bárdossy, A.

    2009-04-01

    It is well known that weather patterns tend to recur from time to time. This property of the atmosphere is used by analogue forecasting techniques. They have a long history in weather forecasting and there are many applications predicting hydrological variables at the local scale for different lead times. The basic idea of the technique is to identify past weather situations which are similar (analogue) to the predicted one and to take the local conditions of the analogues as forecast. But the forecast performance of the analogue method depends on user-defined criteria like the choice of the distance function and the size of the predictor domain. In this study we propose a new methodology of optimising both criteria by minimising the forecast error with simulated annealing. The performance of the methodology is demonstrated for the probability forecast of daily areal precipitation. It is compared with a traditional analogue forecasting algorithm, which is used operational as an element of a hydrological forecasting system. The study is performed for several meso-scale catchments located in the Rhine basin in Germany. The methodology is validated by a jack-knife method in a perfect prognosis framework for a period of 48 years (1958-2005). The predictor variables are derived from the NCEP/NCAR reanalysis data set. The Brier skill score and the economic value are determined to evaluate the forecast skill and value of the technique. In this presentation we will present the concept of the optimisation algorithm and the outcome of the comparison. It will be also demonstrated how a decision maker should apply a probability forecast to maximise the economic benefit from it.

  14. 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. PMID:25413440

  15. Convolutamydine A and synthetic analogues have antinociceptive properties in mice.

    PubMed

    Figueiredo, Gabriela S M; Zardo, Renata S; Silva, Bárbara V; Violante, Flávio A; Pinto, Angelo C; Fernandes, Patricia D

    2013-01-01

    Convolutamydine A, an oxindole that originated from a marine bryozoan, has several biological effects. In this study, we aimed to investigate the antinociceptive effects of convolutamydine A and two new synthetic analogues. Convolutamydine A and the two analogues were given orally to assess their ability to induce antinociceptive effects. Formalin-induced licking response, acetic acid-induced contortions, and hot plate models were used to characterize the effects of convolutamydine A and its analogues. Convolutamydine A (4,6-bromo-3-(2-oxopropyl)-3-hydroxy-2-oxindole), compound 1 (3-(2-oxopropyl)-3-hydroxy-2-oxindole), and compound 2 (5-bromo-3-(2-oxopropyl)-3-hydroxy-2-oxindole) caused peripheral antinociceptive and anti-inflammatory effects in the acetic acid-induced contortions and the formalin-induced licking models. Supraspinal effects were also observed in the hot plate model and were similar to those obtained with morphine. The peripheral effects were not mediated by the cholinergic or opioid systems. The antinociceptive effects of convolutamydine A seem to be mediated by all three systems (cholinergic, opioid, and nitric oxide systems), and the mechanism of action of compounds 1 and 2 involved cholinergic and nitric oxide-mediated mechanisms. Convolutamydine A and its analogues (compounds 1 and 2) showed good antinociceptive ability after systemic administration in acute pain models. The antinociceptive action mediated by cholinergic, opioid, and nitric oxide systems could explain why convolutamydine A, compound 1, and compound 2 retained their antinociceptive effects. The doses used were similar to the doses of morphine and were much lower than that of acetylsalicylic acid, the classical analgesic and anti-inflammatory drug. In conclusion, convolutamydine A and the two analogues demonstrated antinociceptive effects comparable to morphine's effects. PMID:23046852

  16. Analogue Sites for Mars Missions - A report from two workshops

    NASA Astrophysics Data System (ADS)

    Hipkin, V.; Voytek, M. A.; Glamoclija, M.

    2014-12-01

    Fieldwork, at terrestrial sites that are analogous in some way to Mars, has a key role in defining questions addressed by Mars missions. For MSL, the question is whether its landing site was habitable, and for Mars 2020, the question is how do we search for and what are signs of life in ancient habitable environments. Implementing these investigations by means of a rover mission on a distant planetary surface has challenges due to a limited set of tools and period of operations. Using this context of planetary missions is important in shaping how analog research can be used to advance planetary science. Following a successful 2010 AGU fall meeting session entitled "Analogue Sites for Mars Missions", two community workshops were held at The Woodlands, TX March 2011 and the Carnegie Institute of Washington in July 2013. These activities represent an ongoing dialogue with the analogue and mission communities. The AGU session solicited presentations of current analogue research relevant to MSL, at which time the landing site selection process was still considering four final sites. The 2011 Woodlands workshop solicited details on representative science questions and analogue sites by means of an abstract template. The output from The Woodlands workshop was an initial metric to assess the utility of analogue sites against specific science questions, as well as recommendations for future activities. The 2013 Carnegie workshop, followed up on some of the recommendations from 2011. Both on-line interactive dialogue and in person discussions targeted broad topics, including 'the advantages and problems of using a great terrestrial analog for field testing', and 'knowing what we currently do about Mars, what would be the best place on the planet to collect the first suite of samples to be returned to Earth? What would be appropriate analog sites on Earth?'. The results and recommendations from both workshops are summarized to publicize and stimulate this ongoing discussion.

  17. Biofunctional constituent isolated from Citrullus colocynthis fruits and structure-activity relationships of its analogues show acaricidal and insecticidal efficacy.

    PubMed

    Jeon, Ju-Hyun; Lee, Hoi-Seon

    2014-08-27

    The acaricidal and insecticidal potential of the active constituent isolated from Citrullus colocynthis fruits and its structurally related analogues was evaluated by performing leaf disk, contact toxicity, and fumigant toxicity bioassays against Tetranychus urticae, Sitophilus oryzae, and Sitophilus zeamais adults. The active constituent of C. colocynthis fruits was isolated by chromatographic techniques and was identified as 4-methylquinoline on the basis of spectroscopic analyses. To investigate the structure-activity relationships, 4-methylquinoline and its structural analogues were tested against mites and two insect pests. On the basis of the LC50 values, 7,8-benzoquinoline was the most effective against T. urticae. Quinoline, 8-hydroxyquinoline, 2-methylquinoline, 4-methylquinoline, 6-methylquinoline, 8-methylquinoline, and 7,8-benzoquinoline showed high insecticidal activities against S. oryzae and S. zeamais regardless of the application method. These results indicate that introduction of a functional group into the quinoline skeleton and changing the position of the group have an important influence on the acaricidal and insecticidal activities. Furthermore, 4-methylquinoline isolated from C. colocynthis fruits, along with its structural analogues, could be effective natural pesticides for managing spider mites and stored grain weevils. PMID:25110971

  18. The awareness of novelty for strangely familiar words: a laboratory analogue of the déjà vu experience.

    PubMed

    Urquhart, Josephine A; O'Connor, Akira R

    2014-01-01

    Déjà vu is a nebulous memory experience defined by a clash between evaluations of familiarity and novelty for the same stimulus. We sought to generate it in the laboratory by pairing a DRM recognition task, which generates erroneous familiarity for critical words, with a monitoring task by which participants realise that some of these erroneously familiar words are in fact novel. We tested 30 participants in an experiment in which we varied both participant awareness of stimulus novelty and erroneous familiarity strength. We found that déjà vu reports were most frequent for high novelty critical words (∼25%), with low novelty critical words yielding only baseline levels of déjà vu report frequency (∼10%). There was no significant variation in déjà vu report frequency according to familiarity strength. Discursive accounts of the experimentally-generated déjà vu experience suggest that aspects of the naturalistic déjà vu experience were captured by this analogue, but that the analogue was also limited in its focus and prone to influence by demand characteristics. We discuss theoretical and methodological considerations relevant to further development of this procedure and propose that verifiable novelty is an important component of both naturalistic and experimental analogues of déjà vu. PMID:25401055

  19. An analogue conceptual rainfall-runoff model for educational purposes

    NASA Astrophysics Data System (ADS)

    Herrnegger, Mathew; Riedl, Michael; Schulz, Karsten

    2016-04-01

    Conceptual rainfall-runoff models, in which runoff processes are modelled with a series of connected linear and non-linear reservoirs, remain widely applied tools in science and practice. Additionally, the concept is appreciated in teaching due to its somewhat simplicity in explaining and exploring hydrological processes of catchments. However, when a series of reservoirs are used, the model system becomes highly parametrized and complex and the traceability of the model results becomes more difficult to explain to an audience not accustomed to numerical modelling. Since normally the simulations are performed with a not visible digital code, the results are also not easily comprehensible. This contribution therefore presents a liquid analogue model, in which a conceptual rainfall-runoff model is reproduced by a physical model. This consists of different acrylic glass containers representing different storage components within a catchment, e.g. soil water or groundwater storage. The containers are equipped and connected with pipes, in which water movement represents different flow processes, e.g. surface runoff, percolation or base flow. Water from a storage container is pumped to the upper part of the model and represents effective rainfall input. The water then flows by gravity through the different pipes and storages. Valves are used for controlling the flows within the analogue model, comparable to the parameterization procedure in numerical models. Additionally, an inexpensive microcontroller-based board and sensors are used to measure storage water levels, with online visualization of the states as time series data, building a bridge between the analogue and digital world. The ability to physically witness the different flows and water levels in the storages makes the analogue model attractive to the audience. Hands-on experiments can be performed with students, in which different scenarios or catchment types can be simulated, not only with the analogue but

  20. Inhibition of receptor/G protein coupling by suramin analogues.

    PubMed

    Beindl, W; Mitterauer, T; Hohenegger, M; Ijzerman, A P; Nanoff, C; Freissmuth, M

    1996-08-01

    Suramin analogues act as direct antagonists of heterotrimeric G proteins because they block the rate-limiting step of G protein activation (i.e., the dissociation of GDP prebound to the G protein alpha subunit). We have used the human brain A1 adenosine receptor and the rat striatal D2 dopamine receptor, two prototypical Gi/G(o)-coupled receptors, as a model system to test whether the following analogues suppress the receptor-dependent activation of G proteins: 8-(3-nitrobenzamido)-1,3,5-naphthalenetrisulfonic acid (NF007), 8-(3-(3-nitrobenzamido)-benzamido)-1,3,5-naphthalenetrisulfonic acid (NF018); 8,8'-(carbonylbis(imino-3,1-phenylene))bis-(1,3,5-naphthalenetr isulfonic acid) (NF023); 8,8'-(carbonylbis(imino-3,1-phenylene)carbonylimino-(3,1- phenylene)) bis(1,3,5-naphthalenetrisulfonic acid) (NF037); and suramin. Suramin and its analogues inhibit the formation of the agonist-specific ternary complex (agonist/receptor/G protein). This inhibition is (i) quasicompetitive with respect to agonist binding in that it can be overcome by increasing receptor occupancy but (ii) does not result from an interaction of the analogues with the ligand binding pocket of the receptors because the binding of antagonists or of agonists in the absence of functional receptor/G protein interaction is not affected. In addition to suppressing the spontaneous release of GDP from defined G protein alpha subunits, suramin and its analogues reduce receptor-catalyzed guanine nucleotide exchange. The site, to which suramin analogues bind, overlaps with the docking site for the receptor on the G protein alpha subunit. The structure-activity relationships for inhibition of agonist binding to the A1 adenosine receptor (suramin > NF037 > NF023) and of agonist binding to the inhibition D2 dopamine receptor (suramin = NF037 > NF023 > NF018) differ. Thus, NF037 discriminates between the ternary complexes formed by the agonist-liganded D2 dopamine receptors and those formed by the A1 adenosine

  1. The use of prostaglandins and their analogues for abortion.

    PubMed

    Bygdeman, M

    1984-12-01

    In general, termination of second trimester pregnancy is associated with three to five times higher morbidity and mortality risks than termination during the first trimester. The procedures mainly used are extra- or intra-amniotic administration of solutions such as hypertonic saline, ethacridine lactate, PGF2 alpha and PGE2. In comparison with these procedures, the use of prostaglandin analogues may offer important advantages, the most important one being the possibility of using non-invasive routes of administration. The continuous development of new analogues has now resulted in compounds that are highly effective in stimulating uterine contractility and are associated with a low frequency of side-effects; these compounds are suitable for both vaginal and intramuscular administration and are applicable for termination of pregnancy during both the early and late parts of the second trimester. The most widely used method for termination of first trimester pregnancy is vacuum aspiration. It is a highly effective procedure and the overall complication rate is low. One problem with vacuum aspiration is the mechanical dilatation of the cervical canal which is necessary from at least the 8th week and onwards. Pretreatment with laminaria tents or with prostaglandin analogues eliminates or reduces the need for mechanical dilatation and significantly facilitates the procedure. Pretreatment with prostaglandin analogues also reduces the risk of both operative and postoperative complications. The prostaglandins also offer a possibility as a non-surgical procedure for termination of very early pregnancy. Both vaginal and intramuscular administration of the latest generation of PG analogues have been shown in several studies to be equally as effective as vacuum aspiration if the treatment is restricted to the first three weeks following the first missed menstrual period. Gastrointestinal side-effects are still a problem although of significantly less importance than if natural

  2. Design and Synthesis of Simplified Largazole Analogues as Isoform-Selective Human Lysine Deacetylase Inhibitors.

    PubMed

    Reddy, Damodara N; Ballante, Flavio; Chuang, Timothy; Pirolli, Adele; Marrocco, Biagina; Marshall, Garland R

    2016-02-25

    Selective inhibition of KDAC isoforms while maintaining potency remains a challenge. Using the largazole macrocyclic depsipeptide structure as a starting point for developing new KDACIs with increased selectivity, a combination of four different simplified largazole analogue (SLA) scaffolds with diverse zinc-binding groups (for a total of 60 compounds) were designed, synthesized, and evaluated against class I KDACs 1, 3, and 8, and class II KDAC6. Experimental evidence as well as molecular docking poses converged to establish the cyclic tetrapeptides (CTPs) as the primary determinant of both potency and selectivity by influencing the correct alignment of the zinc-binding group in the KDAC active site, providing a further basis for developing new KDACIs of higher isoform selectivity and potency. PMID:26681404

  3. Photoelectron spectra and electronic structure of nitrogen analogues of boron β-diketonates

    NASA Astrophysics Data System (ADS)

    Tikhonov, Sergey A.; Vovna, Vitaliy I.; Borisenko, Aleksandr V.

    2016-07-01

    The electronic structure of the valence levels of seven nitrogen-containing boron complexes was investigated using methods of ultraviolet photoelectron spectroscopy and density functional theory. The ionization energies of π- and σ-levels were obtained from photoelectron spectra. The electronic structure of nitrogen-containing compounds was compared with the electronic structure of β-diketonates. It was shown the influence of various substituents on carbon and nitrogen atoms of six-membered ring on the electronic structure of complexes. The changes in the electronic structure after the substitution of atoms in condensed cycles have been identified. In order to compare the experimental vertical ionization energies IEi with Kohn-Sham orbital energies εi we used the analogue of Koopmans theorem and average amendment to the orbital energy of the electrons (δbari). For 26 electronic levels of seven studied complexes, the calculated values are in good accordance with experimental energy intervals between electron levels.

  4. Mars Analogue Field Research and Sample Analysis

    NASA Astrophysics Data System (ADS)

    Foing, Bernard H.

    2016-07-01

    We describe results from the data analysis from a series of field research campaigns (ILEWG EuroMoonMars campaigns 2009 to 2016) in the Utah desert and in other extreme environments (Iceland, Eifel, La Reunion) relevant to habitability and astrobiology in Mars environments, and in order to help in the interpretation of Mars missions measurements from orbit (MEX, MRO) or from the surface (MER, MSL). We discuss results relevant to the scientific study of the habitability factors influenced by the properties of dust, organics, water history and the diagnostics and characterisation of microbial life. We also discuss perspectives for the preparation of future lander and sample return missions. We deployed at Mars Desert Research station, Utah, a suite of instruments and techniques including sample collection, context imaging from remote to local and microscale, drilling, spectrometers and life sensors. We analyzed how geological and geochemical evolution affected local parameters (mineralogy, organics content, environment variations) and the habitability and signature of organics and biota. We find high diversity in the composition of soil samples even when collected in close proximity, the low abundances of detectable PAHs and amino acids and the presence of biota of all three domains of life with significant heterogeneity. An extraordinary variety of putative extremophiles was observed. A dominant factor seems to be soil porosity and lower clay-sized particle content. A protocol was developed for sterile sampling, contamination issues, and the diagnostics of biodiversity via PCR and DGGE analysis in soils and rocks samples. We compare campaign results from 2009-2013 campaigns in Utah and other sites to new measurements concerning: the comparison between remote sensing and in-situ measurements; the study of minerals; the detection of organics and signs of life.

  5. Mars Analogue Field Research and Sample Analysis

    NASA Astrophysics Data System (ADS)

    Foing, Bernard H.

    2016-07-01

    We describe results from the data analysis from a series of field research campaigns (ILEWG EuroMoonMars campaigns 2009 to 2016) in the Utah desert and in other extreme environments (Iceland, Eifel, La Reunion) relevant to habitability and astrobiology in Mars environments, and in order to help in the interpretation of Mars missions measurements from orbit (MEX, MRO) or from the surface (MER, MSL). We discuss results relevant to the scientific study of the habitability factors influenced by the properties of dust, organics, water history and the diagnostics and characterisation of microbial life. We also discuss perspectives for the preparation of future lander and sample return missions. We deployed at Mars Desert Research station, Utah, a suite of instruments and techniques including sample collection, context imaging from remote to local and microscale, drilling, spectrometers and life sensors. We analyzed how geological and geochemical evolution a ffected local parameters (mineralogy, organics content, environment variations) and the habitability and signature of organics and biota. We find high diversity in the composition of soil samples even when collected in close proximity, the low abundances of detectable PAHs and amino acids and the presence of biota of all three domains of life with significant heterogeneity. An extraordinary variety of putative extremophiles was observed. A dominant factor seems to be soil porosity and lower clay-sized particle content. A protocol was developed for sterile sampling, contamination issues, and the diagnostics of biodiversity via PCR and DGGE analysis in soils and rocks samples. We compare campaign results from 2009-2013 campaigns in Utah and other sites to new measurements concerning: the comparison between remote sensing and in-situ measurements; the study of minerals; the detection of organics and signs of life.

  6. Synthetic analogue of voltage-gated channels

    NASA Astrophysics Data System (ADS)

    Nguyen, Gael Hoang

    Fluids in nanopores with diameters of <100nm exhibit behavior that is not seen at micrometer dimensions and above, such as ion current rectification, ionic selectivity, size exclusion and potential dependent ion concentrations in and near the pore. These properties originate from electrostatic interactions between charges on the nanopore surface and the fluid within the nanopore. The influence of these electrostatic effects is determined from a characteristic screening length for the system known as the Debye length. Typical nanopore systems have diameters on the scale of the Debye length and require the consideration of electrostatic effects which do not need to be considered in micrometer systems. Nanofluidic components may be designed by considering the effect of these surface interactions to control ionic transport and incorporate them in devices.In this study we present single conically shaped polymer nanopores with controlled chemistry of the pore walls and pore opening diameter between 5 nm and 30 nm. Two types of pores were examined. The first group of pores contained a junction between two zones with different surface charges. The first group consists of bipolar diodes, which have a two zones composed of positive and negative surface charges, and unipolar diodes, which have two zones composed of a charged zone and a neutral zone. We find that both bipolar and unipolar diodes show a substantial increase in asymmetrical behavior of current-voltage curves over a conical nanopore with a uniform surface charge. Further is it shown that while both diodes show an increase in current rectification, bipolar diodes in particular have superior rectification abilities. The second group of pores are modified by tethering single-stranded DNA molecules to the pore wall. We find that the DNA occludes the narrow opening of nanopores and that the this occlusion effect decreases with an increase in the concentration of the electrolyte. The results are explained by the

  7. Noncommutative analogue Aharonov-Bohm effect and superresonance

    NASA Astrophysics Data System (ADS)

    Anacleto, M. A.; Brito, F. A.; Passos, E.

    2013-06-01

    We consider the idea of modeling a rotating acoustic black hole by an idealized draining bathtub vortex which is a planar circulating flow phenomenon with a sink at the origin. We find the acoustic metric for this phenomenon from a noncommutative Abelian Higgs model. As such the acoustic metric not only describes a rotating acoustic black hole but also inherits the noncommutative characteristic of the spacetime. We address the issues of superresonance and analogue Aharonov-Bohm (AB) effect in this background. We mainly show that the scattering of planar waves by a draining bathtub vortex leads to a modified AB effect and due to spacetime noncommutativity, the phase shift persists even in the limit where the parameters associated with the circulation and draining vanish. Finally, we also find that the analogue AB effect and superresonance are competing phenomena at a noncommutative spacetime.

  8. Analogue Transformations in Physics and their Application to Acoustics

    PubMed Central

    García-Meca, C.; Carloni, S.; Barceló, C.; Jannes, G.; Sánchez-Dehesa, J.; Martínez, A.

    2013-01-01

    Transformation optics has shaped up a revolutionary electromagnetic design paradigm, enabling scientists to build astonishing devices such as invisibility cloaks. Unfortunately, the application of transformation techniques to other branches of physics is often constrained by the structure of the field equations. We develop here a complete transformation method using the idea of analogue spacetimes. The method is general and could be considered as a new paradigm for controlling waves in different branches of physics, from acoustics in quantum fluids to graphene electronics. As an application, we derive an “analogue transformation acoustics” formalism that naturally allows the use of transformations mixing space and time or involving moving fluids, both of which were impossible with the standard approach. To demonstrate the power of our method, we give explicit designs of a dynamic compressor, a spacetime cloak for acoustic waves and a carpet cloak for a moving aircraft. PMID:23774575

  9. New selenium-75 labeled radiopharmaceuticals: selenonium analogues of dopamine

    SciTech Connect

    Sadek, S.A.; Basmadjian, G.P.; Hsu, P.M.; Rieger, J.A.

    1983-07-01

    Selenium-75 labeled selenonium analogues of dopamine, (2-(3,4-dimethoxyphenyl)ethyl)dimethylselenonium iodide and its dihydroxy analogue, were prepared by reducing (/sup 75/Se)selenious acid with sodium borohydride at pH 6.0 and reacting the NaSeH produced with 1-(3,4-dimethoxyphenyl)-2-(p-toluenesulfonyloxy)ethane. Tissue distribution studies in rats given the /sup 75/Se-labeled selenonium agents intravenously demonstrated high initial heart uptake. Prolonged adrenal retention and high adrenal to blood ratio of compound 4 were observed. The high uptake and adrenal to blood ratio suggest the potential use of compound 4 as a radiopharmaceutical for the adrenal gland.

  10. Novel Azetidine-Containing TZT-1027 Analogues as Antitumor Agents.

    PubMed

    Yan, Qi; Wang, Yujie; Zhang, Wei; Li, Yingxia

    2016-05-01

    A conformational restriction strategy was used to design and synthesize nine TZT-1027 analogues. 3-Aryl-azetidine moiety was used to replace phenylethyl group of TZT-1027 at the C-terminus. These analogues exhibited moderate to excellent antiproliferative activities, and the most potent compound 1a showed IC50 values of 2.2 nM against A549 and 2.1 nM against HCT116 cell lines, respectively. However, 1a could not achieve effective inhibition at all the dose levels in the A549 xenograft model (up to 5 mg/kg, injection, once a day), which is only 16%-35% inhibition at the end of the experiment. PMID:27136567

  11. Alligator rivers analogue project an OECD/NEA international project

    SciTech Connect

    Duerden, P.; Airey, P.; Pescatore, C.

    1994-12-31

    The Koongarra uranium deposit in the Alligator Rivers Region of the Northern Territory of Australia was studied as a natural analogue of the far field behaviour of high level waste repositories following groundwater ingress. A number of mathematical modelling approaches were developed for processes as diverse as groundwater transport, host rock weathering, radionuclide sorption, evolution of the uranium dispersion fan and the distribution of uranium series nuclides between mineral assemblages in weathered host rock. Some of these models are relevant to performance assessment at the level of individual processes and subsystem performance. Through the project, new insights into the application of the natural analogue approach to the assessment of potential waste repository sites were obtained.

  12. Stereocontrolled Synthesis of Key Advanced Intermediates toward Simplified Acetogenin Analogues.

    PubMed

    Le Huérou, Yvan; Doyon, Julien; Grée, René L.

    1999-09-01

    The stereo- and enantiocontrolled synthesis of substituted beta-hydroxy ethers based on glycol and catechol bearing an alkyne group and a series of substituents is reported. These substrates were designed to mimic the bis-THF array of annonaceous acetogenins and to provide an access to simplified and modified analogues. The key steps of the synthesis involve the condensation of the nonracemic mesylate of solketal with ethylene glycol and catechol, followed by an alkylation with a glycidyl derivative. Under appropriate conditions, the reaction is completely stereoselective and allows the synthesis of all the diastereomers. After the epoxide was opened with triethylsilylacetylene, the second epoxide was unmasked and reacted with a series of alkyl, aryl, amine, and alcohol reagents. A series of 28 analogues was prepared having a glycol or a catechol core, a stereodefined configuration of the flanking hydroxyl groups, and an acetylenic appendage suitable for a coupling to a lactone-bearing fragment. PMID:11674687

  13. Synthesis of Methylenecyclopropane Analogues of Antiviral Nucleoside Phosphonates

    PubMed Central

    Yan, Zhaohua; Zhou, Shaoman; Kern, Earl R.; Zemlicka, Jiri

    2006-01-01

    Synthesis of methylenecyclopropane analogues of nucleoside phosphonates 6a, 6b, 7a and 7b is described. Cyclopropyl phosphonate 8 was transformed in four steps to methylenecyclopropane phosphonate 16. The latter intermediate was converted in seven steps to the key Z- and E-methylenecyclopropane alcohols 23 and 24 separated by chromatography. Selenoxide eliminations (15 → 16 and 22 → 23 + 24) were instrumental in the synthesis. The Z- and E-isomers 23 and 24 were transformed to bromides 25a and 25b which were used for alkylation of adenine and 2-amino-6-chloropurine to give intermediates 26a, 26b, 26c and 26d. Acid hydrolysis provided the adenine and guanine analogues 6a, 6b, 7a and 7b. Phosphonates 6b and 7b are potent inhibitors of replication of Epstein-Barr virus (EBV). PMID:16758001

  14. Millimeter and Submillimeter Studies of Interstellar Ice Analogues

    NASA Astrophysics Data System (ADS)

    Mesko, AJ; Wagner, Ian C.; Smith, Houston Hartwell; Milam, Stefanie N.; Widicus Weaver, Susanna L.

    2015-06-01

    The chemistry of interstellar ice analogues has been a topic of great interest to astrochemists over the last 20 years. Currently, the models of interstellar chemistry feature icy-grain reactions as a primary mechanism for the formation of many astrochemical species as well as potentially astrobiologically-relevant complex organic molecules. This talk presents new spectral results collected by a millimeter and submillimeter spectrometer coupled to a vacuum chamber designed to study the sublimation or sputtered products of icy-grain reactions initiated by thermal-processing or photo-processing of interstellar ice analogues. Initial results from thermal desorption and UV photoprocessing experiments of pure water ice and water + methanol ice mixtures will be presented.

  15. Neurological Effects of Bisphenol A and its Analogues

    PubMed Central

    Inadera, Hidekuni

    2015-01-01

    The endocrine disrupting chemical bisphenol A (BPA) is widely used in the production of polycarbonate plastics and epoxy resins. The use of BPA-containing products in daily life makes exposure ubiquitous, and the potential human health risks of this chemical are a major public health concern. Although numerous in vitro and in vivo studies have been published on the effects of BPA on biological systems, there is controversy as to whether ordinary levels of exposure can have adverse effects in humans. However, the increasing incidence of developmental disorders is of concern, and accumulating evidence indicates that BPA has detrimental effects on neurological development. Other bisphenol analogues, used as substitutes for BPA, are also suspected of having a broad range of biological actions. The objective of this review is to summarize our current understanding of the neurobiological effects of BPA and its analogues, and to discuss preventive strategies from a public health perspective. PMID:26664253

  16. Glaucine analogues as inhibitors of mouse splenocyte activity.

    PubMed

    Philipov, S; Ivanovska, N; Nikolova, P

    1998-10-01

    The inhibitory effect of 15 semi-synthetic analogues of glaucine (1) on the lipopolysaccharide (LPS)-induced and the concanavalin A (Con A)-induced proliferation of mouse splenocytes was compared in vitro. Isoboldine (3), bracteoline (4) and dehydroglaucine (9) showed a significantly higher potency to suppress LPS-induced proliferation than 1, while 7-hydroxy-4-methylglaucine (8), 7-formyldehydroglaucine (11), 7-acetyldehydroglaucine (13), 7-benzoyldehydroglaucine (14), oxoglaucine (15) and glaucine-quinol (16) were less inhibitory. Compounds 3, 4, boldine (5), 15 and 16 surpassed significantly the inhibition expressed by 1 on Con A-induced proliferative response. The effect was equal to the inhibition determined for mitomycin C (Mit C) with both mitogens. In contrast to all others analogues, thaliporphine (2) stimulated splenocyte proliferation in both assays. Antibody response against sheep red blood cells (SRBC) was lowered most strongly by cataline (6), 7-methyldehydroglaucine (10) and 16. PMID:9812336

  17. Optical analogue of relativistic Dirac solitons in binary waveguide arrays

    SciTech Connect

    Tran, Truong X.; Longhi, Stefano; Biancalana, Fabio

    2014-01-15

    We study analytically and numerically an optical analogue of Dirac solitons in binary waveguide arrays in the presence of Kerr nonlinearity. Pseudo-relativistic soliton solutions of the coupled-mode equations describing dynamics in the array are analytically derived. We demonstrate that with the found soliton solutions, the coupled mode equations can be converted into the nonlinear relativistic 1D Dirac equation. This paves the way for using binary waveguide arrays as a classical simulator of quantum nonlinear effects arising from the Dirac equation, something that is thought to be impossible to achieve in conventional (i.e. linear) quantum field theory. -- Highlights: •An optical analogue of Dirac solitons in nonlinear binary waveguide arrays is suggested. •Analytical solutions to pseudo-relativistic solitons are presented. •A correspondence of optical coupled-mode equations with the nonlinear relativistic Dirac equation is established.

  18. Analogue transformations in physics and their application to acoustics.

    PubMed

    García-Meca, C; Carloni, S; Barceló, C; Jannes, G; Sánchez-Dehesa, J; Martínez, A

    2013-01-01

    Transformation optics has shaped up a revolutionary electromagnetic design paradigm, enabling scientists to build astonishing devices such as invisibility cloaks. Unfortunately, the application of transformation techniques to other branches of physics is often constrained by the structure of the field equations. We develop here a complete transformation method using the idea of analogue spacetimes. The method is general and could be considered as a new paradigm for controlling waves in different branches of physics, from acoustics in quantum fluids to graphene electronics. As an application, we derive an "analogue transformation acoustics" formalism that naturally allows the use of transformations mixing space and time or involving moving fluids, both of which were impossible with the standard approach. To demonstrate the power of our method, we give explicit designs of a dynamic compressor, a spacetime cloak for acoustic waves and a carpet cloak for a moving aircraft. PMID:23774575

  19. A rationally designed CD4 analogue inhibits experimental allergic encephalomyelitis

    NASA Astrophysics Data System (ADS)

    Jameson, Bradford A.; McDonnell, James M.; Marini, Joseph C.; Korngold, Robert

    1994-04-01

    EXPERIMENTAL allergic encephalomyelitis (EAE) is an acute inflammatory autoimmune disease of the central nervous system that can be elicited in rodents and is the major animal model for the study of multiple sclerosis (MS)1,2. The pathogenesis of both EAE and MS directly involves the CD4+ helper T-cell subset3-5. Anti-CD4 monoclonal antibodies inhibit the development of EAE in rodents6-9, and are currently being used in human clinical trials for MS. We report here that similar therapeutic effects can be achieved in mice using a small (rationally designed) synthetic analogue of the CD4 protein surface. It greatly inhibits both clinical incidence and severity of EAE with a single injection, but does so without depletion of the CD4+ subset and without the inherent immunogenicity of an antibody. Furthermore, this analogue is capable of exerting its effects on disease even after the onset of symptoms.

  20. On-chip learning with analogue VLSI neural networks.

    PubMed

    Tarassenko, L; Tombs, J; Cairns, G

    1993-12-01

    Results from simulations of weight perturbation as an on-chip learning scheme for analogue VLSI neural networks are presented. The limitations of analogue hardware are modelled as realistically as possible. Thus synaptic weight precision is defined according to the smallest change in the weight setting voltage which gives a measurable change at the output of the corresponding neuron. Tests are carried out on a hard classification problem constructed from mobile robot navigation data. The simulations show that the degradation in classification performance on a 500-pattern test set caused by the introduction of realistic hardware constraints is acceptable: with 8-bit weights, updated probabilistically and with a simplified output error criterion, the error rate increases by no more than 7% when compared with weight perturbation implemented with full 32-bit precision. PMID:8049803