Effect of quinine and artesunate combination therapy on platelet count of children with severe malaria.

PubMed

Gupta, Parul; Narang, Manish; Gomber, Sunil; Saha, Rumpa

2017-05-01

There are several case reports of quinine-induced thrombocytopenia but no clinical trials to ascertain its incidence and significance in severe malaria. The primary objective was to assess the effect of quinine on the platelet count in children with severe malaria and to compare it with artesunate combination therapy (ACT), and the secondary objective was to assess outcome of treatment with quinine and ACT. An open-labelled, randomised, controlled trial was undertaken in 100 children aged 6 months to 12 years who were diagnosed with malaria by microscopy and/or rapid diagnostic test kits with at least one WHO clinical or laboratory criterion for severe malaria. All subjects were commenced on either quinine or ACT. Clindamycin was added to artesunate as a combination drug (ACT). It was also given to patients on quinine to avoid its confounding effect on the results. Platelet counts were undertaken every 24 hours for 7 consecutive days, temperature and coma score (Blantyre coma score ≥3 in children <4 years or Glasgow coma score ≥13 in children >4 years) was recorded 6-hourly and peripheral smears were taken 12-hourly until two consecutively negative smears were obtained. The primary outcome was a fall in the platelet count by ≥20% from the time of drug initiation until day 7. The secondary outcome was comparison of the efficacy, parasite clearance time, fever clearance time, coma recovery time and adverse effects of quinine vs ACT. 30.4% patients in the quinine group (n = 48) had ≥20% fall in platelet count and 10.8% of patients in the ACT group (n = 46) (P = 0.02). Despite the fall in platelet count, there was no bleeding. The efficacy of ACT was significantly better than quinine but the other treatment outcomes showed insignificant difference. Quinine should be used with caution in patients with severe malaria because of the potential risk of quinine-induced thrombocytopenia.

Quinine, mosquitoes and empire: reassembling malaria in British India, 1890–1910

PubMed Central

Roy, Rohan Deb

2012-01-01

The drug quinine figured as an object of enforced consumption in British India between the late 1890s and the 1910s, when the corresponding diagnostic category malaria itself was redefined as a mosquito-borne fever disease. This article details an overlapping milieu in which quinine, mosquitoes and malaria emerged as intrinsic components of shared and symbiotic histories. It combines insights from new imperial histories, constructivism in the histories of medicine and literature about non-humans in science studies to examine the ways in which histories of insects, drugs, disease and empire interacted and shaped one another. Firstly, it locates the production of historical intimacies between quinine, malaria and mosquitoes within the exigencies and apparatuses of imperial rule. In so doing, it explores the intersections between the worlds of colonial governance, medical knowledge, vernacular markets and pharmaceutical business. Secondly, it outlines ways to narrate characteristics and enabling properties of non-humans (such as quinines and mosquitoes) while retaining a constructivist critique of scientism and empire. Thirdly, it shows how empire itself was reshaped and reinforced while occasioning the proliferation of categories and entities like malaria, quinine and mosquitoes. PMID:24765235

Screening and Evaluation of Experimental Antiparasitic Drugs.

DTIC Science & Technology

1979-08-01

compounds were tested against one or more of the following lines resistant to chloroquine , cycloguanil, dapsone, mefloquine, pyrimethamine, or quinine...against one or more of the following lines resistant to chloroquine , cycloguanil, dapsone, mefloquine, pyrimeth- amine, or quinine, respectively. Two...four level tests against each drug-resistant line was as follows: mefloquine-resistant line (51); chloroquine -resistant line (67); pyrimethamine

Antagonistic effect of alkaloids and saponins on bioactivity in the quinine tree (Rauvolfia caffra sond.): further evidence to support biotechnology in traditional medicinal plants.

PubMed

Milugo, Trizah K; Omosa, Leonida K; Ochanda, James O; Owuor, Bethwell O; Wamunyokoli, Fred A; Oyugi, Julius O; Ochieng, Joel W

2013-10-26

The Quinine tree (Rauvolfia caffra) is used as a medicinal plant among traditional communities in many countries to manage tumors and other diseases associated with oxidative stress. To validate indigenous knowledge and possibly position this herb for technology uptake and utilization, we established the level of antioxidant activity in R. caffra, and probed for the presence of associated phytochemicals. Antioxidant activity was determined on 1,1-diphenyl-2-picrylhydrazyl (DPPH) while major phytochemicals were identified by multiple tests on methanol fractions. R. caffra showed promise as a cure, with antioxidant activity comparable to the commercially used drug quercetin (R. caffra = 79.7% ±1.9; quercetin = 82.6% ± 2.0). However, we found two phytochemicals with possible antagonistic effect: co-occurrence of alkaloids and saponins significantly reduced antioxidant activity (alkaloids only = 63%; alkaloids plus saponins = 15%; steroids, terpenoids and cardiac glycosides = 82%), thus alkaloids and saponins should be exclusive to each other in drug formulations. Antagonistic relationship among phytochemicals would affect the efficacy of crude extracts as used in traditional medicine. Unlike in herbal medicine, use of modern biotechnology in extraction, purification and design of optimal combinations will ensure efficient drug formulations with optimum bioactivity and minimum toxicity. Metabolic pathway engineering under a controlled environment may optimize availability of desired compounds.

Quinine intoxications reported to the Scottish Poisons Information Bureau 1997–2002: a continuing problem

PubMed Central

Langford, N J; Good, A M; Laing, W J; Bateman, D N

2003-01-01

Quinine is widely prescribed in the UK for night cramps. Its potential toxicity in overdose is well known. We have reviewed the Scottish experience of enquiries regarding quinine overdose to the poisons information service responsible for Scotland over a 6-year period. Between 1997 and 2002 there were 96 reports of suspected quinine toxicity from Scotland (population 5.2 million), 19 of which were in children. The largest quantities of drug ingested were in patients between the ages of 11 and 30. In comparison with older studies the pattern of quinine poisoning does not appear to have changed in the UK over 20 years, despite recognition that it is a toxic agent in overdose, and particularly in children. PMID:14651733

Chitosan-based nanocarriers for antimalarials

NASA Astrophysics Data System (ADS)

Dreve, Simina; Kacso, Iren; Popa, Adriana; Raita, Oana; Bende, A.; Borodi, Gh.; Bratu, I.

2012-02-01

The objective of this research was to synthesize and characterize chitosan-based liquid and solid materials with unique absorptive and mechanical properties as carriers for quinine - one of the most used antimalarial drug. The use of chitosan (CTS) as base in polyelectrolyte complex systems, to prepare solid release systems as sponges is presented. The preparation by double emulsification of CTS hydrogels carrying quinine as anti-malarial drug is reported. The concentration of quinine in the CTS hydrogel was 0.08 mmol. Chitosan - drug loaded hydrogel was used to generate solid sponges by freeze-drying at -610°C and 0.09 atm. Structural investigations of the solid formulations were done by Fourier-transformed infrared spectroscopy (FTIR), ultraviolet-visible spectroscopy (UV-VIS), spectrofluorimetry, differential scanning calorimetry (DSC) and X-ray diffractometry. The results indicated that the drug molecule is forming temporary chelates in CTS hydrogels and sponges. Electron paramagnetic resonance (EPR) demonstrates the presence of free radicals in a wide range and the antioxidant activity for chitosan - drug supramolecular cross-linked assemblies.

Effects of MHRA drug safety advice on time trends in prescribing volume and indices of clinical toxicity for quinine

PubMed Central

Acheampong, Paul; Cooper, Gill; Khazaeli, Behshad; Lupton, David J; White, Sue; May, Margaret T; Thomas, Simon H L

2013-01-01

Aims To ascertain the effects of the Medicines and Healthcare products Regulatory Agency's (MHRA) safety update in June 2010 on the volume of prescribing of quinine and on indices of quinine toxicity. Methods We analysed quarterly primary care total and quinine prescribing data for England and quinine prescribing volume for individual Primary Care Trusts in the North East of England from 2007/8 to 2011/12 obtained from the ePACT.net database. We also analysed quinine toxicity enquiries to the National Poisons Information Service (NPIS) via Toxbase® and by telephone between 2004/5 and 2011/12. Joinpoint regression and Pearson's correlation tests were used to ascertain changes in trends in prescribing and indices of toxicity and associations between prescribing and indices of toxicity, respectively. Results Total prescribing continued to increase, but annual growth in quinine prescribing in England declined from 6.0 to −0.6% following the MHRA update [difference −0.04 (95% confidence interval −0.07 to −0.01) quinine prescriptions per 100 patients per quarter, P = 0.0111]. Much larger reductions were observed in Primary Care Trusts that introduced comprehensive prescribing reviews. The previously increasing trend in Toxbase® quinine searches was reversed [difference −19.76 (95% confidence interval −39.28 to −9.20) user sessions per quarter, P = 0.0575]. Telephone enquiries to NPIS for quinine have declined, with stabilization of the proportion of moderate to severe cases of quinine poisoning since the update. Conclusions The MHRA advice was followed by limited reductions in the growth in quinine prescribing and in indicators of quinine overdose and toxicity. Quinine prescribing, however, remains common, and further efforts are needed to reduce availability and use. PMID:23594200

Experimental Chemotherapy: A Rapid and Simple Screening Method for Drug Binding to DNA

DTIC Science & Technology

1980-06-01

Acriflavine Hydroxystilbamidine Berberine Miracil D Berenil Pentamidine Chloroquine Propamidine Congocidine Quinine Ethidium Bromide Quinacrine...actino- mycin D (AD), Acridine Orange (AO), berberine (BB), side chain of and stoichiometric inter- quinacrine and chloroquine (SC), quinine (Qi

Preparation of polymer-blended quinine nanocomposite particles by spray drying and assessment of their instrumental bitterness-masking effect using a taste sensor.

PubMed

Taki, Moeko; Tagami, Tatsuaki; Ozeki, Tetsuya

2017-05-01

The development of taste-masking technologies for foods and drugs is essential because it would enable people to consume and receive healthy and therapeutic effect without distress. In the current study, in order to develop a novel method to prepare nanocomposite particles (microparticles containing bitter nanoparticles) in only one step, by using spray drying, a two-solution mixing nozzle-equipped spray dryer that we previously reported was used. The nanocomposite particles with or without poorly water-soluble polymers prepared using our spray-drying technique were characterized. (1) The organic solution containing quinine, a model of bitter compound and poorly water-soluble polymers and (2) sugar alcohol (mannitol) aqueous solution were separately flown in tubes and two solutions were spray dried through two-solution type spray nozzle to prepare polymer-blended quinine nanocomposite particles. Mean diameters of nanoparticles, taste-masking effect and dissolution rate of quinine were evaluated. The results of taste masking by taste sensor suggested that the polymer (Eudragit EPO, Eudragit S100 or Ethyl cellulose)-blended quinine nanocomposite particles exhibited marked masking of instrumental quinine bitterness compared with the quinine nanocomposite particles alone. Quinine nanocomposite formulations altered the quinine dissolution rate, indicating that they can control intestinal absorption of quinine. These results suggest that polymer-blended quinine composite particles prepared using our spray-drying technique are useful for masking bitter tastes in the field of food and pharmaceutical industry.

Artesunate, artemether or quinine in severe Plasmodium falciparum malaria?

PubMed

Checkley, Anna M; Whitty, Christopher J M

2007-04-01

Quinine and the artemisinin-derivative drugs artesunate and artemether are effective treatments for severe falciparum malaria. Trials comparing artemether with quinine have not demonstrated convincing evidence of a mortality advantage for artemether. The South East Asian Quinine Artesunate Malaria Trial (SEAQUAMAT), a multicenter, randomized, open-label trial in 1461 adults with severe malaria in Asia compared artesunate with quinine. Mortality was 15% in the artesunate group and 22% in the quinine group, a reduction of 34.7% (95% confidence interval: 18.5-47.6%) in the artesunate group, with almost all the benefit reported in those with high parasite counts. Artesunate should constitute first-line treatment for severe malaria in Asia. These results can probably be generalized to the treatment of severe malaria in adults from all areas, especially in those with hyperparasitemia. However, it is unclear whether these results can be generalized to children in Africa, who constitute the majority of those who die from severe malaria worldwide.

Antagonistic effect of alkaloids and saponins on bioactivity in the quinine tree (Rauvolfia caffra sond.): further evidence to support biotechnology in traditional medicinal plants

PubMed Central

2013-01-01

Background The Quinine tree (Rauvolfia caffra) is used as a medicinal plant among traditional communities in many countries to manage tumors and other diseases associated with oxidative stress. To validate indigenous knowledge and possibly position this herb for technology uptake and utilization, we established the level of antioxidant activity in R. caffra, and probed for the presence of associated phytochemicals. Methods Antioxidant activity was determined on 1,1-diphenyl-2-picrylhydrazyl (DPPH) while major phytochemicals were identified by multiple tests on methanol fractions. Results R. caffra showed promise as a cure, with antioxidant activity comparable to the commercially used drug quercetin (R. caffra = 79.7% ±1.9; quercetin = 82.6% ± 2.0). However, we found two phytochemicals with possible antagonistic effect: co-occurrence of alkaloids and saponins significantly reduced antioxidant activity (alkaloids only = 63%; alkaloids plus saponins = 15%; steroids, terpenoids and cardiac glycosides = 82%), thus alkaloids and saponins should be exclusive to each other in drug formulations. Conclusions Antagonistic relationship among phytochemicals would affect the efficacy of crude extracts as used in traditional medicine. Unlike in herbal medicine, use of modern biotechnology in extraction, purification and design of optimal combinations will ensure efficient drug formulations with optimum bioactivity and minimum toxicity. Metabolic pathway engineering under a controlled environment may optimize availability of desired compounds. PMID:24160735

Quinine conjugates and quinine analogues as potential antimalarial agents.

PubMed

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

2015-06-05

Malaria is a tropical disease, prevalent in Southeast Asia and Africa, resulting in over half a million deaths annually; efforts to develop new antimalarial agents are therefore particularly important. Quinine continues to play a role in the fight against malaria, but quinoline derivatives are more widely used. Drugs based on the quinoline scaffold include chloroquine and primaquine, which are able to act against the blood and liver stages of the parasite's life cycle. The purpose of this review is to discuss reported biologically active compounds based on either the quinine or quinoline scaffold that may have enhanced antimalarial activity. The review emphasises hybrid molecules, and covers advances made in the last five years. The review is divided into three sections: modifications to the quinine scaffold, modifications to aminoquinolines and finally metal-containing antimalarial compounds. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Multiple Drugs Compete for Transport via the Plasmodium falciparum Chloroquine Resistance Transporter at Distinct but Interdependent Sites*

PubMed Central

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

2014-01-01

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

Development, validation and comparison of NIR and Raman methods for the identification and assay of poor-quality oral quinine drops.

PubMed

Mbinze, J K; Sacré, P-Y; Yemoa, A; Mavar Tayey Mbay, J; Habyalimana, V; Kalenda, N; Hubert, Ph; Marini, R D; Ziemons, E

2015-01-01

Poor quality antimalarial drugs are one of the public's major health problems in Africa. The depth of this problem may be explained in part by the lack of effective enforcement and the lack of efficient local drug analysis laboratories. To tackle part of this issue, two spectroscopic methods with the ability to detect and to quantify quinine dihydrochloride in children's oral drops formulations were developed and validated. Raman and near infrared (NIR) spectroscopy were selected for the drug analysis due to their low cost, non-destructive and rapid characteristics. Both of the methods developed were successfully validated using the total error approach in the range of 50-150% of the target concentration (20%W/V) within the 10% acceptance limits. Samples collected on the Congolese pharmaceutical market were analyzed by both techniques to detect potentially substandard drugs. After a comparison of the analytical performance of both methods, it has been decided to implement the method based on NIR spectroscopy to perform the routine analysis of quinine oral drop samples in the Quality Control Laboratory of Drugs at the University of Kinshasa (DRC). Copyright © 2015 Elsevier B.V. All rights reserved.

Artemisinin derivatives for treating severe malaria.

PubMed

McIntosh, H M; Olliaro, P

2000-01-01

Artemisinin derivatives may have advantages over quinoline drugs for treating severe malaria since they are fast acting and effective against quinine resistant malaria parasites. The objective of this review was to assess the effects of artemisinin drugs for severe and complicated falciparum malaria in adults and children. We searched the Cochrane Infectious Diseases Group trials register, Cochrane Controlled Trials Register, Medline, Embase, Science Citation Index, Lilacs, African Index Medicus, conference abstracts and reference lists of articles. We contacted organisations, researchers in the field and drug companies. Randomised and pseudo-randomised trials comparing artemisinin drugs (rectal, intramuscular or intravenous) with standard treatment, or comparisons between artemisinin derivatives in adults or children with severe or complicated falciparum malaria. Eligibility, trial quality assessment and data extraction were done independently by two reviewers. Study authors were contacted for additional information. Twenty three trials are included, allocation concealment was adequate in nine. Sixteen trials compared artemisinin drugs with quinine in 2653 patients. Artemisinin drugs were associated with better survival (mortality odds ratio 0.61, 95% confidence interval 0.46 to 0.82, random effects model). In trials where concealment of allocation was adequate (2261 patients), this was barely statistically significant (odds ratio 0.72, 95% CI 0.54 to 0.96, random effects model). In 1939 patients with cerebral malaria, mortality was also lower with artemisinin drugs overall (odds ratio 0.63, 95% CI 0.44 to 0.88, random effects model). The difference was not significant however when only trials reporting adequate concealment of allocation were analysed (odds ratio 0.78, 95% CI 0.55 to 1.10, random effects model) based on 1607 patients. No difference in neurological sequelae was shown. Compared with quinine, artemisinin drugs showed faster parasite clearance from the blood and similar adverse effects. The evidence suggests that artemisinin drugs are no worse than quinine in preventing death in severe or complicated malaria. No artemisinin derivative appears to be better than the others.

Investigation of the effect of cucurbit[7]uril complexation on the photophysical and acid-base properties of the antimalarial drug quinine.

PubMed

Mallick, Suman; Pal, Kaushik; Chandra, Falguni; Koner, Apurba L

2016-11-09

Host-guest complexation of mono and dicationic quinine with cucurbit[7]uril (CB7), a water-soluble macrocyclic host molecule, has been investigated. Job's plot, time-resolved anisotropy as well as concentration dependent NMR titration confirm the binding of two CB7 macrocycles with one quinine molecule. The binding affinity of dicationic quinine with CB7 is one order of magnitude higher than the binding constant of mono-cationic quinine. Such preferential binding results in one unit pK a shift in the ground-state of the quinoline ring. However, using fluorescence spectroscopy we have obtained two acid-dissociation constants, one for quinoline ring nitrogen and the other for the nitrogen of the quinuclidine moiety. In the excited state, CB7 complexation causes one unit pK a shift for the quinoline ring and 1.9 unit shift for the quinuclidine moiety. Interestingly, a large enhancement of fluorescence lifetime and anisotropy of quinine at pH 2.7 and pH 9.0 upon CB7 complexation was observed due to the restriction of conformational flexibility. Moreover, at pH 3.0, a large fluorescence enhancement of quinine due to CB7 complexation was observed and it was quite significant as compared to that of quinine in 0.1 (M) HCl without CB7. We believe that this study of quinine complexation with CB7 will reduce phototoxicity, increase bioavailability and offer an alternative standard for quantum yield measurements in an amiable condition.

Economic evaluation of artesunate and three quinine regimens in the treatment of severe malaria in children at the Ebolowa Regional Hospital-Cameroon: a cost analysis.

PubMed

Maka, Daniel Ethe; Chiabi, Andreas; Obadeyi, Bolaji; Mah, Evelyn; Nguefack, Séraphin; Nana, Pamela; Mbacham, Wilfred; Mbonda, Elie

2016-12-07

Severe malaria is a leading cause of morbidity and mortality in under-fives in sub-Saharan Africa. Recently quinine has been replaced by artesunate as the first-line drug in the treatment of severe malaria in Cameroon. Artesunate has been shown to be cost-effective in African children, but whether these findings are transferable to Cameroonian children remains to be explored. To conduct a cost-analysis of four different regimens used in the treatment from the perspective of the healthcare payer. An economic evaluation alongside a randomized comparative study was conducted in children aged 3 months to 15 years, admitted at the Ebolowa Regional Hospital with severe malaria due to Plasmodium falciparum. Patients were randomized to receive one of the four treatment alternatives. Group 1 (ARTES) received parenteral artesunate at 2.4 mg/kg at H 0 , H 12 , H 24 and then once daily; Group 2 (QLD) received a loading dose of quinine base at 16.6 mg/kg followed 8 h later by an 8-hourly maintenance dose of 8.3 mg/kg quinine base; Group 3 (QNLD3) received 8.3 mg/kg quinine base every 8 h, and Group 4 (QNLD2) received 12.5 mg/kg quinine base every 12 h. The main outcome measure for effectiveness of treatment was the parasite reduction rate. Based on a healthcare perspective, an evaluation of direct medical costs was done, including costs of anti-malarials, nursing care materials, adjuvant treatment, laboratory investigations, hospitalisation and professional fees. Guided by a cost minimalization approach, the relative costs of these treatment alternatives was compared and reported. Overall cost was higher for ARTES group at $65.14 (95% CI $57.68-72.60) than for quinine groups ($52.49-$62.40), but the difference was not statistically significant. Cost of the anti-malarial drug was significantly higher for artesunate-treated patients than for quinine-treated patients, whereas cost of hospitalization was significantly lower for artesunate-treated patients than for quinine-treated patients. Incremental analysis of ARTES against QLD as a baseline resulted in an ICER of $46.8/PRR 24 and suggests ARTES as the most cost effective of all four treatment options. Artesunate is a cost effective malaria treatment option relative to quinine alternatives with the lowest incremental cost per unit of effectiveness. Trial registration clinicaltrials.gov identifier: NCT02563704. Registered 19 September 2015, retrospectively registered.

Drug Evaluation in the Plasmodium Falciparum-Aotus Model.

DTIC Science & Technology

1986-09-30

strains of Plasmodium falciparum, Uganda Palo Alto ( chloroquine sensi- tive) or Vietnam Smith (chioroquine resistant), in Aotus trivirgatus, were used...Plasmodium falciparum in the Panamanian owl monkey Aotus Two strains of falciparum malaria, Uganda Palo Alto (sensitive to chloroquine anfd quinine...resistant to pyrimetha- mine) and Vietnam Smith (resistant to chloroquine , quinine and pyrimethamine) were used. Previous evaluation of two stereoisomers of

Chemotherapy of Malaria

DTIC Science & Technology

1975-05-31

Vietnam was resistant to drugs such as chloroquine and quinine, gene-ally r,,conized snce World War II as satisfactory antimalarial agents. Tr,e...Trypanosoma rhodesiense infections in mice. (3) structural analogues of compounds found active in our test system and representing several novel chemical...with chloroquine , dapsone, cycloguanil, or pyrimethamine. Out of the 17 good compounds 7 exhibited quinine equivalent values of greater than 25. These 7

In vitro studies on the sensitivity pattern of Plasmodium falciparum to anti-malarial drugs and local herbal extracts.

PubMed

Olasehinde, Grace I; Ojurongbe, Olusola; Adeyeba, Adegboyega O; Fagade, Obasola E; Valecha, Neena; Ayanda, Isaac O; Ajayi, Adesola A; Egwari, Louis O

2014-02-20

The resistance of human malaria parasites to anti-malarial compounds has become considerable concern, particularly in view of the shortage of novel classes of anti-malarial drugs. One way to prevent resistance is by using new compounds that are not based on existing synthetic antimicrobial agents. Sensitivity of 100 Plasmodium falciparum isolates to chloroquine, quinine, amodiaquine, mefloquine, sulphadoxine/pyrimethamine, artemisinin, Momordica charantia ('Ejirin') Diospyros monbuttensis ('Egun eja') and Morinda lucida ('Oruwo') was determined using the in vitro microtest (Mark III) technique to determine the IC50 of the drugs. All the isolates tested were sensitive to quinine, mefloquine and artesunate. Fifty-one percent of the isolates were resistant to chloroquine, 13% to amodiaquine and 5% to sulphadoxine/pyrimethamine. Highest resistance to chloroquine (68.9%) was recorded among isolates from Yewa zone while highest resistance to amodiaquine (30%) was observed in Ijebu zone. Highest resistance to sulphadoxine/pyrimethamine was recorded in Yewa and Egba zones, respectively. A positive correlation was observed between the responses to artemisinin and mefloquine (P<0.05), artemisinin and quinine (P<0.05) and quinine and mefloquine (P<0.05). A negative correlation was observed between the responses to chloroquine and mefloquine (P>0.05). Highest anti-plasmodial activity was obtained with the ethanolic extract of D. monbuttensis (IC50 = 3.2 nM) while the lowest was obtained from M. lucida (IC50 = 25 nM). Natural products isolated from plants used in traditional medicine, which have potent anti-plasmodial action in vitro, represent potential sources of new anti-malarial drugs.

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

PubMed Central

2010-01-01

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

The antimalarial drugs quinine, chloroquine and mefloquine are antagonists at 5-HT3 receptors

PubMed Central

Thompson, A J; Lochner, M; Lummis, S C R

2007-01-01

Background and Purpose: The antimalarial compounds quinine, chloroquine and mefloquine affect the electrophysiological properties of Cys-loop receptors and have structural similarities to 5-HT3 receptor antagonists. They may therefore act at 5-HT3 receptors. Experimental Approach: The effects of quinine, chloroquine and mefloquine on electrophysiological and ligand binding properties of 5-HT3A receptors expressed in HEK 293 cells and Xenopus oocytes were examined. The compounds were also docked into models of the binding site. Key Results: 5-HT3 responses were blocked with IC 50 values of 13.4 μM, 11.8 μM and 9.36 μM for quinine, chloroquine and mefloquine. Schild plots indicated quinine and chloroquine behaved competitively with pA 2 values of 4.92 (K B=12.0 μM) and 4.97 (K B=16.4 μM). Mefloquine displayed weakly voltage-dependent, non-competitive inhibition consistent with channel block. On and off rates for quinine and chloroquine indicated a simple bimolecular reaction scheme. Quinine, chloroquine and mefloquine displaced [3H]granisetron with K i values of 15.0, 24.2 and 35.7 μ M. Docking of quinine into a homology model of the 5-HT3 receptor binding site located the tertiary ammonium between W183 and Y234, and the quinoline ring towards the membrane, stabilised by a hydrogen bond with E129. For chloroquine, the quinoline ring was positioned between W183 and Y234 and the tertiary ammonium stabilised by interactions with F226. Conclusions and Implications: This study shows that quinine and chloroquine competitively inhibit 5-HT3 receptors, while mefloquine inhibits predominantly non-competitively. Both quinine and chloroquine can be docked into a receptor binding site model, consistent with their structural homology to 5-HT3 receptor antagonists. PMID:17502851

In vitro studies on the sensitivity pattern of Plasmodium falciparum to anti-malarial drugs and local herbal extracts

PubMed Central

2014-01-01

Background The resistance of human malaria parasites to anti-malarial compounds has become considerable concern, particularly in view of the shortage of novel classes of anti-malarial drugs. One way to prevent resistance is by using new compounds that are not based on existing synthetic antimicrobial agents. Results Sensitivity of 100 Plasmodium falciparum isolates to chloroquine, quinine, amodiaquine, mefloquine, sulphadoxine/pyrimethamine, artemisinin, Momordica charantia (‘Ejirin’) Diospyros monbuttensis (‘Egun eja’) and Morinda lucida (‘Oruwo’) was determined using the in vitro microtest (Mark III) technique to determine the IC50 of the drugs. All the isolates tested were sensitive to quinine, mefloquine and artesunate. Fifty-one percent of the isolates were resistant to chloroquine, 13% to amodiaquine and 5% to sulphadoxine/pyrimethamine. Highest resistance to chloroquine (68.9%) was recorded among isolates from Yewa zone while highest resistance to amodiaquine (30%) was observed in Ijebu zone. Highest resistance to sulphadoxine/pyrimethamine was recorded in Yewa and Egba zones, respectively. A positive correlation was observed between the responses to artemisinin and mefloquine (P<0.05), artemisinin and quinine (P<0.05) and quinine and mefloquine (P<0.05). A negative correlation was observed between the responses to chloroquine and mefloquine (P>0.05). Highest anti-plasmodial activity was obtained with the ethanolic extract of D. monbuttensis (IC50 = 3.2nM) while the lowest was obtained from M. lucida (IC50 =25nM). Conclusions Natural products isolated from plants used in traditional medicine, which have potent anti-plasmodial action in vitro, represent potential sources of new anti-malarial drugs. PMID:24555525

In vitro susceptibility to quinine and microsatellite variations of the Plasmodium falciparum Na+/H+ exchanger (Pfnhe-1) gene: the absence of association in clinical isolates from the Republic of Congo

PubMed Central

2011-01-01

Background Quinine is still recommended as an effective therapy for severe cases of Plasmodium falciparum malaria, but the parasite has developed resistance to the drug in some cases. Investigations into the genetic basis for quinine resistance (QNR) suggest that QNR is complex and involves several genes, with either an additive or a pairwise effect. The results obtained when assessing one of these genes, the plasmodial Na+/H+ exchanger, Pfnhe-1, were found to depend upon the geographic origin of the parasite strain. Most of the associations identified have been made in Asian strains; in contrast, in African strains, the influence of Pfnhe on QNR is not apparent. However, a recent study carried out in Kenya did show a significant association between a Pfnhe polymorphism and QNR. As genetic differences may exist across the African continent, more field data are needed to determine if this association exists in other African regions. In the present study, association between Pfnhe and QNR is investigated in a series of isolates from central Africa. Methods The sequence analysis of the polymorphisms at the Pfnhe-1 ms4760 microsatellite and the evaluation of in vitro quinine susceptibility (by isotopic assay) were conducted in 74 P. falciparum isolates from the Republic of Congo. Results Polymorphisms in the number of DNNND or NHNDNHNNDDD repeats in the Pfnhe-1 ms4760 microsatellite were not associated with quinine susceptibility. Conclusions The polymorphism in the microsatellite ms4760 in Pfnhe-1 that cannot be used to monitor quinine response in the regions of the Republic of Congo, where the isolates came from. This finding suggests that there exists a genetic background associated with geographic area for the association that will prevent the use of Pfnhe as a molecular marker for QNR. The contribution of Pfnhe to the in vitro response to quinine remains to be assessed in other regions, including in countries with different levels of drug pressure. PMID:21314947

Chloroquine, quinine, procaine, quinidine and clomipramine are prostaglandin agonists and antagonists.

PubMed

Manku, M S; Horrobin, D F

1976-11-01

Chloroquine, quinine, procaine, quinidine and clomipramine behave as prostaglandin (PG) antagonists in a rat mesenteric vascular bed preparation. The ID50 concentrations were within the range of therapeutically effective human plasma levels in each case. Antagonism to PGE2 was studied in detail and seemed to be at least in part competitive. The drugs also antagonized the effects of PGs A1, A2, F2alpha and E1. Each drug also had weak prostaglandin agonist activity but only over a very narrow range of concentrations. It is possible that some of the clinical actions of these drugs may depend on blockade or imitation of natural PG effects. The findings suggest new approaches to the search for PG antagonists, a new screening technique for anti-inflammatory drugs and possible new uses for these established drugs. A preliminary study suggests that chloroquine may be successful in closing a patent ductus arteriosus in infants.

The hydroxyl functionality and a rigid proximal N are required for forming a novel non-covalent quinine-heme complex.

PubMed

Alumasa, John N; Gorka, Alexander P; Casabianca, Leah B; Comstock, Erica; de Dios, Angel C; Roepe, Paul D

2011-03-01

Quinoline antimalarial drugs bind both monomeric and dimeric forms of free heme, with distinct preferences depending on the chemical environment. Under biological conditions, chloroquine (CQ) appears to prefer to bind to μ-oxo dimeric heme, while quinine (QN) preferentially binds monomer. To further explore this important distinction, we study three newly synthesized and several commercially available QN analogues lacking various functional groups. We find that removal of the QN hydroxyl lowers heme affinity, hemozoin (Hz) inhibition efficiency, and antiplasmodial activity. Elimination of the rigid quinuclidyl ring has similar effects, but elimination of either the vinyl or methoxy group does not. Replacing the quinuclidyl N with a less rigid tertiary aliphatic N only partially restores activity. To further study these trends, we probe drug-heme interactions via NMR studies with both Fe and Zn protoporphyrin IX (FPIX, ZnPIX) for QN, dehydroxyQN (DHQN), dequinuclidylQN (DQQN), and deamino-dequinuclidylQN (DADQQN). Magnetic susceptibility measurements in the presence of FPIX demonstrate that these compounds differentially perturb FPIX monomer-dimer equilibrium. We also isolate the QN-FPIX complex formed under mild aqueous conditions and analyze it by mass spectrometry, as well as fluorescence, vibrational, and solid-state NMR spectroscopies. The data elucidate key features of QN pharmacology and allow us to propose a refined model for the preferred binding of QN to monomeric FPIX under biologically relevant conditions. With this model in hand, we also propose how QN, CQ, and amodiaquine (AQ) differ in their ability to inhibit Hz formation. Copyright © 2010 Elsevier Inc. All rights reserved.

Mechanism of inhibition of mouse Slo3 (KCa 5.1) potassium channels by quinine, quinidine and barium.

PubMed

Wrighton, David C; Muench, Stephen P; Lippiat, Jonathan D

2015-09-01

The Slo3 (KCa 5.1) channel is a major component of mammalian KSper (sperm potassium conductance) channels and inhibition of these channels by quinine and barium alters sperm motility. The aim of this investigation was to determine the mechanism by which these drugs inhibit Slo3 channels. Mouse (m) Slo3 (KCa 5.1) channels or mutant forms were expressed in Xenopus oocytes and currents recorded with 2-electrode voltage-clamp. Gain-of-function mSlo3 mutations were used to explore the state-dependence of the inhibition. The interaction between quinidine and mSlo3 channels was modelled by in silico docking. Several drugs known to block KSper also affected mSlo3 channels with similar levels of inhibition. The inhibition induced by extracellular barium was prevented by increasing the extracellular potassium concentration. R196Q and F304Y mutations in the mSlo3 voltage sensor and pore, respectively, both increased channel activity. The F304Y mutation did not alter the effects of barium, but increased the potency of inhibition by both quinine and quinidine approximately 10-fold; this effect was not observed with the R196Q mutation. Block of mSlo3 channels by quinine, quinidine and barium is not state-dependent. Barium inhibits mSlo3 outside the cell by interacting with the selectivity filter, whereas quinine and quinidine act from the inside, by binding in a hydrophobic pocket formed by the S6 segment of each subunit. Furthermore, we propose that the Slo3 channel activation gate lies deep within the pore between F304 in the S6 segment and the selectivity filter. © 2015 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of The British Pharmacological Society.

Investigating the activity of quinine analogues versus chloroquine resistant Plasmodium falciparum.

PubMed

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

2012-05-15

Plasmodium falciparum, the deadliest malarial parasite species, has developed resistance against nearly all man-made antimalarial drugs within the past century. However, quinine (QN), the first antimalarial drug, remains efficacious worldwide. Some chloroquine resistant (CQR) P. falciparum strains or isolates show mild cross resistance to QN, but many do not. Further optimization of QN may provide a well-tolerated therapy with improved activity versus CQR malaria. Thus, using the Heck reaction, we have pursued a structure-activity relationship study, including vinyl group modifications of QN. Certain derivatives show good antiplasmodial activity in QN-resistant and QN-sensitive strains, with lower IC(50) values relative to QN. Copyright © 2012 Elsevier Ltd. All rights reserved.

Ferrocene-chloroquine analogues as antimalarial agents: in vitro activity of ferrochloroquine against 103 Gabonese isolates of Plasmodium falciparum.

PubMed

Pradines, B; Fusai, T; Daries, W; Laloge, V; Rogier, C; Millet, P; Panconi, E; Kombila, M; Parzy, D

2001-08-01

The in vitro activities of ferrochloroquine, chloroquine, quinine, mefloquine, halofantrine, amodiaquine, primaquine, atovaquone and artesunate were evaluated against Plasmodium falciparum isolates from children with uncomplicated malaria from Libreville (Gabon), using an isotopic, micro, drug susceptibility test. The IC(50) values for ferrochloroquine were in the range 0.43-30.9 nM and the geometric mean IC(50) for the 103 isolates was 10.8 nM (95% CI 8.6-13.5 nM), while the geometric means for chloroquine, quinine, mefloquine, amodiaquine and primaquine were 370 nM, 341 nM, 8.3 nM, 18.1 nM and 7.6 microM, respectively. Ferrochloroquine was active against P. falciparum isolates, 95% of which showed in vitro resistance to chloroquine. Weak positive significant correlations were observed between the responses to ferrochloroquine and that to chloroquine, amodiaquine and quinine, but too low to suggest cross-resistance. There was no significant correlation between the response to ferrochloroquine and those to mefloquine, halofantrine, primaquine, atovaquone or artesunate. Ferrochloroquine may be an important alternative drug for the treatment of chloroquine-resistant malaria.

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

PubMed Central

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

2010-01-01

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

Development, validation and utility of an in vitro technique for assessment of potential clinical drug-drug interactions involving P-glycoprotein.

PubMed

Keogh, John P; Kunta, Jeevan R

2006-04-01

Regulatory interest is increasing for drug transporters generally and P-glycoprotein (Pgp) in particular, primarily in the area of drug-drug interactions. To aid in both identifying and discharging the potential liabilities associated with drug-transporter interactions, the pharmaceutical industry has a growing requirement for routine and robust non-clinical assays. An assay was designed, optimised and validated to determine the in vitro inhibitory potency of new chemical entities (NCEs) towards human Pgp-mediated transport. [3H]-Digoxin was established as a suitable probe substrate by investigating its characteristics in the in vitro system (MDCKII-MDR1 cells grown in 24-multiwell inserts). The inhibitory potencies (apparent IC50) of known Pgp inhibitors astemizole, GF120918, ketoconazole, itraconazole, quinidine, verapamil and quinine were determined over at least a 1000-fold concentration range. Validation was carried out using manual and automatic techniques. [3H]-Digoxin was found to be stable and have good mass balance in the system. In contrast to [A-->B] transport, [3H]-digoxin [B-->A] transport rates were readily measured with good reproducibility. There was no evidence of saturation of transport up to 10 microM digoxin and 30 nM digoxin was selected for routine assay use, reflecting clinical therapeutic concentrations. IC50 values ranged over approximately 100-fold with excellent reproducibility. Results from manual and automated versions were in close agreement. This method is suitable for routine use to assess the in vitro inhibitory potency of NCEs on Pgp-mediated digoxin transport. Comparison of IC50 values against clinical interaction profiles for the probe inhibitors indicated the in vitro assay is predictive of clinical digoxin-drug interactions mediated via Pgp.

Use of refractometry and colorimetry as field methods to rapidly assess antimalarial drug quality.

PubMed

Green, Michael D; Nettey, Henry; Villalva Rojas, Ofelia; Pamanivong, Chansapha; Khounsaknalath, Lamphet; Grande Ortiz, Miguel; Newton, Paul N; Fernández, Facundo M; Vongsack, Latsamy; Manolin, Ot

2007-01-04

The proliferation of counterfeit and poor-quality drugs is a major public health problem; especially in developing countries lacking adequate resources to effectively monitor their prevalence. Simple and affordable field methods provide a practical means of rapidly monitoring drug quality in circumstances where more advanced techniques are not available. Therefore, we have evaluated refractometry, colorimetry and a technique combining both processes as simple and accurate field assays to rapidly test the quality of the commonly available antimalarial drugs; artesunate, chloroquine, quinine, and sulfadoxine. Method bias, sensitivity, specificity and accuracy relative to high-performance liquid chromatographic (HPLC) analysis of drugs collected in the Lao PDR were assessed for each technique. The HPLC method for each drug was evaluated in terms of assay variability and accuracy. The accuracy of the combined method ranged from 0.96 to 1.00 for artesunate tablets, chloroquine injectables, quinine capsules, and sulfadoxine tablets while the accuracy was 0.78 for enterically coated chloroquine tablets. These techniques provide a generally accurate, yet simple and affordable means to assess drug quality in resource-poor settings.

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’s sensitivity to this antimalarial. These insights provide a foundation for understanding clinically-relevant observations of inverse drug susceptibilities in the malaria parasite. PMID:27441371

Cost-effectiveness of parenteral artesunate for treating children with severe malaria in sub-Saharan Africa

PubMed Central

Riewpaiboon, Arthorn; Dondorp, Arjen M; von Seidlein, Lorenz; Mokuolu, Olugbenga A; Nansumba, Margaret; Gesase, Samwel; Kent, Alison; Mtove, George; Olaosebikan, Rasaq; Ngum, Wirichada Pan; Fanello, Caterina I; Hendriksen, Ilse; Day, Nicholas PJ; White, Nicholas J; Yeung, Shunmay

2011-01-01

Abstract Objective To explore the cost-effectiveness of parenteral artesunate for the treatment of severe malaria in children and its potential impact on hospital budgets. Methods The costs of inpatient care of children with severe malaria were assessed in four of the 11 sites included in the African Quinine Artesunate Malaria Treatment trial, conducted with over 5400 children. The drugs, laboratory tests and intravenous fluids provided to 2300 patients from admission to discharge were recorded, as was the length of inpatient stay, to calculate the cost of inpatient care. The data were matched with pooled clinical outcomes and entered into a decision model to calculate the cost per disability-adjusted life year (DALY) averted and the cost per death averted. Findings The mean cost of treating severe malaria patients was similar in the two study groups: 63.5 United States dollars (US$) (95% confidence interval, CI: 61.7–65.2) in the quinine arm and US$ 66.5 (95% CI: 63.7–69.2) in the artesunate arm. Children treated with artesunate had 22.5% lower mortality than those treated with quinine and the same rate of neurological sequelae: (artesunate arm: 2.3 DALYs per patient; quinine arm: 3.0 DALYs per patient). Compared with quinine as a baseline, artesunate showed an incremental cost per DALY averted and an incremental cost per death averted of US$ 3.8 and US$ 123, respectively. Conclusion Artesunate is a highly cost-effective and affordable alternative to quinine for treating children with severe malaria. The budgetary implications of adopting artesunate for routine use in hospital-based care are negligible. PMID:21734764

D-Serine and D-Cycloserine Reduce Compulsive Alcohol Intake in Rats

PubMed Central

Seif, Taban; Simms, Jeffrey A; Lei, Kelly; Wegner, Scott; Bonci, Antonello; Messing, Robert O; Hopf, F Woodward

2015-01-01

There is considerable interest in NMDAR modulators to enhance memory and treat neuropsychiatric disorders such as addiction, depression, and schizophrenia. D-serine and D-cycloserine, the NMDAR activators at the glycine site, are of particular interest because they have been used in humans without serious adverse effects. Interestingly, D-serine also inhibits some NMDARs active at hyperpolarized potentials (HA-NMDARs), and we previously found that HA-NMDARs within the nucleus accumbens core (NAcore) are critical for promoting compulsion-like alcohol drinking, where rats consume alcohol despite pairing with an aversive stimulus such as quinine, a paradigm considered to model compulsive aspects of human alcohol use disorders (AUDs). Here, we examined the impact of D-serine and D-cycloserine on this aversion-resistant alcohol intake (that persists despite adulteration with quinine) and consumption of quinine-free alcohol. Systemic D-serine reduced aversion-resistant alcohol drinking, without altering consumption of quinine-free alcohol or saccharin with or without quinine. Importantly, D-serine within the NAcore but not the dorsolateral striatum also selectively reduced aversion-resistant alcohol drinking. In addition, D-serine inhibited EPSCs evoked at −70 mV in vitro by optogenetic stimulation of mPFC–NAcore terminals in alcohol-drinking rats, similar to reported effects of the NMDAR blocker AP5. Further, D-serine preexposure occluded AP5 inhibition of mPFC-evoked EPSCs, suggesting that D-serine reduced EPSCs by inhibiting HA-NMDARs. Systemic D-cycloserine also selectively reduced intake of quinine-adulterated alcohol, and D-cycloserine inhibited NAcore HA-NMDARs in vitro. Our results indicate that HA-NMDAR modulators can reduce aversion-resistant alcohol drinking, and support testing of D-serine and D-cycloserine as immediately accessible, FDA-approved drugs to treat AUDs. PMID:25801502

Case management of malaria in Swaziland, 2011-2015: on track for elimination?

PubMed

Dlamini, S V; Kosgei, R J; Mkhonta, N; Zulu, Z; Makadzange, K; Zhou, S; Owiti, P; Sikhondze, W; Namboze, J; Reid, A; Kunene, S

2018-04-25

Objective: To assess adherence to malaria diagnosis and treatment guidelines (2010 and 2014) in all health care facilities in Swaziland between 2011 and 2015. Methods: This was a cross-sectional descriptive study involving all health care facilities that diagnosed and managed malaria cases in Swaziland. Patients' age, sex, diagnosis method and type of treatment were analysed. Results: Of 1981 records for severe and uncomplicated malaria analysed, 56% of cases were uncomplicated and 14% had severe malaria. The type of malaria was not recorded for 30% of cases. Approximately 71% of cases were confirmed by rapid diagnostic tests (RDT) alone, 3% by microscopy alone and 26% by both RDT and microscopy. Of the uncomplicated cases, 93% were treated with artemether-lumefantrine (AL) alone, 5% with quinine alone and 2% with AL and quinine. Amongst the severe cases, 11% were treated with AL alone, 44% with quinine alone and 45% with AL and quinine. For severe malaria, clinics and health centres prescribed AL alone more often than hospitals (respectively 13%, 12% and 4%, P = 0.03). Conclusion: RDTs and/or microscopy results are used at all facilities to inform treatment. Poor recording of malaria type causes difficulties in assessing the prescription of antimalarial drugs.

Surveillance of in vivo resistance of Plasmodium falciparum to antimalarial drugs from 1992 to 1999 in Malabo (Equatorial Guinea).

PubMed

Roche, Jesús; Guerra-Neira, Ana; Raso, José; Benito, Agustîn

2003-05-01

From 1992-1999, we have assessed the therapeutic efficacy of three malaria treatment regimens (chloroquine 25 mg/kg over three days, pyrimethamine/sulfadoxine 1.25/25 mg/kg in one dose, and quinine 25-30 mg/kg daily in three oral doses over a four-, five-, or seven-day period) in 1,189 children under age 10 at Malabo Regional Hospital in Equatorial Guinea. Of those children, 958 were followed up clinically and parasitologically for 14 days. With chloroquine, the failure rate varied from 55% in 1996 to 40% in 1999; the early treatment failure rate increased progressively over the years, from 6% in 1992 to 30% in 1999. With pyrimethamine/sulfadoxine, the failure rate varied from 0% in 1996 to 16% in 1995. The short quinine treatment regimens used in 1992 and 1993 (4 and 5 days, respectively) resulted in significantly higher failure rates (19% and 22%, respectively) than the 7d regimen (3-5.5%). We conclude that: a) failure rates for chloroquine are in the change period (> 25%), and urgent action is needed; b) pyrimethamine/ sulfadoxine failure rates are in the alert period (6-15%), and surveillance must be continued; and c) quinine failure rates are in the grace period (< 6%), so quinine can be recommended.

Ototoxicity of salicylate, nonsteroidal antiinflammatory drugs, and quinine.

PubMed

Jung, T T; Rhee, C K; Lee, C S; Park, Y S; Choi, D C

1993-10-01

Salicylates and most NSAIDS in high doses cause mild to moderate temporary hearing loss, either flat or greater in the high frequencies. Hearing loss is accompanied by tinnitus and suprathreshold changes. Salicylates may or may not exacerbate hearing loss and cochlear damage induced by noise. The mechanism of salicylate ototoxicity seems to be multifactorial. Morphologic studies suggest that no permanent cochlear damage occurs with salicylate ototoxicity. Electrophysiologic, morphologic, and in vitro data conclusively demonstrate that salicylate affects outer hair cells. In addition, salicylates appear to decrease cochlear blood flow. Salicylates and NSAIDs inhibit PG-forming cyclooxygenase, and recent studies suggest that abnormal levels of arachidonic acid metabolites consisting of decreased PGs and increased LTs may mediate salicylate ototoxicity. As with salicylate, quinine ototoxicity appears to be multifactorial in origin. The mechanism includes vasoconstriction and decreases in cochlear blood flow, as measured by laser Doppler flowmetry, motion photographic studies, and histologic studies. Reversible alterations of outer hair cells also appear to play an important role, as demonstrated by histology, electron microscopy, isolated hair cell studies, and cochlear potential evaluations. Unlike with salicylate, however, the role of prostaglandins in quinine ototoxicity has not been clearly demonstrated. Also, one of quinine's principal actions, antagonism of calcium-dependent potassium channels, has yet to be investigated for its potential role in ototoxicity.

A systematic review of the safety and efficacy of artemether-lumefantrine against uncomplicated Plasmodium falciparum malaria during pregnancy.

PubMed

Manyando, Christine; Kayentao, Kassoum; D'Alessandro, Umberto; Okafor, Henrietta U; Juma, Elizabeth; Hamed, Kamal

2012-05-01

Malaria during pregnancy, particularly Plasmodium falciparum malaria, has been linked to increased morbidity and mortality, which must be reduced by both preventive measures and effective case management. The World Health Organization (WHO) recommends artemisinin-based combination therapy (ACT) to treat uncomplicated falciparum malaria during the second and third trimesters of pregnancy, and quinine plus clindamycin during the first trimester. However, the national policies of many African countries currently recommend quinine throughout pregnancy. Therefore, the aim of this article is to provide a summary of the available data on the safety and efficacy of artemether-lumefantrine (AL) in pregnancy. An English-language search identified 16 publications from 1989 to October 2011 with reports of artemether or AL exposure in pregnancy, including randomized clinical trials, observational studies and systematic reviews. Overall, there were 1,103 reports of AL use in pregnant women: 890 second/third trimester exposures; 212 first trimester exposures; and one case where the trimester of exposure was not reported. In the second and third trimesters, AL was not associated with increased adverse pregnancy outcomes as compared with quinine or sulphadoxine-pyrimethamine, showed improved tolerability relative to quinine, and its efficacy was non-inferior to quinine. There is evidence to suggest that the pharmacokinetics of anti-malarial drugs may change in pregnancy, although the impact on efficacy and safety needs to be studied further, especially since the majority of studies report high cure rates and adequate tolerability. As there are fewer reports of AL safety in the first trimester, additional data are required to assess the potential to use AL in the first trimester. Though the available safety and efficacy data support the use of AL in the second and third trimesters, there is still a need for further information. These findings reinforce the WHO recommendation to treat uncomplicated falciparum malaria with quinine plus clindamycin in early pregnancy and ACT in later pregnancy.

Rapid analysis of Δ-9-tetrahydrocannabinol in hair using direct analysis in real time ambient ionization orbitrap mass spectrometry.

PubMed

Duvivier, Wilco F; van Beek, Teris A; Pennings, Ed J M; Nielen, Michel W F

2014-04-15

Forensic hair analysis methods are laborious, time-consuming and provide only a rough retrospective estimate of the time of drug intake. Recently, hair imaging methods using matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) were reported, but these methods require the application of MALDI matrix and are performed under vacuum. Direct analysis of entire locks of hair without any sample pretreatment and with improved spatial resolution would thus address a need. Hair samples were attached to stainless steel mesh screens and scanned in the X-direction using direct analysis in real time (DART) ambient ionization orbitrap MS. The DART gas temperature and the accuracy of the probed hair zone were optimized using Δ-9-tetrahydrocannabinol (THC) as a model compound. Since external contamination is a major issue in forensic hair analysis, sub-samples were measured before and after dichloromethane decontamination. The relative intensity of the THC signal in spiked blank hair versus that of quinine as the internal standard showed good reproducibility (26% RSD) and linearity of the method (R(2)  = 0.991). With the DART hair scan THC could be detected in hair samples from different chronic cannabis users. The presence of THC was confirmed by quantitative liquid chromatography/tandem mass spectrometry. Zones with different THC content could be clearly distinguished, indicating that the method might be used for retrospective timeline assessments. Detection of THC in decontaminated drug user hair showed that the DART hair scan not only probes THC on the surface of hair, but penetrates deeply enough to measure incorporated THC. A new approach in forensic hair analysis has been developed by probing complete locks of hair using DART-MS. Longitudinal scanning enables detection of incorporated compounds and can be used as pre-screening for THC without sample preparation. The method could also be adjusted for the analysis of other drugs of abuse. Copyright © 2014 John Wiley & Sons, Ltd.

[Resistance to the antimalarial drugs].

PubMed

Venanzi, E; López-Vélez, R

2016-09-01

Malaria is one of the most widespread infectious diseases around the world with 214 million cases and 438,000 deaths in 2015. In the early twentieth century it was described for the first time the resistance to quinine and, since then, drug resistance to antimalarial drugs has spread up to represent a global challenge in the fight and control of malaria. Understanding the mechanisms, geography and monitoring tools that we can act against resistance to antimalarial drugs is critical to prevent its expansion.

21 CFR 310.546 - Drug products containing active ingredients offered over-the-counter (OTC) for the treatment and...

Code of Federal Regulations, 2010 CFR

2010-04-01

.... Quinine sulfate may cause unpredictable serious and life-threatening hypersensitivity reactions requiring... commerce that is not in compliance with this section is subject to regulatory action. [59 FR 43252, Aug. 22...

[Comparative observation on inhibition of hemozoin formation and their in vitro and in vivo anti-schistosome activity displayed by 7 antimalarial drugs].

PubMed

Xue, Jian; Jiang, Bin; Liu, Cong-Shan; Sun, Jun; Xiao, Shu-Hua

2013-06-01

To observe and compare the inhibition of hemozoin formation and the in vitro as well as in vivo antischistosomal activity induced by seven antimalarial drugs. Inhibition of hemozoin formation displayed by chloroquine phosphate, quinine hydrochloride, quinidine, mefloquine hydrochloride, pyronaridine phosphate and lumefantrine at 25 micromol/L, and artemether at 100 micromol/L was performed by assay of inhibition of beta-hematin formation in 1 mol/L sodium acetate buffers containing hematin with various pH of 4.0, 4.2, 4.4, 4.6, 4.8, and 5.0. In in vitro antischistosomal study, the medium of RPMI 1640 supplemented by 10% calf serum was used to maintain the adult Schistosoma japonicum, and the 50% and 95% lethal concentrations (LC50 and LC95) to kill the adult worms of each drug were then determined. Meanwhile, the interaction of quinine, pyronaridine and chloroquine combined with hemin against adult schistosomes was also undertaken. As to in vivo test, the efficacy of seven antimalarial drugs administered orally or intraperitoneally to mice infected with adult schistosomes was observed. In the acidic acetate-hematin solution, 25 micromol/L pyronaridine showed significant inhibition of beta-hematin formation at pH 4.4-5.0 with inhibition rates of 81.3%-97.0%. At pH 4.6, the inhibition rates of beta-hematin formation in acetate-hematin solution induced by mefloquine, chloroquine or quinine at concentration of 25 beta mol/L were 79.7%, 72.8% or 65.8%, respectively, and the beta-hematin formation was continually inhibited by these 3 antimalarial drugs at pH 4.8 and 5.0 with inhibition rates of 83.1%-90.6%, 41.9%-49.0% or 53.2-62.0%. The inhibition rates of beta-hematin formation at pH 4.6 and 4.8-5.0 induced by lumefantrine 25 micromol/L were 74.3% and 40.4%-40.5%, respectively. While under the same concentration of quinidine, 53.4% and 50.9% inhibition rates of beta-hematin formation were observed at pH 4.8 and 5.0. As to artemether, higher concentration of 100 micromol/L only showed light inhibition of beta-hematin formation at pH 4.4-4.8 with inhibition rates of 16.6%-25.0%. As regard to in vitro test, the LC50 and LC95 of mefloquine, pyronaridine, quinine and quinidine were 4.93 and 6.123 microg/ml, 37.278 and 75.703 microg/ml, 93.688 and 134.578 microg/ml, as well as 101.534 and 129.957 microg/ml, respectively. When adult schistosomes were exposed to the medium containing chloroquine, lumefantrine or artemether at higher concentrations of 100 or 120 microg/ml for 72 h, no or only individual worms died. Hence the LC50 and LC95 of these 3 drugs could not be determined. In other in vitro test, adult schistosomes exposed to quinine 50 micromol/L (20 microg/ml) in combination with 153.4 micromol/L (100 microg/ml) hemin, all worms died within 72 h post incubation. While the worms exposed to 50 micromol/L (26 microg/ml) chloroquine combined with the same concentration of hemin, only 18.8%(3/16) of worm died at 72 h post exposure. Unexpectedly, in schistosomes exposed to pyronaridine at a toxic concentrations of 50 micromol/L (46 microg/ml) in combination with 153.4 mol/L (100 microg/ml) hemin for 72 h, all of the worms were protected from the toxic action induced by pyronaridine, which revealed in normal motor activity and appearance of morphology in majority of the worms. In in vivo test, mice infected with adult schistosomes were treated orally with chloroquine, pyronaridine or lumefantrine at a daily dose of 400 mg/kg for 3 days, or intraperitoneally with chloroquine or pyronaridine at a daily dose of 100 mg/kg for 2 or 3 days, no apparent efficacy was seen. When mefloquine, quinine, quinidine or artemether were administered orally to infected mice at a single dose of 400 mg/kg or 200 mg/kg (mefloquine), all groups of mice treated showed moderate or higher efficacy with worm burden reductions of 61.1%-98.1%. Among the seven antimalarial drugs tested, their inhibitions of hemozoin (beta-hematin) exhibit no definite correlation to their in vitro and in vivo antischistosomal activity. Quinine in combination with hemin shows synergistic effect against schistosomes in vitro. While antagonist effect is observed in pyronaridine combined with hemin.

21 CFR 310.546 - Drug products containing active ingredients offered over-the-counter (OTC) for the treatment and...

Code of Federal Regulations, 2011 CFR

2011-04-01

... life and beyond with no regular pattern concerning time or severity. There is a lack of adequate data to establish general recognition of the safety and effectiveness of quinine sulfate, vitamin E, or...

Effect of cranberry dietary supplements with different brands on human CYP3A4 enzyme

PubMed Central

Wanwimolruk, Sompon; Prachayasittikul, Supaluk; Prachayasittikul, Virapong; Bernichi, Bouchra

2012-01-01

The use of dietary supplements has increased dramatically, making drug interactions with those supplements a major concern. Because dietary supplements are not subject to the same regulations as prescription drugs, we hypothesize that the content of their active ingredients may vary among manufacturers, potentially causing a large variation in therapeutic outcome. The current study aimed to test this hypothesis on commonly used cranberry dietary supplements. Activity of human CYP3A4 enzyme was used as a parameter to determine the effect of cranberry supplement from nine manufacturers. The content of a cranberry product, equivalent to one capsule, was extracted with methanol. Aliquots of the extract were tested for their ability to inhibit the metabolism of the human CYP3A4 substrate quinine, using an in vitro liver microsomal technique. Human liver microsomes and quinine were incubated with or without (i.e. as control) cranberry extract. Formation of quinine's metabolite 3-hydroxyquinine, generated by the CYP3A4-mediated reaction was measured by a HPLC method. Of nine cranberry products tested, eight products had little or no effect but only one brand (Nature's Herbs 600 mg) caused very strong inhibition (67.2 %) of CYP3A4. The reason for this inhibition is unknown. The effect of cranberry was varied and ranged from 4.4 % activation by Ride Aid 800 mg to 67.2 % inhibition by Nature's Herbs 600 mg. Lack of effect on human CYP3A4 activity suggests that use of cranberry dietary supplement is unlikely to cause significant interactions with drugs metabolized by CYP3A4. PMID:27366135

A single alcohol drinking session is sufficient to enable subsequent aversion-resistant consumption in mice

PubMed Central

Lei, Kelly; Wegner, Scott A.; Yu, Ji-Hwan; Simms, Jeffrey A.; Hopf, F. Woodward

2016-01-01

Addiction is mediated in large part by pathological motivation for rewarding, addictive substances, and alcohol-use disorders (AUDs) continue to extract a very high physical and economic toll on society. Compulsive alcohol drinking, where intake continues despite negative consequences, is considered a particular obstacle during treatment of AUDs. Aversion-resistant drives for alcohol have been modeled in rodents, where animals continue to consume even when alcohol is adulterated with the bitter tastant quinine, or is paired with another aversive consequence. Here, we describe a two-bottle choice paradigm where C57BL/6 mice first had 24-h access to 15% alcohol or water. Afterward, they drank quinine-free alcohol (alcohol-only) or alcohol with quinine (100 μM), in a limited daily access (LDA) two-bottle-choice paradigm (2 h/day, 5 days/week, starting 3 h into the dark cycle), and achieved nearly binge-level blood alcohol concentrations. Interestingly, a single, initial 24-h experience with alcohol-only enhanced subsequent quinine-resistant drinking. In contrast, mice that drank alcohol–quinine in the 24-h session showed significantly reduced alcohol–quinine intake and preference during the subsequent LDA sessions, relative to mice that drank alcohol-only in the initial 24-h session and alcohol–quinine in LDA sessions. Thus, mice could find the concentration of quinine we used aversive, but were able to disregard the quinine after a single alcohol-only drinking session. Finally, mice had low intake and preference for quinine in water, both before and after weeks of alcohol-drinking sessions, suggesting that quinine resistance was not a consequence of increased quinine preference after weeks of drinking of alcohol–quinine. Together, we demonstrate that a single alcohol-only session was sufficient to enable subsequent aversion-resistant consumption in C57BL/6 mice, which did not reflect changes in quinine taste palatability. Given the rapid development of quinine-resistant alcohol drinking patterns, this model provides a simple, quick, and robust method for uncovering the mechanisms that promote aversion-resistant consumption. PMID:27788780

A single alcohol drinking session is sufficient to enable subsequent aversion-resistant consumption in mice.

PubMed

Lei, Kelly; Wegner, Scott A; Yu, Ji-Hwan; Simms, Jeffrey A; Hopf, F Woodward

2016-09-01

Addiction is mediated in large part by pathological motivation for rewarding, addictive substances, and alcohol-use disorders (AUDs) continue to extract a very high physical and economic toll on society. Compulsive alcohol drinking, where intake continues despite negative consequences, is considered a particular obstacle during treatment of AUDs. Aversion-resistant drives for alcohol have been modeled in rodents, where animals continue to consume even when alcohol is adulterated with the bitter tastant quinine, or is paired with another aversive consequence. Here, we describe a two-bottle choice paradigm where C57BL/6 mice first had 24-h access to 15% alcohol or water. Afterward, they drank quinine-free alcohol (alcohol-only) or alcohol with quinine (100 μM), in a limited daily access (LDA) two-bottle-choice paradigm (2 h/day, 5 days/week, starting 3 h into the dark cycle), and achieved nearly binge-level blood alcohol concentrations. Interestingly, a single, initial 24-h experience with alcohol-only enhanced subsequent quinine-resistant drinking. In contrast, mice that drank alcohol-quinine in the 24-h session showed significantly reduced alcohol-quinine intake and preference during the subsequent LDA sessions, relative to mice that drank alcohol-only in the initial 24-h session and alcohol-quinine in LDA sessions. Thus, mice could find the concentration of quinine we used aversive, but were able to disregard the quinine after a single alcohol-only drinking session. Finally, mice had low intake and preference for quinine in water, both before and after weeks of alcohol-drinking sessions, suggesting that quinine resistance was not a consequence of increased quinine preference after weeks of drinking of alcohol-quinine. Together, we demonstrate that a single alcohol-only session was sufficient to enable subsequent aversion-resistant consumption in C57BL/6 mice, which did not reflect changes in quinine taste palatability. Given the rapid development of quinine-resistant alcohol drinking patterns, this model provides a simple, quick, and robust method for uncovering the mechanisms that promote aversion-resistant consumption. Copyright © 2016 Elsevier Inc. All rights reserved.

Quinine-induced tinnitus in rats.

PubMed

Jastreboff, P J; Brennan, J F; Sasaki, C T

1991-10-01

Quinine ingestion reportedly induces tinnitus in humans. To expand our salicylate-based animal model of tinnitus, a series of conditioned suppression experiments was performed on 54 male-pigmented rats using quinine injections to induce tinnitus. Quinine induced changes in both the extent of suppression and recovery of licking, which followed a pattern that paralleled those produced after salicylate injections, and which may be interpreted as the result of tinnitus perception in animals. These changes depended on the dose and time schedule of quinine administration. Additionally, the calcium channel blocker, nimodipine, abolished the quinine-induced effect in a dose-dependent manner.

Medications and Characteristics of Drugs Causing Ototoxicity.

ERIC Educational Resources Information Center

Pappas, Dennis G.; Pappas, Dennis G., Jr.

1997-01-01

This article discusses medications which, by entering the confines of the inner ear, can be toxic and destroy the structures of hearing. Medications that may produce ototoxicity are explained and include aminoglycosides, quinine, salycilates, and diuretics. Factors that should be considered relating to ototoxicity are provided. Contains…

Selection and clonal propagation of high artemisinin genotypes of Artemisia annua

USDA-ARS?s Scientific Manuscript database

Artemisinin, produced in the glandular trichomes of Artemisia annua L. is a vital antimalarial drug effective against Plasmodium falciparum resistant to quinine-derived medicines. Although work has progressed on the semi-synthetic production of artemisinin, field production of A. annua remains the p...

Substandard Antimalarials Available in Afghanistan: A Case for Assessing the Quality of Drugs in Resource Poor Settings

PubMed Central

Lalani, Mirza; Kaur, Harparkash; Mohammed, Nader; Mailk, Naiela; van Wyk, Albert; Jan, Sakhi; Kakar, Rishtya Meena; Mojadidi, Mohammed Khalid; Leslie, Toby

2015-01-01

Good-quality antimalarials are crucial for the effective treatment and control of malaria. A total of 7,740 individual and packaged tablets, ampoules, and syrups were obtained from 60 randomly selected public (N = 35) and private outlets (N = 25) in Afghanistan. Of these, 134 samples were screened using the Global Pharma Health Fund (GPHF) MiniLab® in Kabul with 33/126 (26%) samples failing the MiniLab® disintegration test. The quality of a subsample (N = 37) of cholorquine, quinine, and sulfadoxine/pyrimethamine tablets was assessed by in vitro dissolution testing following U.S. Pharmacopeia (USP) monographs at a bioanalytical laboratory in London, United Kingdom. Overall, 12/32 (32%) samples of sulfadoxine/pyrimethamine and quinine were found not to comply with the USP tolerance limits. Substandard antimalarials were available in Afghanistan demonstrating that continuous monitoring of drug quality is warranted. However, in Afghanistan as in many low-income countries, capacity to determine and monitor drug quality using methods such as dissolution testing needs to be established to empower national authorities to take appropriate action in setting up legislation and regulation. PMID:25897070

Effect of quinine on the release of catecholamines from bovine cultured chromaffin cells.

PubMed Central

Tang, R.; Novas, M. L.; Glavinovic, M. I.; Trifaró, J. M.

1990-01-01

1. The effects of quinine on catecholamine release from cultured bovine chromaffin cells were studied. 2. Quinine (25-400 microM) produced a dose-related inhibition of catecholamine release in response to depolarizing concentrations (12.5-50 mM) of K+. 3. The inhibition of the secretory response to high K+ produced by quinine decreased with the increase in the extracellular concentration of Ca2+. 4. Stimulation of cultured chromaffin cells with 50 mM K+ produced a significant increase in Ca2+ influx. In the presence of 100 microM quinine a 54% inhibition of the K(+)-induced Ca2+ influx was observed. 5. Quinine treatment of chromaffin cell cultures produced a small but significant decrease in membrane resting potential and a less pronounced depolarization in response to 50 mM K+. 6. The results suggest that the inhibition of the K(+)-evoked release of catecholamines produced by quinine is at least partly due to a decrease in Ca2+ influx. Ca2+ influx is lower because quinine reduces the sensitivity of the membrane potential to changes in extracellular K+ but direct effects of quinine on Ca2+ channels cannot be excluded. PMID:2158846

Quinine, Malaria, and the Cinchona Bureau: Marketing Practices and Knowledge Circulation in a Dutch Transoceanic Cinchona–Quinine Enterprise (1920s–30s)

PubMed Central

Roersch Van Der Hoogte, Arjo; Pieters, Toine

2016-01-01

In this study, we will show how a Dutch pharmaceutical consortium of cinchona producers and quinine manufacturers was able to capitalize on one of the first international public health campaigns to fight malaria, thereby promoting the sale of quinine, an antimalarial medicine. During the 1920s and 1930s, the international markets for quinine were controlled by this Dutch consortium, which was a transoceanic cinchona–quinine enterprise centered in the Cinchona Bureau in the Netherlands. We will argue that during the interwar period, the Cinchona Bureau became the decision-making center of this Dutch cinchona–quinine pharmaceutical enterprise and monopolized the production and trade of an essential medicine. In addition, we will argue that capitalizing on the international public health campaign in the fight against malaria by the Dutch cinchona–quinine enterprise via the Cinchona Bureau can be regarded as an early example of corporate colonization of public health by a private pharmaceutical consortium. Furthermore, we will show how commercial interests prevailed over scientific interests within the Dutch cinchona–quinine consortium, thus interfering with and ultimately curtailing the transoceanic circulation of knowledge in the Dutch empire. PMID:26054829

In vitro action of antiparasitic drugs, especially artesunate, against Toxoplasma gondii.

PubMed

Gomes, Thaís Cobellis; de Andrade Júnior, Heitor Franco; Lescano, Susana Angélica Zevallos; Amato-Neto, Vicente

2012-01-01

Toxoplasmosis is usually a benign infection, except in the event of ocular, central nervous system (CNS), or congenital disease and particularly when the patient is immunocompromised. Treatment consists of drugs that frequently cause adverse effects; thus, newer, more effective drugs are needed. In this study, the possible activity of artesunate, a drug successfully being used for the treatment of malaria, on Toxoplasma gondii growth in cell culture is evaluated and compared with the action of drugs that are already being used against this parasite. LLC-MK2 cells were cultivated in RPMI medium, kept in disposable plastic bottles, and incubated at 36ºC with 5% CO2. Tachyzoites of the RH strain were used. The following drugs were tested: artesunate, cotrimoxazole, pentamidine, pyrimethamine, quinine, and trimethoprim. The effects of these drugs on tachyzoites and LLC-MK2 cells were analyzed using nonlinear regression analysis with Prism 3.0 software. Artesunate showed a mean tachyzoite inhibitory concentration (IC50) of 0.075µM and an LLC MK2 toxicity of 2.003µM. Pyrimethamine was effective at an IC50 of 0.482µM and a toxicity of 11.178µM. Trimethoprim alone was effective against the in vitro parasite. Cotrimoxazole also was effective against the parasite but at higher concentrations than those observed for artesunate and pyrimethamine. Pentamidine and quinine had no inhibitory effect over tachyzoites. Artesunate is proven in vitro to be a useful alternative for the treatment of toxoplasmosis, implying a subsequent in vivo effect and suggesting the mechanism of this drug against the parasite.

Quinine-induced hearing loss in the guinea pig is not affected by the Ca2+ channel antagonist verapamil.

PubMed

Jäger, W; Idrizbegovic, E; Karlsson, K K; Alván, G

1997-01-01

It is well documented that quinine induces reversible hearing loss and tinnitus. The purpose in this study was to induce a quinine hearing loss and to investigate if verapamil, a Ca2+ channel antagonist of L-type might affect the response. Pigmented guinea pigs (n = 24) were anaesthetized by atropine. Hypnorm and midazolam but permitting spontaneous respiration. An electrode of platinum was placed on the round window and short (10 msec) tone pulses at 8 kHz were presented to the external ear. A typical deflection of the N1-wave was determined as the hearing threshold. Quinine hydrochloride 40 mg/kg and verapamil 1 mg/kg were given intravenously. Quinine induced a significant and reversible hearing loss (mean 16 dB). This hearing loss was not at all affected by verapamil given before or after quinine. Verapamil often caused acute cardiac arrest and particularly the combination verapamil followed by quinine-induced death to the animal. We conclude that verapamil and quinine had no in vivo interaction with regard to the hearing ability.

Resolution pattern of jaundice among children presenting with severe malaria in rural South-West Nigeria.

PubMed

Osonuga, O A; Osonuga, A; Osonuga, A A; Osonuga, I O

2012-07-01

To compare the pattern of jaundice resolution among children with severe malaria treated with quinine and artemether. Thirty two children who fulfilled the inclusion criteria were recruited for the study from two hospitals with intensive care facilities. They were divided into two groups; 'Q' and 'A', receiving quinine and artemether, respectively. Jaundice was assessed by clinical examination. Sixteen out of 32 children recruited (representing 50%) presented with jaundice on the day of recruitment. The mean age was (7.00°C2.56) years. On day 3, four patients in 'A' and six patients in 'Q' had jaundice. By day 7, no child had jaundice. The study has shown that both drugs resolve jaundice although artemether relatively resolves it faster by the third day.

Citric Acid and Quinine Share Perceived Chemosensory Features Making Oral Discrimination Difficult in C57BL/6J Mice

PubMed Central

Treesukosol, Yada; Mathes, Clare M.

2011-01-01

Evidence in the literature shows that in rodents, some taste-responsive neurons respond to both quinine and acid stimuli. Also, under certain circumstances, rodents display some degree of difficulty in discriminating quinine and acid stimuli. Here, C57BL/6J mice were trained and tested in a 2-response operant discrimination task. Mice had severe difficulty discriminating citric acid from quinine and 6-n-propylthiouracil (PROP) with performance slightly, but significantly, above chance. In contrast, mice were able to competently discriminate sucrose from citric acid, NaCl, quinine, and PROP. In another experiment, mice that were conditioned to avoid quinine by pairings with LiCl injections subsequently suppressed licking responses to quinine and citric acid but not to NaCl or sucrose in a brief-access test, relative to NaCl-injected control animals. However, mice that were conditioned to avoid citric acid did not display cross-generalization to quinine. These mice significantly suppressed licking only to citric acid, and to a much lesser extent NaCl, compared with controls. Collectively, the findings from these experiments suggest that in mice, citric acid and quinine share chemosensory features making discrimination difficult but are not perceptually identical. PMID:21421543

Quinine, Malaria, and the Cinchona Bureau: Marketing Practices and Knowledge Circulation in a Dutch Transoceanic Cinchona-Quinine Enterprise (1920s-30s).

PubMed

Van Der Hoogte, Arjo Roersch; Pieters, Toine

2016-04-01

In this study, we will show how a Dutch pharmaceutical consortium of cinchona producers and quinine manufacturers was able to capitalize on one of the first international public health campaigns to fight malaria, thereby promoting the sale of quinine, an antimalarial medicine. During the 1920s and 1930s, the international markets for quinine were controlled by this Dutch consortium, which was a transoceanic cinchona-quinine enterprise centered in the Cinchona Bureau in the Netherlands. We will argue that during the interwar period, the Cinchona Bureau became the decision-making center of this Dutch cinchona-quinine pharmaceutical enterprise and monopolized the production and trade of an essential medicine. In addition, we will argue that capitalizing on the international public health campaign in the fight against malaria by the Dutch cinchona-quinine enterprise via the Cinchona Bureau can be regarded as an early example of corporate colonization of public health by a private pharmaceutical consortium. Furthermore, we will show how commercial interests prevailed over scientific interests within the Dutch cinchona-quinine consortium, thus interfering with and ultimately curtailing the transoceanic circulation of knowledge in the Dutch empire. © The Author 2015. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Bitter tastant quinine modulates glucagon-like peptide-1 exocytosis from clonal GLUTag enteroendocrine L cells via actin reorganization.

PubMed

Harada, Kazuki; Sakaguchi, Hidekazu; Sada, Shoko; Ishida, Rika; Hayasaka, Yuki; Tsuboi, Takashi

2018-06-07

Enteroendocrine L cells in the gastrointestinal tract secrete glucagon-like peptide-1 (GLP-1), which plays an important role in glucose homeostasis. Here we investigated the effect of bitter tastant quinine on GLP-1 secretion using clonal GLUTag mouse enteroendocrine L cells. We found that GLUTag cells expressed putative quinine receptors at mRNA levels. Although application of quinine resulted in an increase of intracellular Ca 2+ levels, which was mediated by Ca 2+ release from the endoplasmic reticulum and Ca 2+ influx through voltage-sensitive Ca 2+ channels, quinine had little effect on GLP-1 secretion. Total internal reflection fluorescence microscopy and immunocytochemistry revealed that GLP-1-containing vesicles remained unfused with the plasma membrane and facilitated actin polymerization beneath the plasma membrane after application of quinine, respectively. Interestingly, application of forskolin together with quinine induced GLP-1 exocytosis from the cells. These results suggest that quinine does not induce GLP-1 secretion because it facilitates Ca 2+ increase and actin reorganization but not cAMP increase, and both Ca 2+ and cAMP are essential for GLP-1 secretion. Copyright © 2018 Elsevier Inc. All rights reserved.

Quinine-induced thrombocytopenia following intravenous use of heroin

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

Christie, D.J.; Walker, R.H.; Kolins, M.D.

1983-06-01

Profound thrombocytopenia developed in a 22-year-old man after intravenous use of heroin. A high-titer, quinine-dependent, platelet-specific antibody was detected in his serum using lysis of normal platelets labeled with chromium 51 and an electroimmunoassay for measurement of platelet-associated IgG. The antibody was specific for quinine and failed to react with platelets in the presence of quinidine hydrochloride or two structural analogues of heroin. Quinine, a common adulterant found in heroin, was detected in the patient's blood and urine. On the basis of these observations, the patient was judged to have quinine-induced immunologic thrombocytopenia. To our knowledge, this report is themore » first to confirm that quinine used as an adulterant can induce immunologic thrombocytopenia following an injection of heroin.« less

Resolution pattern of jaundice among children presenting with severe malaria in rural South-West Nigeria

PubMed Central

Osonuga, OA; Osonuga, A; Osonuga, AA; Osonuga, IO

2012-01-01

Objective To compare the pattern of jaundice resolution among children with severe malaria treated with quinine and artemether. Methods Thirty two children who fulfilled the inclusion criteria were recruited for the study from two hospitals with intensive care facilities. They were divided into two groups; ‘Q’ and ‘A’, receiving quinine and artemether, respectively. Jaundice was assessed by clinical examination. Results Sixteen out of 32 children recruited (representing 50%) presented with jaundice on the day of recruitment. The mean age was (7.00°C2.56) years. On day 3, four patients in ‘A’ and six patients in ‘Q’ had jaundice. By day 7, no child had jaundice. Conclusion The study has shown that both drugs resolve jaundice although artemether relatively resolves it faster by the third day. PMID:23569969

Modulating effects of plasma containing anti-malarial antibodies on in vitro anti-malarial drug susceptibility in Plasmodium falciparum.

PubMed

Monatrakul, Preeyaporn; Mungthin, Mathirut; Dondorp, Arjen M; Krudsood, Srivicha; Udomsangpetch, Rachanee; Wilairatana, Polrat; White, Nicholas J; Chotivanich, Kesinee

2010-11-16

The efficacy of anti-malarial drugs is determined by the level of parasite susceptibility, anti-malarial drug bioavailability and pharmacokinetics, and host factors including immunity. Host immunity improves the in vivo therapeutic efficacy of anti-malarial drugs, but the mechanism and magnitude of this effect has not been characterized. This study characterized the effects of 'immune' plasma to Plasmodium falciparumon the in vitro susceptibility of P. falciparum to anti-malarial drugs. Titres of antibodies against blood stage antigens (mainly the ring-infected erythrocyte surface antigen [RESA]) were measured in plasma samples obtained from Thai patients with acute falciparum malaria. 'Immune' plasma was selected and its effects on in vitro parasite growth and multiplication of the Thai P. falciparum laboratory strain TM267 were assessed by light microscopy. The in vitro susceptibility to quinine and artesunate was then determined in the presence and absence of 'immune' plasma using the 3H-hypoxanthine uptake inhibition method. Drug susceptibility was expressed as the concentrations causing 50% and 90% inhibition (IC50 and IC90), of 3H-hypoxanthine uptake. Incubation with 'immune' plasma reduced parasite maturation and decreased parasite multiplication in a dose dependent manner. 3H-hypoxanthine incorporation after incubation with 'immune' plasma was decreased significantly compared to controls (median [range]; 181.5 [0 to 3,269] cpm versus 1,222.5 [388 to 5,932] cpm) (p= 0.001). As a result 'immune' plasma reduced apparent susceptibility to quinine substantially; median (range) IC50 6.4 (0.5 to 23.8) ng/ml versus 221.5 (174.4 to 250.4) ng/ml (p = 0.02), and also had a borderline effect on artesunate susceptibility; IC50 0.2 (0.02 to 0.3) ng/ml versus 0.8 (0.2 to 2.3) ng/ml (p = 0.08). Effects were greatest at low concentrations, changing the shape of the concentration-effect relationship. IC90 values were not significantly affected; median (range) IC90 448.0 (65 to > 500) ng/ml versus 368.8 (261 to 501) ng/ml for quinine (p > 0.05) and 17.0 (0.1 to 29.5) ng/ml versus 7.6 (2.3 to 19.5) ng/ml for artesunate (p = 0.4). 'Immune' plasma containing anti-malarial antibodies inhibits parasite development and multiplication and increases apparent in vitro anti-malarial drug susceptibility of P. falciparum. The IC90 was much less affected than the IC50 measurement.

Intramuscular arteether for treating severe malaria.

PubMed

Afolabi, B B; Okoromah, C N

2004-10-18

Quinine and artemisinin drugs are used in severe malaria, but quinine resistance is increasing. Arteether is a recently developed artemisinin derivative that is oil soluble, has a long elimination half life, and is more stable than other derivatives. To compare intramuscular arteether with other antimalarial drugs to treat severe malaria. We searched the Cochrane Infectious Diseases Group Specialized Register (August 2004), CENTRAL (The Cochrane Library Issue 3, 2004), MEDLINE (1966 to August 2004), EMBASE (1980 to August 2004), U.S. National Library of Medicine (NLM) Gateway (1953 to 1965), Web Science Citation (1981 to August 2004), LILACS (August 2004), Google search engine (August 2004), conference proceedings, and reference lists. We also contacted researchers, organizations, and pharmaceutical companies to help identify trials. Randomized and quasi-randomized controlled trials of intramuscular arteether in adults and children with severe malaria. We independently assessed the methodological quality of the trials and extracted data, and analysed data using Review Manager 4.2. Two small trials (n = 194) met the inclusion criteria. Both trials compared arteether with quinine in children with cerebral malaria and reported on similar outcomes. There was no statistically significant difference in the number of deaths (relative risk 0.75, 95% confidence interval 0.43 to 1.30; n = 194, 2 trials), neurological complications (relative risk 1.18, 95% confidence interval 0.31 to 4.46; n = 58, 1 trial), or other outcomes including time to regain consciousness, parasite clearance time, and fever clearance time. The meta-analyses lack statistical power to detect important differences. More trials with a larger number of participants are needed before a firm conclusion about the efficacy and safety of arteether can be reached.

Synthesizing a nano-composite of BSA-capped Au nanoclusters/graphitic carbon nitride nanosheets as a new fluorescent probe for dopamine detection.

PubMed

Guo, Xinrong; Wu, Fangying; Ni, Yongnian; Kokot, Serge

2016-10-26

A strong red fluorescent nanocomposite, consisting of graphite-like carbon nitride nanosheets (g-C 3 N 4 NSs) and serum albumin-capped Au nanoclusters (AuNCs), was synthesized. Dopamine (DA) can quench the red fluorescence of the nanocomposite, based on the Forster resonance energy transfer (FRET) mechanism. In this quenching process, the energy is transferred from the fluorescent g-C 3 N 4 NSs-AuNCs to the oxidized DA quinine molecules (DA is easily oxidated to form DA quinine in air). The red fluorescence emission at 420 nm decreases dramatically and the quenching ratio (F 0 - F)/F 0 is linearly related to the concentration of DA in the range of 0.05-8.0 μmol L -1 with a detection limit of 0.018 μmol L -1  (S/N = 3). Additionally, this sensor has a potential of application to assay the DA in the real samples, such as human serum and human urine. Copyright © 2016 Elsevier B.V. All rights reserved.

Defining Surrogate Endpoints for Clinical Trials in Severe Falciparum Malaria

PubMed Central

Plewes, Katherine; Maude, Richard J.; Hanson, Josh; Herdman, M. Trent; Leopold, Stije J.; Ngernseng, Thatsanun; Charunwatthana, Prakaykaew; Phu, Nguyen Hoan; Ghose, Aniruddha; Hasan, M. Mahtab Uddin; Fanello, Caterina I.; Faiz, Md Abul; Hien, Tran Tinh; Day, Nicholas P. J.; White, Nicholas J.; Dondorp, Arjen M.

2017-01-01

Background Clinical trials in severe falciparum malaria require a large sample size to detect clinically meaningful differences in mortality. This means few interventions can be evaluated at any time. Using a validated surrogate endpoint for mortality would provide a useful alternative allowing a smaller sample size. Here we evaluate changes in coma score and plasma lactate as surrogate endpoints for mortality in severe falciparum malaria. Methods Three datasets of clinical studies in severe malaria were re-evaluated: studies from Chittagong, Bangladesh (adults), the African ‘AQUAMAT’ trial comparing artesunate and quinine (children), and the Vietnamese ‘AQ’ study (adults) comparing artemether with quinine. The absolute change, relative change, slope of the normalization over time, and time to normalization were derived from sequential measurements of plasma lactate and coma score, and validated for their use as surrogate endpoint, including the proportion of treatment effect on mortality explained (PTE) by these surrogate measures. Results Improvements in lactate concentration or coma scores over the first 24 hours of admission, were strongly prognostic for survival in all datasets. In hyperlactataemic patients in the AQ study (n = 173), lower mortality with artemether compared to quinine closely correlated with faster reduction in plasma lactate concentration, with a high PTE of the relative change in plasma lactate at 8 and 12 hours of 0.81 and 0.75, respectively. In paediatric patients enrolled in the ‘AQUAMAT’ study with cerebral malaria (n = 785), mortality was lower with artesunate compared to quinine, but this was not associated with faster coma recovery. Conclusions The relative changes in plasma lactate concentration assessed at 8 or 12 hours after admission are valid surrogate endpoints for severe malaria studies on antimalarial drugs or adjuvant treatments aiming at improving the microcirculation. Measures of coma recovery are not valid surrogate endpoints for mortality. PMID:28052109

Defining Surrogate Endpoints for Clinical Trials in Severe Falciparum Malaria.

PubMed

Jeeyapant, Atthanee; Kingston, Hugh W; Plewes, Katherine; Maude, Richard J; Hanson, Josh; Herdman, M Trent; Leopold, Stije J; Ngernseng, Thatsanun; Charunwatthana, Prakaykaew; Phu, Nguyen Hoan; Ghose, Aniruddha; Hasan, M Mahtab Uddin; Fanello, Caterina I; Faiz, Md Abul; Hien, Tran Tinh; Day, Nicholas P J; White, Nicholas J; Dondorp, Arjen M

2017-01-01

Clinical trials in severe falciparum malaria require a large sample size to detect clinically meaningful differences in mortality. This means few interventions can be evaluated at any time. Using a validated surrogate endpoint for mortality would provide a useful alternative allowing a smaller sample size. Here we evaluate changes in coma score and plasma lactate as surrogate endpoints for mortality in severe falciparum malaria. Three datasets of clinical studies in severe malaria were re-evaluated: studies from Chittagong, Bangladesh (adults), the African 'AQUAMAT' trial comparing artesunate and quinine (children), and the Vietnamese 'AQ' study (adults) comparing artemether with quinine. The absolute change, relative change, slope of the normalization over time, and time to normalization were derived from sequential measurements of plasma lactate and coma score, and validated for their use as surrogate endpoint, including the proportion of treatment effect on mortality explained (PTE) by these surrogate measures. Improvements in lactate concentration or coma scores over the first 24 hours of admission, were strongly prognostic for survival in all datasets. In hyperlactataemic patients in the AQ study (n = 173), lower mortality with artemether compared to quinine closely correlated with faster reduction in plasma lactate concentration, with a high PTE of the relative change in plasma lactate at 8 and 12 hours of 0.81 and 0.75, respectively. In paediatric patients enrolled in the 'AQUAMAT' study with cerebral malaria (n = 785), mortality was lower with artesunate compared to quinine, but this was not associated with faster coma recovery. The relative changes in plasma lactate concentration assessed at 8 or 12 hours after admission are valid surrogate endpoints for severe malaria studies on antimalarial drugs or adjuvant treatments aiming at improving the microcirculation. Measures of coma recovery are not valid surrogate endpoints for mortality.

FT-Raman study of quinine aqueous solutions with varying pH: 2D correlation study

NASA Astrophysics Data System (ADS)

Wesełucha-Birczyńska, Aleksandra

2007-01-01

Quinine (C 20H 24N 2O 2) is one of the best known, for its antimalarial activity, Cinchona alkaloid. In the current study 2D correlation method was applied to analyze FT-Raman spectra of quinine aqueous solutions with varying pH, which was regarded as an external perturbation. Protonation appears to be the main cause leading to the emergence of cross peaks in the synchronous and asynchronous correlation maps. One should know that protonation process is an important step associated with quinine antimalarial activity. Methoxy group manifests its presence by creation of the respective correlation peaks and seems to be significant for quinine mode of action.

The bite of Jesuits' bark.

PubMed

Balfour, A J

1989-07-01

Cinchonism is the well-known syndrome of quinine overdose involving disturbances of vision, hearing, and balance, which has occasional importance in aviation pathology, usually related to ingestion of tonic water. One study showed 100 mg of quinine taken in tonic water is sufficient to produce positional abnormalities of the electronystagmograph. Blood levels of quinine of about 0.2 mg.L-1 found at autopsy in pilots who died in aviation accidents in which positional cues seemed to be important suggest that quinine toxicity played a causative role.

Chemotherapy of Malaria

DTIC Science & Technology

1976-03-11

res:stant to drugs such as chloroquine and quinine, generally reccqnized sin.ce World War II as satisfactory antimalarial agents.. The urgent need for...Trypanosoma rhodesiense infections in mice. (3) structural analogues of compounds found active in our test system and representing several novel chemical...treatment or prevention of T. rhodesiense infections and; (3) structural analogues of compounds that have demonstrated activity in our screening

Quinine-induced disseminated intravascular coagulation.

PubMed

Spearing, R L; Hickton, C M; Sizeland, P; Hannah, A; Bailey, R R

Recurrent disseminated intravascular coagulation occurred in 3 women after ingestion of quinine tablets for cramp. All had circulating quinine-dependent antibodies to platelets and in 2 there was initial evidence of antibody consumption, with low titres that rose steeply over the next few days and remained high for many months.

Ethanol, saccharin, and quinine: early ontogeny of taste responsiveness and intake.

PubMed

Kozlov, Andrey P; Varlinskaya, Elena I; Spear, Norman E

2008-02-01

Rat pups demonstrate high levels of immediate acceptance of ethanol during the first 2 weeks of postnatal life. Given that the taste of ethanol is most likely perceived by infant rats as a combination of sweet and bitter, high intake of ethanol early in ontogeny may be associated with age-related enhanced responsiveness to the sweet component of ethanol taste, as well as with ontogenetic decreases in sensitivity to its bitter component. Therefore, the present study compared responsiveness to ethanol and solutions with bitter (quinine) and sweet (saccharin) taste in terms of intake and palatability across the first 2 weeks of postnatal life. Characteristic patterns of responsiveness to 10% (v/v) ethanol, 0.1% saccharin, 0.2% quinine, and water in terms of taste reactivity and fluid intake were assessed in rat pups tested on postnatal day (P) 4, 9, or 12 using a new technique of on-line monitoring of fluid flow through a two-channel intraoral cannula. Taste reactivity included analysis of ingestive and aversive responses following six intraoral infusions of the test fluids. This taste reactivity probe was followed by the intake test, in which animals were allowed to voluntarily ingest fluids from an intraoral cannula. Pups of all ages showed more appetitive responses to saccharin and ethanol than to water or quinine. No age-related differences were apparent in taste responsiveness to saccharin and ethanol. However, the age-related pattern of ethanol intake drastically differed from that of saccharin. Intake of saccharin increased from P4 to P9 and decreased substantially by P12, whereas intake of ethanol gradually increased from P4 to P12. Intake of ethanol was significantly lower than intake of saccharin on P9, whereas P12 pups took in more ethanol than saccharin. The findings of the present study indicate ontogenetic dissociations between taste reactivity to ethanol and saccharin and intake of these solutions, and suggest that high acceptance of ethanol early in ontogeny may not be associated with its orosensory properties but rather with the pharmacological effects of ethanol.

Chloroquine, quinine, procaine, quinidine, tricyclic antidepressants, and methylxanthines as prostaglandin agonists and antagonists.

PubMed

Manku, M S; Horrobin, D F

1976-11-20

Chloroquine, quanine, procaine, quinidine, clomipramine, theophylline, and caffeine have been shown to be strong prostaglandin antagonists and weak agonists. The antagonist effect is clearly demonstrable at concentrations reached in human plasma when the drugs are used therapeutically. This suggests that prostaglandins are important in several situations in which their role has hitherto been unsuspected. New approaches to the development of prostaglandin antagonists and new uses for established drugs are indicated. In a preliminary study chloroquine has been successfully used to close patent ductus arteriosus in three infants.

Elimination of quinine in two subjects after ingestion of tonic water : an exploratory study.

DOT National Transportation Integrated Search

1994-08-01

Biological specimens from 8 fatal aviation accidents out of 775 fatal aviation accidents analyzed in 1991 and 1992 were found to contain quinine. In one case, the investigators sought to identify the source of quinine found in the pilot. It was sugge...

Bioactivities examination of Cinchona leaves ethanol extracts

NASA Astrophysics Data System (ADS)

Artanti, Nina; Udin, Linar Z.; Hanafi, M.; Jamilah, Kurniasih, Ida Rahmi; Primahana, Gian; Anita, Yulia; Sundowo, Andini; Kandace, Yoice Sri

2017-01-01

Cinchona species especially the barks are commonly known for commercial production of quinine as antimalarial. Although it is also reported for treatment of depurative, whooping cough, influenza and dysentery. In this paper we reported in vitro examination of other bioactivities (antidiabetes, antioxidant and in vitro cytotoxicity) of 70% ethanol extract of Cinchona ledgeriana and C. succirubra leaves as well as qunine, quinidine, and cinchonine the major alkaloids found in Cinchona species. Antidiabetes was conducted using α-glucosidase inhibitory activity assay. Antioxidant was conducted using DPPH free radical scavenging activity assay. In vitro cytotoxic activity was concucted by microscopic observation on growth of breast cancer cell line MCF-7. The results showed that at concentration of 100 µg/ml, C. ledgeriana leaves ethanol extracts showed the best activity as antidiabetes (98% inhibitory of α-glucosidase activity) and antioxidant (92% DPPH free radical scavenging activity), whereas at the same concentration C. succirubra, quinine, quinidine and cinchonine showed very low activities of antidiabetes and antioxidant. Microscopic observation of in vitro cytotoxicity showed that C. ledgeriana also has excellent cytotoxicity to breast cancer cell line MCF-7 which better than quinine, quinidine and cinchonine, whereas C. succirubra showed low cytotoxicity. These results suggest that cinchona species have many potential as the source of drugs discovery and development other than just for malaria treatment. Therefore it is important to conduct further studies and to maintain the available Cinchona plantation in Indonesia.

Quinine reduces the dynamic range of the human auditory system.

PubMed

Berninger, E; Karlsson, K K; Alván, G

1998-01-01

The aim of the study was to evaluate and quantify quinine-induced changes in the human auditory dynamic range, as a model for cochlear hearing loss. Six otologically normal volunteers (21-40 years old) received quinine hydrochloride (15 mg/kg body weight) in two identical oral doses and one intravenous infusion. Refined hearing tests were performed monaurally at threshold, at moderate hearing levels and at high hearing levels. Quinine induced a maximal pure-tone threshold shift of 23 dB (1000-2000 Hz). The increase in the psychoacoustical click threshold agreed with an increase in the detection threshold of click-evoked otoacoustic emissions. The change in the stimulus-response relationship of the emissions reflected recruitment. The self-attained most comfortable speech level and the acoustic stapedius reflex thresholds were not affected by quinine administration. Quinine is a useful model substance for reversibly inducing complete loudness recruitment in humans as it acts specifically on some parts of the hearing function. Its mechanism of action on the molecular level is likely to reveal further information on the physiology of hearing.

Vegetable Intake in College-Aged Adults Is Explained by Oral Sensory Phenotypes and TAS2R38 Genotype

PubMed Central

Hayes, John E.; Davidson, Andrew C.; Kidd, Judith R.; Kidd, Kenneth K.; Bartoshuk, Linda M.

2010-01-01

Taste and oral sensations vary in humans. Some of this variation has a genetic basis, and two commonly measured phenotypes are the bitterness of propylthiouracil (PROP) and the number of fungiform papillae on the anterior tongue. While the genetic control of fungiform papilla is unclear, PROP bitterness associates with allelic variation in the taste receptor gene, TAS2R38. The two common alleles are AVI and PAV (proline, alanine, valine, and isoleucine); AVI/AVI homozygotes taste PROP as less bitter than heterozygous or homozygous PAV carriers. In this laboratory-based study, we determined whether taste of a bitter probe (quinine) and vegetable intake varied by taste phenotypes and TAS2R38 genotype in healthy adults (mean age=26 years). Vegetable intake was assessed via two validated, complementary methods: food records (Food Pyramid servings standardized to energy intake) and food frequency questionnaire (general intake question and composite vegetable groups). Quinine bitterness varied with phenotypes but not TAS2R38; quinine was more bitter to those who tasted PROP as more bitter or had more papillae. Nontasters by phenotype or genotype reported greater consumption of vegetables, regardless of type (i.e., the effect generalized to all vegetables and was not restricted to those typically thought of as being bitter). Furthermore, nontasters with more papillae reported greater vegetable consumption than nontasters with fewer papillae, suggesting that when bitterness does not predominate, more papillae enhance vegetable liking. These findings suggest that genetic variation in taste, measured by multiple phenotypes or TAS2R38 genotype, can explain differences in overall consumption of vegetables, and this was not restricted to vegetables that are predominantly bitter. PMID:21157576

Animal Embryotoxicity Studies of Key Non-Artemisinin Antimalarials and Use in Women in the First Trimester.

PubMed

Clark, Robert L

2017-08-15

The World Health Organization currently recommends quinine+clindamycin for use against malaria in the first trimester. This may soon change to recommending artemisinin-based combination therapies (standard duration of dosing = 3 days). The non-artemisinin partner drugs include amodiaquine, lumefantrine, mefloquine, piperaquine, sulfadoxine+pyrimethamine, and pyronaridine. For quinine, clindamycin, and mefloquine and the combinations of sulfadoxine+pyrimethamine and artemether+lumefantrine, there are reports (including studies without internal comparison groups) that combined describe 304 to >1100 exposures of women in the first trimester for each drug with no conclusive evidence of adverse effects on pregnancy at therapeutic doses. This is despite the fact that all of these drugs or drug combinations caused embryo deaths and/or malformations in at least one animal species and all except lumefantrine had at least one exposure ratio <1. It now seems that these animal studies overestimated the risk of developmental toxicity in women with malaria. Three other non-artemisinins (amodiaquine, piperaquine, and pyronaridine) have few or no reported exposures in women in the first trimester and have exposure ratios ≤2 based on studies in pregnant rats and rabbits with dosing throughout organogenesis. However, none of these drugs caused embryo deaths or malformations in pregnant rats and rabbits with the exception of pyronaridine, which caused embryo deaths only at a dose that was excessively toxic to the mothers. Thus, for amodiaquine, piperaquine, and pyronaridine, the testing in animals did not reveal findings of concern and the exposure ratios were in the range of the other non-artemisinin antimalarials described above. Birth Defects Research 109:1075-1126, 2017. © 2017 The Authors. Birth Defects Research Published by Wiley Periodicals, Inc. © 2017 The Authors. Birth Defects Research Published by Wiley Periodicals, Inc.

Quinine Treatment Selects the pfnhe–1 ms4760–1 Polymorphism in Malian Patients with Falciparum Malaria

PubMed Central

Kone, Aminatou; Mu, Jianbing; Maiga, Hamma; Beavogui, Abdoul H.; Yattara, Omar; Sagara, Issaka; Tekete, Mamadou M.; Traore, Oumar B.; Dara, Antoine; Dama, Souleymane; Diallo, Nouhoum; Kodio, Aly; Traoré, Aliou; Björkman, Anders; Gil, Jose P.; Doumbo, Ogobara K.; Wellems, Thomas E.; Djimde, Abdoulaye A.

2013-01-01

Background. The mechanism of Plasmodium falciparum resistance to quinine is not known. In vitro quantitative trait loci mapping suggests involvement of a predicted P. falciparum sodium–hydrogen exchanger (pfnhe–1) on chromosome 13. Methods. We conducted prospective quinine efficacy studies in 2 villages, Kollé and Faladié, Mali. Cases of clinical malaria requiring intravenous therapy were treated with standard doses of quinine and followed for 28 days. Treatment outcomes were classified using modified World Health Organization protocols. Molecular markers of parasite polymorphisms were used to distinguish recrudescent parasites from new infections. The prevalence of pfnhe–1 ms4760–1 among parasites before versus after quinine treatment was determined by direct sequencing. Results. Overall, 163 patients were enrolled and successfully followed. Without molecular correction, the mean adequate clinical and parasitological response (ACPR) was 50.3% (n = 163). After polymerase chain reaction correction to account for new infections, the corrected ACPR was 100%. The prevalence of ms4760–1 increased significantly, from 26.2% (n = 107) before quinine treatment to 46.3% (n = 54) after therapy (P = .01). In a control sulfadoxine–pyrimethamine study, the prevalence of ms4760–1 was similar before and after treatment. Conclusions. This study supports a role for pfnhe–1 in decreased susceptibility of P. falciparum to quinine in the field. PMID:23162138

Peripheral gustatory processing of sweet stimuli by golden hamsters.

PubMed

Frank, Marion E; Formaker, Bradley K; Hettinger, Thomas P

2005-07-15

Behaviors and taste-nerve responses to bitter stimuli are linked to compounds that bind T2 receptors expressed in one subset of taste-bud receptor cells (TRCs); and behavioral and neural responses to sweet stimuli are linked to chemical compounds that bind a T1 receptor expressed in a different TRC subset. Neural and behavioral responses to bitter-sweet mixtures, however, complicate the ostensible bitter and sweet labeled lines. In the golden hamster, Mesocricetus auratus, quinine hydrochloride, the bitter prototype, suppresses chorda tympani (CT) nerve responses to the sweet prototype: sucrose. This bitter-sweet inhibition was tested with concentration series of sucrose and dulcin, a hydrophobic synthetic sweetener that hamsters behaviorally cross-generalize with sucrose. Dulcin, sucrose and other sweeteners activate one subset of CT fibers: S neurons; whereas, quinine activates a separate subset of CT fibers: E neurons. Whole-nerve and S-neuron CT responses to a sweetener concentration series, mixed with 0, 1, 3 and 10 mM quinine, were measured for 0-2.5 s transient and/or 2.6-10 s steady-state response periods. Ten-sec total single-fiber records, aligned at response onset, were averaged for 100 ms bins to identify response oscillations. Quinine inhibition of dulcin and sucrose responses was identical. Each log molar increment in quinine resulted in equivalent declines in response to either sweetener. Furthermore, sucrose response decrements paralleled response increments in quinine-sensitive CT neurons to the same quinine increases. A 1.43 Hz bursting rhythm to the sweeteners was unchanged by quinine inhibition or decreases in sweetener concentration. Taste-bud processing, possibly between-cell inhibition and within-cell negative feedback, must modify signals initiated by T1 receptors before they are transmitted to the brain.

Effects of orally administered chemotherapeutics (quinine, salinomycin) against Henneguya sp. Thelohán, 1892 (Myxozoa: Myxobolidae), a gill parasite in the tapir fish Gnathonemus petersii Günther, 1862 (Teleostei).

PubMed

Dohle, Angelika; Schmahl, Günter; Raether, Wolfgang; Schmidt, Hartmut; Ritter, Günter

2002-09-01

When given orally, quinine or salinomycin cause irreversible damage to the plasmodial developmental stages of Henneguya sp., a gill parasite in the tapir fish Gnathonemus petersii. Naturally infected tapir fish measured 75-169 mm in total length and their total weight ranged over 4.3-11.7 g. The fish bore 7-77 plasmodia in their gill arches. Medicinal food containing either quinine (5 g/1000 g food) or salinomycin (0.075 g/1000 g food) was given once a day to naturally infected fish in a food chain via water fleas ( Daphnia spp) for a period of 3, 6, or 9 days. From the monitored feeding of the tapir fish and weight determinations of the water fleas, it was calculated that gross uptake was 18.5 micro g/kg body weight fish daily for pure salinomycin and was 1.25 mg/kg body weight daily for quinine. After the end of the experiments, the fish were sacrificed and the plasmodia were carefully prepared from the gill arches and processed for transmission electron microscopy. As seen by ultrastructure investigations, for both substances the grade of damage in the parasites correlated positively with the period of application. When quinine was given for a 3-day period, the trophozoite ecto- and endoplasm exerted numerous vacuoles, caused by the drug, and the presporogonous and the pansporoblastic stages were malformed. Following a 6-day period, numerous abortive polar capsules were found in the trophozoite cytoplasm. To a large extent, the limiting membranes of the polaroblasts and valvogenic cells were destroyed. In addition, deep clefts between the polaroblasts, the valvogenic cells and between the two sporoblasts were observed. Following a 9-day treatment, all damage increased and, in addition, generative cells and two-cell stages were no longer detectable. As a first sign for the effects of salinomycin, following a 3-day treatment, a shrinking of the whole plasmodia occurred and the sutures in the pansporoblasts were enlarged. The polar capsules were malformed and the zonar structures of the polar filament were no longer detectable. The sporoplasmosomes were more electron-pale than those of the control samples. After a 9-day treatment, the pansporoblasts were completely destroyed. Under the experimental conditions chosen, both compounds were very well tolerated by the fishes.

Access to artesunate-amodiaquine, quinine and other anti-malarials: policy and markets in Burundi.

PubMed

Amuasi, John H; Diap, Graciela; Blay-Nguah, Samuel; Boakye, Isaac; Karikari, Patrick E; Dismas, Baza; Karenzo, Jeanne; Nsabiyumva, Lievin; Louie, Karly S; Kiechel, Jean-René

2011-02-10

Malaria is the leading cause of morbidity and mortality in post-conflict Burundi. To counter the increasing challenge of anti-malarial drug resistance and improve highly effective treatment Burundi adopted artesunate-amodiaquine (AS-AQ) as first-line treatment for uncomplicated Plasmodium falciparum malaria and oral quinine as second-line treatment in its national treatment policy in 2003. Uptake of this policy in the public, private and non-governmental (NGO) retail market sectors of Burundi is relatively unknown. This study was conducted to evaluate access to national policy recommended anti-malarials. Adapting a standardized methodology developed by Health Action International/World Health Organization (HAI/WHO), a cross-sectional survey of 70 (24 public, 36 private, and 10 NGO) medicine outlets was conducted in three regions of Burundi, representing different levels of transmission of malaria. The availability on day of the survey, the median prices, and affordability (in terms of number of days' wages to purchase treatment) of AS-AQ, quinine and other anti-malarials were calculated. Anti-malarials were stocked in all outlets surveyed. AS-AQ was available in 87.5%, 33.3%, and 90% of public, private, and NGO retail outlets, respectively. Quinine was the most common anti-malarial found in all outlet types. Non-policy recommended anti-malarials were mainly found in the private outlets (38.9%) compared to public (4.2%) and NGO (0%) outlets. The median price of a course of AS-AQ was US$0.16 (200 Burundi Francs, FBu) for the public and NGO markets, and 3.5-fold higher in the private sector (US$0.56 or 700 FBu). Quinine tablets were similarly priced in the public (US$1.53 or 1,892.50 FBu), private and NGO sectors (both US$1.61 or 2,000 FBu). Non-policy anti-malarials were priced 50-fold higher than the price of AS-AQ in the public sector. A course of AS-AQ was affordable at 0.4 of a day's wage in the public and NGO sectors, whereas, it was equivalent to 1.5 days worth of wages in the private sector. AS-AQ was widely available and affordable in the public and NGO markets of hard-to-reach post-conflict communities in Burundi. However greater accessibility and affordability of policy recommended anti-malarials in the private market sector is needed to improve country-wide policy uptake.

Heritability and genetic covariation of sensitivity to PROP, SOA, quinine HCl, and caffeine.

PubMed

Hansen, Jonathan L; Reed, Danielle R; Wright, Margaret J; Martin, Nicholas G; Breslin, Paul A S

2006-06-01

The perceived bitterness intensity for bitter solutions of propylthiouracil (PROP), sucrose octa-acetate (SOA), quinine HCl and caffeine were examined in a genetically informative sample of 392 females and 313 males (mean age of 17.8 +/- 3.1 years), including 62 monozygotic and 131 dizygotic twin pairs and 237 sib pairs. Broad-sense heritabilities were estimated at 0.72, 0.28, 0.34, and 0.30 for PROP, SOA, quinine, and caffeine, respectively, for perceived intensity measures. Modeling showed 1) a group factor which explained a large amount of the genetic variation in SOA, quinine, and caffeine (22-28% phenotypic variation), 2) a factor responsible for all the genetic variation in PROP (72% phenotypic variation), which only accounted for 1% and 2% of the phenotypic variation in SOA and caffeine, respectively, and 3) a modest specific genetic factor for quinine (12% phenotypic variation). Unique environmental influences for all four compounds were due to a single factor responsible for 7-22% of phenotypic variation. The results suggest that the perception of PROP and the perception of SOA, quinine, and caffeine are influenced by two distinct sets of genes.

Heritability and Genetic Covariation of Sensitivity to PROP, SOA, Quinine HCl, and Caffeine

PubMed Central

Hansen, Jonathan L.; Reed, Danielle R.; Wright, Margaret J.; Martin, Nicholas G.; Breslin, Paul A. S.

2006-01-01

The perceived bitterness intensity for bitter solutions of propylthiouracil (PROP), sucrose octa-acetate (SOA), quinine HCl and caffeine were examined in a genetically informative sample of 392 females and 313 males (mean age of 17.8 ± 3.1 years), including 62 MZ and 131 DZ twin pairs and 237 sib pairs. Broad-sense heritabilities were estimated at 0.72, 0.28, 0.34, and 0.30 for PROP, SOA, quinine, and caffeine, respectively, for perceived intensity measures. Modeling showed 1) a group factor which explained a large amount of the genetic variation in SOA, quinine, and caffeine (22–28% phenotypic variation), 2) a factor responsible for all the genetic variation in PROP (72% phenotypic variation), which only accounted for 1% and 2% of the phenotypic variation in SOA and caffeine, respectively, and 3) a modest specific genetic factor for quinine (12% phenotypic variation). Unique environmental influences for all four compounds were due to a single factor responsible for 7–22% of phenotypic variation. The results suggest that the perception of PROP and the perception of SOA, quinine, and caffeine are influenced by two distinct sets of genes. PMID:16527870

Access to artemisinin-combination therapy (ACT) and other anti-malarials: national policy and markets in Sierra Leone.

PubMed

Amuasi, John H; Diap, Graciela; Nguah, Samuel Blay; Karikari, Patrick; Boakye, Isaac; Jambai, Amara; Lahai, Wani Kumba; Louie, Karly S; Kiechel, Jean-Rene

2012-01-01

Malaria remains the leading burden of disease in post-conflict Sierra Leone. To overcome the challenge of anti-malarial drug resistance and improve effective treatment, Sierra Leone adopted artemisinin-combination therapy artesunate-amodiaquine (AS+AQ) as first-line treatment for uncomplicated P. falciparum malaria. Other national policy anti-malarials include artemether-lumefantrine (AL) as an alternative to AS+AQ, quinine and artemether for treatment of complicated malaria; and sulphadoxine-pyrimethamine (SP) for intermittent preventive treatment (IPTp). This study was conducted to evaluate access to national policy recommended anti-malarials. A cross-sectional survey of 127 medicine outlets (public, private and NGO) was conducted in urban and rural areas. The availability on the day of the survey, median prices, and affordability policy and available non-policy anti-malarials were calculated. Anti-malarials were stocked in 79% of all outlets surveyed. AS+AQ was widely available in public medicine outlets; AL was only available in the private and NGO sectors. Quinine was available in nearly two-thirds of public and NGO outlets and over one-third of private outlets. SP was widely available in all outlets. Non-policy anti-malarials were predominantly available in the private outlets. AS+AQ in the public sector was widely offered for free. Among the anti-malarials sold at a cost, the same median price of a course of AS+AQ (US$1.56), quinine tablets (US$0.63), were found in both the public and private sectors. Quinine injection had a median cost of US$0.31 in the public sector and US$0.47 in the private sector, while SP had a median cost of US$0.31 in the public sector compared to US$ 0.63 in the private sector. Non-policy anti-malarials were more affordable than first-line AS+AQ in all sectors. A course of AS+AQ was affordable at nearly two days' worth of wages in both the public and private sectors.

High School Students Are a Target Group for Fight against Self-Medication with Antimalarial Drugs: A Pilot Study in University of Kinshasa, Democratic Republic of Congo.

PubMed

Kabongo Kamitalu, Ramsès; Aloni, Michel Ntetani

2016-01-01

Aim. To assess the self-medication against malaria infection in population of Congolese students in Kinshasa, Democratic Republic of Congo (DRC). Methods. A cross-sectional study was carried out in University of Kinshasa, Kinshasa, Democratic Republic of Congo. Medical records of all students with malaria admitted to Centre de Santé Universitaire of University of Kinshasa from January 1, 2008, to April 30, 2008, were reviewed retrospectively. Results. The median age of the patients was 25.4 years (range: from 18 to 36 years). The majority of them were male (67.9%). Artemisinin-based combination treatments (ACTs) was the most used self-prescribed antimalarial drugs. However, self-medication was associated with the ingestion of quinine in 19.9% of cases. No case of ingestion of artesunate/artemether in monotherapy was found. All the medicines taken were registered in DRC. In this series, self-prescribed antimalarial was very irrational in terms of dose and duration of treatment. Conclusion. This paper highlights self-medication by a group who should be aware of malaria treatment protocols. The level of self-prescribing quinine is relatively high among students and is disturbing for a molecule reserved for severe disease in Congolese health care policy in management of malaria.

Fetal ethanol exposure increases ethanol intake by making it smell and taste better

PubMed Central

Youngentob, Steven L.; Glendinning, John I.

2009-01-01

Human epidemiologic studies reveal that fetal ethanol exposure is highly predictive of adolescent ethanol avidity and abuse. Little is known about how fetal exposure produces these effects. It is hypothesized that fetal ethanol exposure results in stimulus-induced chemosensory plasticity. Here, we asked whether gestational ethanol exposure increases postnatal ethanol avidity in rats by altering its taste and odor. Experimental rats were exposed to ethanol in utero via the dam's diet, whereas control rats were either pair-fed an iso-caloric diet or given food ad libitum. We found that fetal ethanol exposure increased the taste-mediated acceptability of both ethanol and quinine hydrochloride (bitter), but not sucrose (sweet). Importantly, a significant proportion of the increased ethanol acceptability could be attributed directly to the attenuated aversion to ethanol's quinine-like taste quality. Fetal ethanol exposure also enhanced ethanol intake and the behavioral response to ethanol odor. Notably, the elevated intake of ethanol was also causally linked to the enhanced odor response. Our results demonstrate that fetal exposure specifically increases ethanol avidity by, in part, making it taste and smell better. More generally, they establish an epigenetic chemosensory mechanism by which maternal patterns of drug use can be transferred to offspring. Given that many licit (e.g., tobacco products) and illicit (e.g., marijuana) drugs have noteworthy chemosensory components, our findings have broad implications for the relationship between maternal patterns of drug use, child development, and postnatal vulnerability. PMID:19273846

Fetal ethanol exposure increases ethanol intake by making it smell and taste better.

PubMed

Youngentob, Steven L; Glendinning, John I

2009-03-31

Human epidemiologic studies reveal that fetal ethanol exposure is highly predictive of adolescent ethanol avidity and abuse. Little is known about how fetal exposure produces these effects. It is hypothesized that fetal ethanol exposure results in stimulus-induced chemosensory plasticity. Here, we asked whether gestational ethanol exposure increases postnatal ethanol avidity in rats by altering its taste and odor. Experimental rats were exposed to ethanol in utero via the dam's diet, whereas control rats were either pair-fed an iso-caloric diet or given food ad libitum. We found that fetal ethanol exposure increased the taste-mediated acceptability of both ethanol and quinine hydrochloride (bitter), but not sucrose (sweet). Importantly, a significant proportion of the increased ethanol acceptability could be attributed directly to the attenuated aversion to ethanol's quinine-like taste quality. Fetal ethanol exposure also enhanced ethanol intake and the behavioral response to ethanol odor. Notably, the elevated intake of ethanol was also causally linked to the enhanced odor response. Our results demonstrate that fetal exposure specifically increases ethanol avidity by, in part, making it taste and smell better. More generally, they establish an epigenetic chemosensory mechanism by which maternal patterns of drug use can be transferred to offspring. Given that many licit (e.g., tobacco products) and illicit (e.g., marijuana) drugs have noteworthy chemosensory components, our findings have broad implications for the relationship between maternal patterns of drug use, child development, and postnatal vulnerability.

A novel complexity-to-diversity strategy for the diversity-oriented synthesis of structurally diverse and complex macrocycles from quinine.

PubMed

Ciardiello, J J; Stewart, H L; Sore, H F; Galloway, W R J D; Spring, D R

2017-06-01

Recent years have witnessed a global decline in the productivity and advancement of the pharmaceutical industry. A major contributing factor to this is the downturn in drug discovery successes. This can be attributed to the lack of structural (particularly scaffold) diversity and structural complexity exhibited by current small molecule screening collections. Macrocycles have been shown to exhibit a diverse range of biological properties, with over 100 natural product-derived examples currently marketed as FDA-approved drugs. Despite this, synthetic macrocycles are widely considered to be a poorly explored structural class within drug discovery, which can be attributed to their synthetic intractability. Herein we describe a novel complexity-to-diversity strategy for the diversity-oriented synthesis of novel, structurally complex and diverse macrocyclic scaffolds from natural product starting materials. This approach exploits the inherent structural (including functional) and stereochemical complexity of natural products in order to rapidly generate diversity and complexity. Readily-accessible natural product-derived intermediates serve as structural templates which can be divergently functionalized with different building blocks to generate a diverse range of acyclic precursors. Subsequent macrocyclisation then furnishes compounds that are each based around a distinct molecular scaffold. Thus, high levels of library scaffold diversity can be rapidly achieved. In this proof-of-concept study, the natural product quinine was used as the foundation for library synthesis, and six novel structurally diverse, highly complex and functionalized macrocycles were generated. Copyright © 2017 Elsevier Ltd. All rights reserved.

Concise Stereocontrolled Formal Synthesis of (±)-Quinine and Total Synthesis of (±)-7-Hydroxyquinine via Merged Morita-Baylis-Hillman-Tsuji-Trost Cyclization

PubMed Central

Webber, Peter; Krische, Michael J.

2010-01-01

Concise stereoselective syntheses of (±)-quinine and (±)-7-hydroxyquinine are achieved using a catalytic enone cycloallylation that combines the nucleophilic features of the Morita-Baylis-Hillman reaction and the electrophilic features of the Tsuji-Trost reaction. Cyclization of enone-allyl carbonate 11 delivers the product of cycloallylation 13 in 68% yield. Diastereoselective conjugate reduction of the enone 13 (>20:1 dr) followed by exchange of N-protecting groups provides the saturated N-Boc-protected methyl ketone 19, which upon aldol dehydration provides quinoline containing enone 15, possessing all carbon atoms of quinine. Exposure of ketone 15 to L-selectride enables diastereoselective carbonyl reduction (>20:1 dr) to furnish the allylic alcohol 16. Stereoselective hydroxyl-directed epoxidation using an oxovanadium catalyst modified by N-hydroxy-N-Me-pivalamide delivers epoxide 17 (17:1 dr). Cyclization of the resulting amine-epoxide 17 provides (±)-7-hydroxyquinine in 13 steps and 11% overall yield from aminoacetaldehyde diethyl acetal. Notably, highly stereoselective formation of five contiguous stereocenters is achieved through a series of 1,2-asymmetric induction events. A formal synthesis of (±)-quinine is achieved upon deoxygenation of the N-Cbz-protected allylic acetate 22 to provide olefin 23, which previously has been converted to quinine. Thus, (±)-quinine is accessible in 16 steps and 4% overall yield from commercial aminoacetaldehyde diethyl acetal, making this route the most concise approach to quinine, to date. PMID:18989927

The neuronal and molecular basis of quinine-dependent bitter taste signaling in Drosophila larvae

PubMed Central

Apostolopoulou, Anthi A.; Mazija, Lorena; Wüst, Alexander; Thum, Andreas S.

2014-01-01

The sensation of bitter substances can alert an animal that a specific type of food is harmful and should not be consumed. However, not all bitter compounds are equally toxic and some may even be beneficial in certain contexts. Thus, taste systems in general may have a broader range of functions than just in alerting the animal. In this study we investigate bitter sensing and processing in Drosophila larvae using quinine, a substance perceived by humans as bitter. We show that behavioral choice, feeding, survival, and associative olfactory learning are all directly affected by quinine. On the cellular level, we show that 12 gustatory sensory receptor neurons that express both GR66a and GR33a are required for quinine-dependent choice and feeding behavior. Interestingly, these neurons are not necessary for quinine-dependent survival or associative learning. On the molecular receptor gene level, the GR33a receptor, but not GR66a, is required for quinine-dependent choice behavior. A screen for gustatory sensory receptor neurons that trigger quinine-dependent choice behavior revealed that a single GR97a receptor gene expressing neuron located in the peripheral terminal sense organ is partially necessary and sufficient. For the first time, we show that the elementary chemosensory system of the Drosophila larva can serve as a simple model to understand the neuronal basis of taste information processing on the single cell level with respect to different behavioral outputs. PMID:24478653

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

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

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

Medicines and Drugs from Plants

NASA Astrophysics Data System (ADS)

Agosta, William C.

1997-07-01

Natural preparations have been used for thousands of ages for a variety of purposes including as medicines, poisons, and psychotropic drugs. The largest grouped of preparations from living organisms are medicines, and historically these have come from plants. Quinine and aspirin are two examples of medicines which were extracted originally from plants. Mind-altering, or psychotropic, drugs come mostly from plants or fungi. In many traditional cultures, sickness and death are attributed to maligned spirits so that medicine and religion become inseparable. Uses of cohohba, snakeplant, coca, and peyote are discussed. The process by which new pharmaceuticals are discovered from natural products is described. The implications of an agreement between a major pharmaceutical company and a country in the tropics are discussed.

History and Epistemology of Science in the Classroom: The Synthesis of Quinine as a Proposal

ERIC Educational Resources Information Center

Souza, Karina Ap. F. D.; Porto, Paulo A.

2012-01-01

The history of the quinine synthesis can be used as a case study to emphasize that science is influenced by social and historical processes. The first efforts toward the synthesis of this substance, which until recently was the only treatment for malaria, were by Perkin in 1856 when, trying to obtain quinine, he synthesized mauveine. Since then,…

Analysis of Species-Selectivity of Human, Mouse and Rat Cytochrome P450 1A and 2B Subfamily Enzymes using Molecular Modeling, Docking and Dynamics Simulations.

PubMed

Karthikeyan, Bagavathy Shanmugam; Suvaithenamudhan, Suvaiyarasan; Akbarsha, Mohammad Abdulkader; Parthasarathy, Subbiah

2018-06-01

Cytochrome P450 (CYP) 1A and 2B subfamily enzymes are important drug metabolizing enzymes, and are highly conserved across species in terms of sequence homology. However, there are major to minor structural and macromolecular differences which provide for species-selectivity and substrate-selectivity. Therefore, species-selectivity of CYP1A and CYP2B subfamily proteins across human, mouse and rat was analyzed using molecular modeling, docking and dynamics simulations when the chiral molecules quinine and quinidine were used as ligands. The three-dimensional structures of 17 proteins belonging to CYP1A and CYP2B subfamilies of mouse and rat were predicted by adopting homology modeling using the available structures of human CYP1A and CYP2B proteins as templates. Molecular docking and dynamics simulations of quinine and quinidine with CYP1A subfamily proteins revealed the existence of species-selectivity across the three species. On the other hand, in the case of CYP2B subfamily proteins, no role for chirality of quinine and quinidine in forming complexes with CYP2B subfamily proteins of the three species was indicated. Our findings reveal the roles of active site amino acid residues of CYP1A and CYP2B subfamily proteins and provide insights into species-selectivity of these enzymes across human, mouse, and rat.

Assessment of bitterness intensity and suppression effects using an Electronic Tongue

NASA Astrophysics Data System (ADS)

Legin, A.; Rudnitskaya, A.; Kirsanov, D.; Frolova, Yu.; Clapham, D.; Caricofe, R.

2009-05-01

Quantification of bitterness intensity and effectivness of bitterness suppression of a novel active pharmacological ingredient (API) being developed by GSK was performed using an Electronic Tongue (ET) based on potentiometric chemical sensors. Calibration of the ET was performed with solutions of quinine hydrochloride in the concentration range 0.4-360 mgL-1. An MLR calibration model was developed for predicting bitterness intensity expressed as "equivalent quinine concentration" of a series of solutions of quinine, bittrex and the API. Additionally the effectiveness of sucralose, mixture of aspartame and acesulfame K, and grape juice in masking the bitter taste of the API was assessed using two approaches. PCA models were produced and distances between compound containing solutions and corresponding placebos were calculated. The other approach consisted in calculating "equivalent quinine concentration" using a calibration model with respect to quinine concentration. According to both methods, the most effective taste masking was produced by grape juice, followed by the mixture of aspartame and acesulfame K.

On vibrational circular dichroism chirality transfer in electron donor-acceptor complexes: a prediction for the quinine···BF3 system.

PubMed

Rode, Joanna E; Jamróz, Michał H; Dobrowolski, Jan Cz; Sadlej, Joanna

2012-08-02

Vibrational circular dichroism (VCD) chirality transfer occurs when an achiral molecule interacts with a chiral one and becomes VCD-active. Unlike for H-bonds, for organic electron donor-acceptor (EDA) complexes this phenomenon remains almost unknown. Here, the VCD chirality transfer from chiral quinine to achiral BF3 is studied at the B3LYP/aug-cc-pVDZ level. Accessibility of four quinine electron donor sites changes with conformation. Therefore, the quinine conformational landscape was explored and a considerable agreement between X-ray and the most stable conformer geometries was achieved. The BF3 complex through the aliphatic quinuclidine N atom is definitely dominating and is predicted to be easily recognizable in the VCD spectrum. Out of several VCD chirality transfer modes, the ν(s)(BF3) mode, the most intense in the entire VCD spectrum, satisfies the VCD mode robustness criterion and can be used for monitoring the chirality transfer phenomenon in quinine···BF3 system.

Conformational analysis of quinine and its pseudo enantiomer quinidine: a combined jet-cooled spectroscopy and vibrational circular dichroism study.

PubMed

Sen, Ananya; Bouchet, Aude; Lepère, Valeria; Le Barbu-Debus, Katia; Scuderi, D; Piuzzi, F; Zehnacker-Rentien, A

2012-08-16

Laser-desorbed quinine and quinidine have been studied in the gas phase by combining supersonic expansion with laser spectroscopy, namely, laser-induced fluorescence (LIF), resonance-enhanced multiphoton ionization (REMPI), and IR-UV double resonance experiments. Density funtional theory (DFT) calculations have been done in conjunction with the experimental work. The first electronic transition of quinine and quinidine is of π-π* nature, and the studied molecules weakly fluoresce in the gas phase, in contrast to what was observed in solution (Qin, W. W.; et al. J. Phys. Chem. C2009, 113, 11790). The two pseudo enantiomers quinine and quinidine show limited differences in the gas phase; their main conformation is of open type as it is in solution. However, vibrational circular dichroism (VCD) experiments in solution show that additional conformers exist in condensed phase for quinidine, which are not observed for quinine. This difference in behavior between the two pseudo enantiomers is discussed.

Brief Exposures to the Taste of Ethanol (EtOH) and Quinine Promote Subsequent Acceptance of EtOH in a Paradigm that Minimizes Postingestive Consequences.

PubMed

Loney, Gregory C; Meyer, Paul J

2018-03-01

Aversion to the orosensory properties of concentrated ethanol (EtOH) solutions is often cited as a primary barrier to initiation of drinking and may contribute to abstention. These aversive properties include gustatory processes which encompass both bitter-like taste qualities and trigeminal-mediated irritation. Chronic intermittent EtOH access (CIA) results in substantial and persistent increases in EtOH consumption, but the degree to which this facilitation involves sensory responding to EtOH and other bitter stimuli is currently undetermined. Long-Evans rats were given brief-access licking tests designed to examine the immediate, taste-guided assessment of the palatability of EtOH and quinine solutions. Rats were assessed once in a naïve state and again following previous brief-access exposure, or following 4 weeks of CIA. The relationship between the sensitivity to the aversive orosensory properties of EtOH and quinine following EtOH access and the impact of antecedent quinine exposure on the acceptance of EtOH were determined in 2 parallel studies. Both brief access to EtOH and 4-week CIA resulted in substantial rightward shifts in the concentration-response function of brief-access EtOH licking, indicating that EtOH exposure increased acceptance of the taste of EtOH. The initial sensitivity to the aversive orosensory properties of EtOH and quinine was positively correlated in naïve rats, such that rats that were initially more accepting of quinine were also more accepting of EtOH. Rats that sampled quinine immediately prior to tasting EtOH exhibited successive positive contrast in that they were more accepting of highly concentrated EtOH, relative to a water-control group. Increased EtOH acceptance following exposure is, at least in part, facilitated by a decrease in its aversive sensory properties. Both long- and short-term access increase the palatability of the taste of EtOH in brief-access licking tests. Moreover, the sensitivity to the bitterness of quinine was predictive of acceptance of EtOH indicating some commonality in the sensory mechanisms that mediate the initial acceptance of the 2 stimuli. Accordingly, immediate prior exposure to quinine results in increased acceptance of EtOH, suggesting that successive positive contrast between oral stimuli may contribute to increased alcohol consumption. Copyright © 2017 by the Research Society on Alcoholism.

A Nationwide Survey of the Quality of Antimalarials in Retail Outlets in Tanzania

PubMed Central

Kaur, Harparkash; Goodman, Catherine; Thompson, Eloise; Thompson, Katy-Anne; Masanja, Irene; Kachur, S. Patrick; Abdulla, Salim

2008-01-01

Introduction Retail pharmaceutical products are commonly used to treat fever and malaria in sub-Saharan African countries. Small scale studies have suggested that poor quality antimalarials are widespread throughout the region, but nationwide data are not available that could lead to generalizable conclusions about the extent to which poor quality drugs are available in African communities. This study aimed to assess the quality of antimalarials available from retail outlets across mainland Tanzania. Methods and Findings We systematically purchased samples of oral antimalarial tablets from retail outlets across 21 districts in mainland Tanzania in 2005. A total of 1080 antimalarial formulations were collected including 679 antifol antimalarial samples (394 sulfadoxine/pyrimethamine and 285 sulfamethoxypyrazine/pyrimethamine), 260 amodiaquine samples, 63 quinine samples, and 51 artemisinin derivative samples. A systematic subsample of 304 products was assessed for quality by laboratory based analysis to determine the amount of the active ingredient and dissolution profile by following the published United States Pharmacopoeia (USP) monogram for the particular tablet being tested. Products for which a published analytical monogram did not exist were assessed on amount of active ingredient alone. Overall 38 or 12.2% of the samples were found to be of poor quality. Of the antifolate antimalarial drugs tested 13.4% were found to be of poor quality by dissolution and content analysis using high-performance liquid chromatography (HPLC). Nearly one quarter (23.8%) of quinine tablets did not comply within the tolerance limits of the dissolution and quantification analysis. Quality of amodiaquine drugs was relatively better but still unacceptable as 7.5% did not comply within the tolerance limits of the dissolution analysis. Formulations of the artemisinin derivatives all contained the stated amount of active ingredient when analysed using HPLC alone. Conclusions Substandard antimalarial formulations were widely available in Tanzania at the time of this study. No products were detected that did not contain any amount of the stated active ingredient. Quinine and sulfadoxine/pyrimethamine products were the most widely available and also the most likely to be of poor quality. Substandard products were identified in all parts of the country and were labeled as made by both domestic and international manufacturers. With the expansion of the retail pharmaceutical sector as a delivery channel for antimalarial formulations the need for regular nationwide monitoring of their quality will become increasingly important. PMID:18923672

A nationwide survey of the quality of antimalarials in retail outlets in Tanzania.

PubMed

Kaur, Harparkash; Goodman, Catherine; Thompson, Eloise; Thompson, Katy-Anne; Masanja, Irene; Kachur, S Patrick; Abdulla, Salim

2008-01-01

Retail pharmaceutical products are commonly used to treat fever and malaria in sub-Saharan African countries. Small scale studies have suggested that poor quality antimalarials are widespread throughout the region, but nationwide data are not available that could lead to generalizable conclusions about the extent to which poor quality drugs are available in African communities. This study aimed to assess the quality of antimalarials available from retail outlets across mainland Tanzania. We systematically purchased samples of oral antimalarial tablets from retail outlets across 21 districts in mainland Tanzania in 2005. A total of 1080 antimalarial formulations were collected including 679 antifol antimalarial samples (394 sulfadoxine/pyrimethamine and 285 sulfamethoxypyrazine/pyrimethamine), 260 amodiaquine samples, 63 quinine samples, and 51 artemisinin derivative samples. A systematic subsample of 304 products was assessed for quality by laboratory based analysis to determine the amount of the active ingredient and dissolution profile by following the published United States Pharmacopoeia (USP) monogram for the particular tablet being tested. Products for which a published analytical monogram did not exist were assessed on amount of active ingredient alone. Overall 38 or 12.2% of the samples were found to be of poor quality. Of the antifolate antimalarial drugs tested 13.4% were found to be of poor quality by dissolution and content analysis using high-performance liquid chromatography (HPLC). Nearly one quarter (23.8%) of quinine tablets did not comply within the tolerance limits of the dissolution and quantification analysis. Quality of amodiaquine drugs was relatively better but still unacceptable as 7.5% did not comply within the tolerance limits of the dissolution analysis. Formulations of the artemisinin derivatives all contained the stated amount of active ingredient when analysed using HPLC alone. Substandard antimalarial formulations were widely available in Tanzania at the time of this study. No products were detected that did not contain any amount of the stated active ingredient. Quinine and sulfadoxine/pyrimethamine products were the most widely available and also the most likely to be of poor quality. Substandard products were identified in all parts of the country and were labeled as made by both domestic and international manufacturers. With the expansion of the retail pharmaceutical sector as a delivery channel for antimalarial formulations the need for regular nationwide monitoring of their quality will become increasingly important.

Evaluation of Glucose Dehydrogenase and Pyrroloquinoline Quinine (pqq) Mutagenesis that Renders Functional Inadequacies in Host Plants.

PubMed

Naveed, Muhammad; Sohail, Younas; Khalid, Nauman; Ahmed, Iftikhar; Mumtaz, Abdul Samad

2015-08-01

The rhizospheric zone abutting plant roots usually clutches a wealth of microbes. In the recent past, enormous genetic resources have been excavated with potential applications in host plant interaction and ancillary aspects. Two Pseudomonas strains were isolated and identified through 16S rRNA and rpoD sequence analyses as P. fluorescens QAU67 and P. putida QAU90. Initial biochemical characterization and their root-colonizing traits indicated their potential role in plant growth promotion. Such aerobic systems, involved in gluconic acid production and phosphate solubilization, essentially require the pyrroloquinoline quinine (PQQ)- dependent glucose dehydrogenase (GDH) in the genome. The PCR screening and amplification of GDH and PQQ and subsequent induction of mutagenesis characterized their possible role as antioxidants as well as in growth promotion, as probed in vitro in lettuce and in vivo in rice, bean, and tomato plants. The results showed significant differences (p < or = 0.05) in parameters of plant height, fresh weight, and dry weight, etc., deciphering a clear and in fact complementary role of GDH and PQQ in plant growth promotion. Our study not only provides direct evidence of the in vivo role of GDH and PQQ in host plants but also reveals their functional inadequacy in the event of mutation at either of these loci.

Restoration of quinine-stimulated Fos-immunoreactive neurons in the central nucleus of the amygdala and gustatory cortex following reinnervation or cross-reinnervation of the lingual taste nerves in rats.

PubMed

King, Camille Tessitore; Garcea, Mircea; Spector, Alan C

2014-08-01

Remarkably, when lingual gustatory nerves are surgically rerouted to inappropriate taste fields in the tongue, some taste functions recover. We previously demonstrated that quinine-stimulated oromotor rejection reflexes and neural activity (assessed by Fos immunoreactivity) in subregions of hindbrain gustatory nuclei were restored if the posterior tongue, which contains receptor cells that respond strongly to bitter compounds, was cross-reinnervated by the chorda tympani nerve. Such functional recovery was not seen if instead, the anterior tongue, where receptor cells are less responsive to bitter compounds, was cross-reinnervated by the glossopharyngeal nerve, even though this nerve typically responds robustly to bitter substances. Thus, recovery depended more on the taste field being reinnervated than on the nerve itself. Here, the distribution of quinine-stimulated Fos-immunoreactive neurons in two taste-associated forebrain areas was examined in these same rats. In the central nucleus of the amygdala (CeA), a rostrocaudal gradient characterized the normal quinine-stimulated Fos response, with the greatest number of labeled cells situated rostrally. Quinine-stimulated neurons were found throughout the gustatory cortex, but a "hot spot" was observed in its anterior-posterior center in subregions approximating the dysgranular/agranular layers. Fos neurons here and in the rostral CeA were highly correlated with quinine-elicited gapes. Denervation of the posterior tongue eliminated, and its reinnervation by either nerve restored, numbers of quinine-stimulated labeled cells in the rostralmost CeA and in the subregion approximating the dysgranular gustatory cortex. These results underscore the remarkable plasticity of the gustatory system and also help clarify the functional anatomy of neural circuits activated by bitter taste stimulation. © 2014 Wiley Periodicals, Inc.

Exchange transfusion with red blood cells preserved in adenine clears a child of severe falciparum malaria.

PubMed

Boctor, F N; Ali, N M; Choi, Y J; Morse, E E

1997-01-01

Falciparum malaria may be associated with significant morbidity and mortality. The degree of mortality and morbidity usually corresponds to the degree of parasitemia. Quinine and other antimalarial drugs are relatively slow acting and not always effective owing to the presence of drug resistance falciparum. Rapid reduction of the number of circulating parasites may be required. Exchange transfusion has been used as a safe and quick approach to decreasing the parasitemia and antimalaria drugs used to eradicate the rest of the Plasmodium. In the present report, a case is described of a child with severe falciparum malaria who was successfully treated with exchange transfusion using the new adenine and mannitol enriched preservative media, Adsol.

Antimalarial Activity of New Water-Soluble Dihydroartemisinin Derivatives. 2. Stereospecificity of the Ether Side Chain

DTIC Science & Technology

1989-06-01

vitro antimalarial activity of the acids are chloroquine 3.1 43.60 weak and the number of ester derivatives synthesized was quinine 3.61 59.00 limited...is resistant to the 4/5 mice in the 20 MKD group did not have extended antimalarials chloroquine , sulfadoxine, pyrimethamine, and survival times...quinine, whereas the Sierra Leone is resistant to mefloquine but susceptible to chloroquine , quinine, sulfadoxine, and pyrime- When these three new

Direct solid surface fluorescence spectroscopy of standard chemicals and humic acid in ternary system

NASA Astrophysics Data System (ADS)

Mounier, S.; Nicolodelli, G.; Redon, R.; Milori, D. M. B. P.

2017-04-01

The front face fluorescence spectroscopy is often used to quantify chemicals in well-known matrices as it is a rapid and powerful technique, with no sample preparation. However it was not used to investigate extracted organic matter like humic substances. This work aims to fully investigate for the first time front face fluorescence spectroscopy response of a ternary system including boric acid, tryptophan and humic substances, and two binaries system containing quinine sulfate or humic substance in boric acid. Pure chemicals, boric acid, tryptophan, quinine sulfate and humic acid were mixed together in solid pellet at different contents from 0 to 100% in mass. The measurement of excitation emission matrix of fluorescence (3D fluorescence) and laser induced fluorescence were then done in the front face mode. Fluorescence matrices were decomposed using the CP/PARAFAC tools after scattering treatments. Results show that for 3D fluorescence there is no specific component for tryptophan and quinine sulfate, and that humic substances lead to a strong extinction effect for mixture containing quinine sulfate. Laser induced fluorescence gives a very good but non-specific related response for both quinine sulfate and tryptophan. No humic substances fluorescence response was found, but extinction effect is observed as for 3D fluorescence. This effect is stronger for quinine sulfate than for tryptophan. These responses were modeled using a simple absorbance versus emission model.

Poor quality drugs: grand challenges in high throughput detection, countrywide sampling, and forensics in developing countries†

PubMed Central

Fernandez, Facundo M.; Hostetler, Dana; Powell, Kristen; Kaur, Harparkash; Green, Michael D.; Mildenhall, Dallas C.; Newton, Paul N.

2012-01-01

Throughout history, poor quality medicines have been a persistent problem, with periodical crises in the supply of antimicrobials, such as fake cinchona bark in the 1600s and fake quinine in the 1800s. Regrettably, this problem seems to have grown in the last decade, especially afflicting unsuspecting patients and those seeking medicines via on-line pharmacies. Here we discuss some of the challenges related to the fight against poor quality drugs, and counterfeits in particular, with an emphasis on the analytical tools available, their relative performance, and the necessary workflows needed for distinguishing between genuine, substandard, degraded and counterfeit medicines. PMID:21107455

In Vitro Activities of Benflumetol against 158 Senegalese Isolates of Plasmodium falciparum in Comparison with Those of Standard Antimalarial Drugs

PubMed Central

Pradines, Bruno; Tall, Adama; Fusai, Thierry; Spiegel, Andre; Hienne, Remi; Rogier, Christophe; Trape, Jean Francois; Le Bras, Jacques; Parzy, Daniel

1999-01-01

The 50% inhibitory concentration (IC50s) of benflumetol (range, 12.5 to 240 nM; mean, 55.1 nM) for 158 Senegalese isolates were evaluated. Ten isolates (6%) showed decreased susceptibility to benflumetol. Benflumetol was slightly more potent against chloroquine-resistant isolates (P < 0.025). No correlation or weak correlations in the responses to benflumetol and pyrimethamine, chloroquine, amodiaquine, artemether, quinine, and pyronaridine were observed, and these correlations are insufficient to suggest cross-resistance. Benflumetol may be an important alternative drug for the treatment of chloroquine-resistant malaria. PMID:9925550

Lead Poison Detection

NASA Technical Reports Server (NTRS)

1976-01-01

With NASA contracts, Whittaker Corporations Space Science division has developed an electro-optical instrument to mass screen for lead poisoning. Device is portable and detects protoporphyrin in whole blood. Free corpuscular porphyrins occur as an early effect of lead ingestion. Also detects lead in urine used to confirm blood tests. Test is inexpensive and can be applied by relatively unskilled personnel. Similar Whittaker fluorometry device called "drug screen" can measure morphine and quinine in urine much faster and cheaper than other methods.

Quinine for cramps.

PubMed

Pinn, G

1998-10-01

The bark of the cinchona tree was used by the Incas of South America to treat tropical fevers. It was brought back to Europe by the Jesuit priests and used in error to treat all types of fever. Because of its cost and lack of availability, apothecaries found an alternative antipyretic in willow bark. Subsequently salicylates were isolated from willow and quinine from cinchona bark. Quinine is used worldwide for the treatment of fever due to malaria, but in the Western environment has long been used for muscle cramps because of its neuro muscular junction blocking action. Quinine is a widely used medication which has been reported to cause thrombocytopenia on occasion. This potentially life threatening complication should be borne in mind when it is prescribed for minor symptoms such as muscle cramps.

In vivo testing of the therapeutic efficacy of chloroquine on falciparum malaria infections in Chirundu, Mashonaland West, Zimbabwe.

PubMed

Barduagni, P; Schwartz, U; Nyamayaro, W; Chauke, T L

1998-10-01

To detect the level of the in vivo chloroquine efficacy in falciparum malaria infections, in order to assess the need for change in the management and treatment of uncomplicated malaria. Prospective descriptive study. Chirundu Rural Clinic, Mashonaland West Province. 63 patients confirmed by a positive blood slide for P. falciparum who attended Chirundu clinic, who were eligible for the study and, who also agreed to participate. Frequency of treatment success, early treatment failure and late treatment failure in uncomplicated patients treated with chloroquine. Out of 63 cases enrolled and completely followed up, chloroquine treatment was effective in 54 cases (85.7%) and was not effective in nine cases (14.3%). All treatment failures were successfully treated with sulphadoxine + pyrimethamine (Fansidar) or quinine following the approved guidelines. Chloroquine remains highly effective in the treatment of malaria due to P. falciparum in the Zambezi Valley of Hurungwe district and therefore, has to remain the first line drug. Likewise, guidelines for the use of sulphadoxine + pyrimethamine (Fansidar) or quinine as second line drugs, are adequate to the local situation. Health workers directly supervised the patients when they were swallowing the tablets during the whole course, and this without doubt, indirectly increased the efficacy of chloroquine. It is vital to confirm the malaria diagnosis on the spot appointing microscopists or distributing a limited stock of Parasight-F test.

Quantitative extraction and concentration of synthetic water-soluble acid dyes from aqueous media using a quinine-chloroform solution

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

Kobayashi, F.; Ozawa, N.; Hanai, J.

Twenty-one water-soluble acid dyes, including eleven azo, five triphenylmethane four xanthene, one naphthol derivatives, used at practical concentrations for food coloration, were quantitatively extracted from water and various carbonated beverages into a 0.1 M quinine-chloroform solution in the presence of 0.5 M boric acid by brief shaking. Quantitative extraction of these dyes was also accomplished by the 0.1 M quinine-chloroform solution made conveniently from chloroform, quinine hydrochloride, and sodium hydroxide added successively to water or beverages containing boric acid. Quinine acted as a countercation on the dyes having sulfonic and/or carboxylic acid group(s) to form chloroform-soluble ion-pair complexes. The diacidicmore » base alkaloid interacted with each acid group of mono-, di-, tri-, and tetrasulfonic acid dyes approximately in the ratio 0.8-0.9 to 1. The dyes in the chloroform solution were quantitatively concentrated into a small volume of sodium hydroxide solution also by brief shaking. The convenient quinine-chloroform method was applicable to the quantitative extraction of a mixture of 12 dyes from carbonated beverages, which are all currently used for food coloration. A high-pressure liquid chromatographic method is also presented for the systematic separation and determination of these 12 dyes following their concentration into the aqueous alkaline solution. The chromatogram was monitored by double-wavelength absorptiometry in the visible and ultraviolet ray regions.« less

Electrochemical studies of quinine in surfactant media using hanging mercury drop electrode: a cyclic voltammetric study.

PubMed

Dar, Riyaz Ahmad; Brahman, Pradeep Kumar; Tiwari, Sweety; Pitre, Krishna Sadashiv

2012-10-01

The electrochemical behavior of quinine was investigated by cyclic voltammetry (CV) and square wave voltammetry (SWV) using surfactant. The reduction peak current of quinine increases remarkably in presence of 1% CTAB. Its electrochemical behavior is quasi-reversible in the Britton-Robinson buffers of pH 10.38 by exhibiting the well-defined single cathodic and anodic waves and the ratio of I(p)(a)/I(p)(c) approaching one at the scan rate of 500 mVs(-1). On the basis of CV, SWV and Coulometry, electrochemical reduction mechanism of quinine has been proposed which has shown that protonation occurs on the nitrogen of the quinoline moiety. Linearity was obtained when the peak currents (I(p)) were plotted against concentrations of quinine in the range of 30.0-230.0 ng mL(-1) with a detection limit of 0.132 ng mL(-1) in SWV and 90.0-630.0 ng mL(-1) with a detection limit of 0.238 ng mL(-1) in DPV. Fast and sensitive SWV has been applied for the quantitative analysis of quinine in bark of Cinchona sp. and in soft drinks and a good recovery was obtained. The accuracy and precision of the method are determined and validated statistically. No interferences from other food additives were observed. The relative standard deviation for intraday and interday assay was 0.89 and 0.73% (n=3) respectively. Copyright © 2012 Elsevier B.V. All rights reserved.

Increased ethanol consumption despite taste aversion in mice with a human tryptophan hydroxylase 2 loss of function mutation.

PubMed

Lemay, Francis; Doré, François Y; Beaulieu, Jean-Martin

2015-11-16

Polymorphisms in the gene encoding the brain serotonin synthesis enzyme Tph2 have been identified in mental illnesses, with co-morbidity of substance use disorder. However, little is known about the impact of Tph2 gene variants on addiction. Mice expressing a human Tph2 loss of function variant were used to investigate consequences of aversive conditions on ethanol intake. Mice were familiarized either with ethanol or a solution containing both ethanol and the bittering agent quinine. Effect of familiarization to ethanol or an ethanol-quinine solution was then evaluated using a two-bottles preference test in Tph2-KI and control littermates. Mice from both genotypes displayed similar levels of ethanol consumption and quinine avoidance when habituated to ethanol alone. In contrast, addition of quinine to ethanol during the familiarization period resulted in a reduction of avoidance for the quinine-ethanol solution only in mutant mice. These results indicate that loss of function mutation in Tph2 results in greater motivation for ethanol consumption under aversive conditions and may confer enhanced sensitivity to alcohol use disorder. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Taste thresholds and suprathreshold responses to tannin-rich plant extracts and quinine in a primate species (Microcebus murinus).

PubMed

Iaconelli, S; Simmen, B

2002-11-01

Theories of plant chemical defenses discriminate between quantitative digestibility reducers (e.g., tannins) and qualitative toxins (e.g., alkaloids). Since the differential effect on taste of these compounds is poorly known, we recorded ingestive responses of a primate species, Microcebus murinus, to four tannin-rich plant extracts and to quinine, by using the behavioral method of the "two-bottle test." The efficiency of tannic extracts at precipitating protein was measured with the blue BSA method. Inhibition taste thresholds for tannins added to a moderately sweet solution varied between 0.25 and 2 g/l. The threshold for quinine hydrochloride was 0.32 g/l. The profiles of the response/concentration curves established for these astringent and bitter substances were similar, with maximal inhibition of consumption occurring for near-threshold concentrations. The large amounts of quinine required to deter this small-bodied species from feeding were unexpected, given its unspecialized frugivorous/insectivorous diet. We propose that the taste responses of Microcebus to tannins have been shaped in relation to the widespread occurrence of efficient polyphenols in food plants, while low responsiveness to quinine reflects a low risk of ingesting toxic alkaloids when feeding on ripe fruits and insects.

SMS for Life: a pilot project to improve anti-malarial drug supply management in rural Tanzania using standard technology

PubMed Central

2010-01-01

Background Maintaining adequate supplies of anti-malarial medicines at the health facility level in rural sub-Saharan Africa is a major barrier to effective management of the disease. Lack of visibility of anti-malarial stock levels at the health facility level is an important contributor to this problem. Methods A 21-week pilot study, 'SMS for Life', was undertaken during 2009-2010 in three districts of rural Tanzania, involving 129 health facilities. Undertaken through a collaborative partnership of public and private institutions, SMS for Life used mobile telephones, SMS messages and electronic mapping technology to facilitate provision of comprehensive and accurate stock counts from all health facilities to each district management team on a weekly basis. The system covered stocks of the four different dosage packs of artemether-lumefantrine (AL) and quinine injectable. Results Stock count data was provided in 95% of cases, on average. A high response rate (≥ 93%) was maintained throughout the pilot. The error rate for composition of SMS responses averaged 7.5% throughout the study; almost all errors were corrected and messages re-sent. Data accuracy, based on surveillance visits to health facilities, was 94%. District stock reports were accessed on average once a day. The proportion of health facilities with no stock of one or more anti-malarial medicine (i.e. any of the four dosages of AL or quinine injectable) fell from 78% at week 1 to 26% at week 21. In Lindi Rural district, stock-outs were eliminated by week 8 with virtually no stock-outs thereafter. During the study, AL stocks increased by 64% and quinine stock increased 36% across the three districts. Conclusions The SMS for Life pilot provided visibility of anti-malarial stock levels to support more efficient stock management using simple and widely available SMS technology, via a public-private partnership model that worked highly effectively. The SMS for Life system has the potential to alleviate restricted availability of anti-malarial drugs or other medicines in rural or under-resourced areas. PMID:20979633

SMS for Life: a pilot project to improve anti-malarial drug supply management in rural Tanzania using standard technology.

PubMed

Barrington, Jim; Wereko-Brobby, Olympia; Ward, Peter; Mwafongo, Winfred; Kungulwe, Seif

2010-10-27

Maintaining adequate supplies of anti-malarial medicines at the health facility level in rural sub-Saharan Africa is a major barrier to effective management of the disease. Lack of visibility of anti-malarial stock levels at the health facility level is an important contributor to this problem. A 21-week pilot study, 'SMS for Life', was undertaken during 2009-2010 in three districts of rural Tanzania, involving 129 health facilities. Undertaken through a collaborative partnership of public and private institutions, SMS for Life used mobile telephones, SMS messages and electronic mapping technology to facilitate provision of comprehensive and accurate stock counts from all health facilities to each district management team on a weekly basis. The system covered stocks of the four different dosage packs of artemether-lumefantrine (AL) and quinine injectable. Stock count data was provided in 95% of cases, on average. A high response rate (≥ 93%) was maintained throughout the pilot. The error rate for composition of SMS responses averaged 7.5% throughout the study; almost all errors were corrected and messages re-sent. Data accuracy, based on surveillance visits to health facilities, was 94%. District stock reports were accessed on average once a day. The proportion of health facilities with no stock of one or more anti-malarial medicine (i.e. any of the four dosages of AL or quinine injectable) fell from 78% at week 1 to 26% at week 21. In Lindi Rural district, stock-outs were eliminated by week 8 with virtually no stock-outs thereafter. During the study, AL stocks increased by 64% and quinine stock increased 36% across the three districts. The SMS for Life pilot provided visibility of anti-malarial stock levels to support more efficient stock management using simple and widely available SMS technology, via a public-private partnership model that worked highly effectively. The SMS for Life system has the potential to alleviate restricted availability of anti-malarial drugs or other medicines in rural or under-resourced areas.

In Vitro Susceptibility of Plasmodium vivax to Antimalarials in Colombia

PubMed Central

Fernández, Diana; Segura, César; Arboleda, Margarita; Garavito, Giovanny; Blair, Silvia

2014-01-01

The in vitro susceptibilities of 30 isolates of Plasmodium vivax to a number of antimalarials (chloroquine [CQ], mefloquine, amodiaquine, quinine, and artesunate [AS]) were evaluated. The isolates came from the region of Urabá in Colombia, in which malaria is endemic, and were evaluated by the schizont maturation test. The 50% inhibitory concentration (IC50) was 0.6 nM (95% confidence interval [CI], 0.3 to 1.0 nM) for artesunate, 8.5 nM (95% CI, 5.6 to 13.0 nM) for amodiaquine, 23.3 nM (95% CI, 12.4 to 44.1 nM) for chloroquine, 55.6 nM (95% CI, 36.8 to 84.1 nM) for mefloquine, and 115.3 nM (95% CI, 57.7 to 230.5 nM) for quinine. The isolates were classified according to whether the initial parasites were mature or immature trophozoites (Tfz). It was found that the IC50s for chloroquine and artesunate were significantly different in the two aforementioned groups (P < 0.001). The IC50s of CQ and AS were higher in the isolates from mature Tfz (CQ, 39.3 nM versus 17 nM; AS, 1.4 nM versus 0.3 nM), and 10% of the isolates showed lower susceptibilities to one of the antimalarial drugs, 13.3% to two antimalarial drugs, and 3.3% to more than three antimalarial drugs. It should be highlighted that despite the extensive use of chloroquine in Colombia, P. vivax continues to be susceptible to antimalarials. This is the first report, to our knowledge, showing in vitro susceptibilities of P. vivax isolates to antimalarials in Colombia. PMID:25114141

Treatment regimens for pregnant women with falciparum malaria.

PubMed

Moore, Brioni R; Salman, Sam; Davis, Timothy M E

2016-08-01

With increasing parasite drug resistance, the WHO has updated treatment recommendations for falciparum malaria including in pregnancy. This review assesses the evidence for choice of treatment for pregnant women. Relevant studies, primarily those published since 2010, were identified from reference databases and were used to identify secondary data sources. Expert commentary: WHO recommends use of intravenous artesunate for severe malaria, quinine-clindamycin for uncomplicated malaria in first trimester, and artemisinin combination therapy for uncomplicated malaria in second/third trimesters. Because fear of adverse outcomes has often excluded pregnant women from conventional drug development, available data for novel therapies are usually based on preclinical studies and cases of inadvertent exposure. Changes in antimalarial drug disposition in pregnancy have been observed but are yet to be translated into specific treatment recommendations. Such targeted regimens may become important as parasite resistance demands that drug exposure is optimized.

Intra-/inter-laboratory validation study on reactive oxygen species assay for chemical photosafety evaluation using two different solar simulators.

PubMed

Onoue, Satomi; Hosoi, Kazuhiro; Toda, Tsuguto; Takagi, Hironori; Osaki, Naoto; Matsumoto, Yasuhiro; Kawakami, Satoru; Wakuri, Shinobu; Iwase, Yumiko; Yamamoto, Toshinobu; Nakamura, Kazuichi; Ohno, Yasuo; Kojima, Hajime

2014-06-01

A previous multi-center validation study demonstrated high transferability and reliability of reactive oxygen species (ROS) assay for photosafety evaluation. The present validation study was undertaken to verify further the applicability of different solar simulators and assay performance. In 7 participating laboratories, 2 standards and 42 coded chemicals, including 23 phototoxins and 19 non-phototoxic drugs/chemicals, were assessed by the ROS assay using two different solar simulators (Atlas Suntest CPS series, 3 labs; and Seric SXL-2500V2, 4 labs). Irradiation conditions could be optimized using quinine and sulisobenzone as positive and negative standards to offer consistent assay outcomes. In both solar simulators, the intra- and inter-day precisions (coefficient of variation; CV) for quinine were found to be below 10%. The inter-laboratory CV for quinine averaged 15.4% (Atlas Suntest CPS) and 13.2% (Seric SXL-2500V2) for singlet oxygen and 17.0% (Atlas Suntest CPS) and 7.1% (Seric SXL-2500V2) for superoxide, suggesting high inter-laboratory reproducibility even though different solar simulators were employed for the ROS assay. In the ROS assay on 42 coded chemicals, some chemicals (ca. 19-29%) were unevaluable because of limited solubility and spectral interference. Although several false positives appeared with positive predictivity of ca. 76-92% (Atlas Suntest CPS) and ca. 75-84% (Seric SXL-2500V2), there were no false negative predictions in both solar simulators. A multi-center validation study on the ROS assay demonstrated satisfactory transferability, accuracy, precision, and predictivity, as well as the availability of other solar simulators. Copyright © 2013 Elsevier Ltd. All rights reserved.

Increased preference for ethanol in the infant rat after prenatal ethanol exposure, expressed on intake and taste reactivity tests.

PubMed

Arias, Carlos; Chotro, M Gabriela

2005-03-01

Previous studies have shown that prenatal exposure during gestational days 17 to 20 to low or moderate doses of ethanol (1 or 2 g/kg) increases alcohol intake in infant rats. Taking into account that higher consumption does not necessarily suggest a preference for alcohol, in the present study, the hedonic nature of the prenatal experience was analyzed further with the use of a taste reactivity test. General activity, wall climbing, passive drips, paw licking, and mouthing in response to intraoral infusions of alcohol, water, and a sucrose-quinine solution (which resembles alcohol taste in rats) were tested in 161 preweanling 14-day-old rat pups that were prenatally exposed to 0, 1, or 2 g/kg of alcohol during gestational days 17 to 20. Consumption of those substances was measured during the taste reactivity test and on postnatal day 15. Pups that were prenatally exposed to both doses of ethanol displayed lower levels of general activity and wall climbing than controls in response to ethanol. Infant rats that were treated prenatally with both doses of ethanol showed higher intake of the drug and also more mouthing and paw licking in response to ethanol taste. Only pups that were exposed to the higher ethanol dose in utero generalized those responses to the sucrose-quinine compound. These results seem to indicate that for the infant rat, the palatability of ethanol is enhanced after exposure to the drug during the last days of gestation.

Calcium-Binding Properties of Sarcoplasmic Reticulum As Influenced by ATP, Caffeine, Quinine, and Local Anesthetics

PubMed Central

Carvalho, Arselio P.

1968-01-01

Calcium retained at binding sites of the sarcoplasmic reticulum membranes isolated from rabbit skeletal muscle requires 10-5 – 10-4 M ATP to exchange with 45Ca added to the medium. The ATP requirement for Ca exchangeability was observed with respect to the "intrinsic" Ca of the reticulum membranes and the fraction of Ca that is "actively" bound in the presence of ATP. Furthermore, a concentration of free Ca in the medium higher than 10-8 M is required for ATP to promote Ca exchangeability. This exchangeability is not influenced by caffeine, quinine, procaine, and tetracaine, and Ca that is either nonexchangeable (in the absence of ATP) or exchangeable (in the presence of ATP) is released by 1–5 mM quinine or tetracaine, but neither caffeine (6 mM) nor procaine (2–5 mM) has this effect. Quinine or tetracaine also releases Ca and Mg bound passively to the reticulum membranes. A possible role of ATP in maintaining the integrity of cellular membranes is discussed, and the effects of caffeine, quinine, and of local anesthetics on the binding of Ca by the isolated reticulum are related to the effects of these agents on 45Ca fluxes and on the twitch output observed in whole muscles. PMID:19873636

Multidrug and toxin extrusion proteins as transporters of antimicrobial drugs.

PubMed

Nies, Anne T; Damme, Katja; Schaeffeler, Elke; Schwab, Matthias

2012-12-01

Antimicrobial drugs are essential in the treatment of infectious diseases. A better understanding of transport processes involved in drug disposition will improve the predictability of drug-drug interactions with consequences for drug response. Multidrug And Toxin Extrusion (MATE; SLC47A) proteins are efflux transporters mediating the excretion of several antimicrobial drugs as well as other organic compounds into bile and urine, thereby contributing to drug disposition. This review summarizes current knowledge of the structural and molecular features of human MATE transporters including their functional role in drug transport with a specific focus on antimicrobial drugs. The PubMed database was searched using the terms "MATE1," "MATE-2K," "MATE2," "SLC47A1," "SLC47A2," and "toxin extrusion protein" (up to June 2012). MATE proteins have been recognized as important transporters mediating the final excretion step of cationic drugs into bile and urine. These include the antiviral drugs acyclovir, amprenavir, and ganciclovir, the antibiotics cephalexin, cephradine and levofloxacin, as well as the antimalarial agents chloroquine and quinine. It is therefore important to enhance our understanding of the role of MATEs in drug extrusion with particular emphasis on the functional consequences of genetic variants on disposition of these antimicrobial drugs.

Artemether for severe malaria

PubMed Central

Esu, Ekpereonne; Effa, Emmanuel E; Opie, Oko N; Uwaoma, Amirahobu; Meremikwu, Martin M

2014-01-01

Background In 2011 the World Health Organization (WHO) recommended parenteral artesunate in preference to quinine as first-line treatment for people with severe malaria. Prior to this recommendation, many countries, particularly in Africa, had begun to use artemether, an alternative artemisinin derivative. This review evaluates intramuscular artemether compared with both quinine and artesunate. Objectives To assess the efficacy and safety of intramuscular artemether versus any other parenteral medication in treating severe malaria in adults and children. Search methods We searched the Cochrane Infectious Diseases Group Specialized Register, CENTRAL (The Cochrane Library), MEDLINE, EMBASE and LILACS, ISI Web of Science, conference proceedings and reference lists of articles. We also searched the WHO clinical trial registry platform, ClinicalTrials.gov and the metaRegister of Controlled Trials (mRCT) for ongoing trials up to 9 April 2014. Selection criteria Randomized controlled trials (RCTs) comparing intramuscular artemether with intravenous or intramuscular antimalarial for treating severe malaria. Data collection and analysis The primary outcome was all-cause death.Two authors independently assessed trial eligibility, risk of bias and extracted data. We summarized dichotomous outcomes using risk ratios (RR) and continuous outcomes using mean differences (MD), and presented both measures with 95% confidence intervals (CI). Where appropriate, we combined data in meta-analyses and assessed the quality of the evidence using the GRADE approach. Main results We included 18 RCTs, enrolling 2662 adults and children with severe malaria, carried out in Africa (11) and in Asia (7). Artemether versus quinine For children in Africa, there is probably little or no difference in the risk of death between intramuscular artemether and quinine (RR 0.96, 95% CI 0.76 to 1.20; 12 trials, 1447 participants, moderate quality evidence). Coma recovery may be about five hours shorter with artemether (MD -5.45, 95% CI -7.90 to -3.00; six trials, 358 participants, low quality evidence), and artemether may result in fewer neurological sequelae, but larger trials would be needed to confirm this (RR 0.84, 95% CI 0.66 to 1.07; seven trials, 968 participants, low quality evidence). Artemether probably shortens the parasite clearance time by about nine hours (MD -9.03, 95% CI -11.43 to -6.63; seven trials, 420 participants, moderate quality evidence), and may shorten the fever clearance time by about three hours (MD -3.73, 95% CI -6.55 to -0.92; eight trials, 457 participants, low quality evidence). For adults in Asia, treatment with intramuscular artemether probably results in fewer deaths than treatment with quinine (RR 0.59, 95% CI 0.42 to 0.83; four trials, 716 participants, moderate quality evidence). Artemether versus artesunate Artemether and artesunate have not been directly compared in randomized trials in African children. For adults in Asia, mortality is probably higher with intramuscular artemether (RR 1.80, 95% CI 1.09 to 2.97, two trials,494 participants, moderate quality evidence). Authors' conclusions Although there is a lack of direct evidence comparing artemether with artesunate, artemether is probably less effective than artesunate at preventing deaths from severe malaria. In circumstances where artesunate is not available, artemether is an alternative to quinine. PLAIN LANGUAGE SUMMARY Artemether injection for treating people with severe malaria In this review, researchers from The Cochrane Collaboration examined the effects of treating people that have severe malaria with artemether injected intramuscularly, and compared it to treatment with other antimalarial drugs given intramuscularly or intravenously. After searching for relevant trials up to 9 April 2014, we included 18 randomized controlled trials that recruited 2662 adults and children and were conducted mainly in Africa and Asia. What is severe malaria and how might artemether injection reduce deaths Severe malaria is caused by infection with the Plasmodium parasite, which is transmitted to people through the bite of an infected female Anopheles mosquito. It is a serious medical condition and can cause vomiting, anaemia, convulsions and death. People need to be treated as quickly as possible. Injection of artesunate is recommended by the World Health Organization (WHO) for treating adults and children that have severe malaria as trials have shown that it results in fewer deaths compared to quinine treatment. Artemether is an alternative artemisinin derivative but is only available as a pre-mixed oil-based solution for intramuscular injection. Artemether is now widely available and is used in many African countries, although it is not specifically recommended by the WHO. What the research says Artemether versus quinine: For children in Africa, intramuscular artemether is probably as good as quinine at preventing deaths from severe malaria (moderate quality evidence). Artemether may shorten recovery time from coma by about five hours (low quality evidence), and may reduce the number of children with signs of brain damage at the time of hospital discharge (low quality evidence). In older children (= 15 years) and adults in Asia, treatment with artemether probably results in fewer deaths than quinine (moderate quality evidence). Artemether versus artesunate: In adults from Asia, artesunate probably prevents more deaths than artemether (moderate quality evidence), but no trials have been conducted in young children from Africa. Authors conclusions Although there is a lack of direct evidence comparing artemether with artesunate, artemether is probably less effective than artesunate at preventing deaths from severe malaria. In circumstances where artesunate is not available, artemether is an alternative to quinine. PMID:25209020

Strengthening of national capacity in implementation of antimalarial drug quality assurance in Thailand.

PubMed

Vijaykadga, Saowanit; Cholpol, Sawat; Sitthimongkol, Saipin; Pawaphutanan, Anusorn; Pinyoratanachot, Arunya; Rojanawatsirivet, Chaiporn; Kovithvattanapong, Rojana; Thimasarn, Krongthong

2006-01-01

Substandard and counterfeit pharmaceutical products, including antimalarial drugs, appear to be widespread internationally and affect both the developing and developed countries. The aim of the study was to investigate the quality of antimalarial drugs, ie, artesunate (ART), chloroquine (CHL), mefloquine (MEF), quinine (QUI), sulfadoxine/pyrimethamine (S/P) and tetracycline (TT) obtained from the government sector and private pharmacies in 4 Thai provinces: Mae Hong Son, Kanchanaburi, Ranong, and Chanthaburi. Three hundred sixty-nine samples of 6 antimalarial drugs from 27 government hospitals, 27 malaria clinics, and 53 drugstores, were collected. Drug quality was assessed by simple disintegration test and semi-quantitative thin-layer chromatography in each province; 10% passed, 100% failed and doubtful samples were sent to be verified by high performance liquid chromatography (HPLC) at the Thai National Drug Analysis Laboratory, (NL). Fifteen point four percent of ART, 11.1% of CHL and 29.4% of QUI were substandard. Based on the finding, drug regulatory authorities in the country took appropriate action against violators to ensure that antimalarial drugs consumed by malaria patients are of good quality.

Antimalarial drug policy in India: past, present & future.

PubMed

Anvikar, Anupkumar R; Arora, Usha; Sonal, G S; Mishra, Neelima; Shahi, Bharatendu; Savargaonkar, Deepali; Kumar, Navin; Shah, Naman K; Valecha, Neena

2014-02-01

The use of antimalarial drugs in India has evolved since the introduction of quinine in the 17 th century. Since the formal establishment of a malaria control programme in 1953, shortly after independence, treatments provided by the public sector ranged from chloroquine, the mainstay drug for many decades, to the newer, recently introduced artemisinin based combination therapy. The complexity of considerations in antimalarial treatment led to the formulation of a National Antimalarial Drug Policy to guide procurement as well as communicate best practices to both public and private healthcare providers. Challenges addressed in the policy include the use of presumptive treatment, the introduction of alternate treatments for drug-resistant malaria, the duration of primaquine therapy to prevent relapses of vivax malaria, the treatment of malaria in pregnancy, and the choice of drugs for chemoprophylaxis. While data on antimalarial drug resistance and both public and private sector treatment practices have been recently reviewed, the policy process of setting national standards has not. In this perspective on antimalarial drug policy, this review highlights its relevant history, analyzes the current policy, and examines future directions.

Antimalarial drug discovery: screening of Brazilian medicinal plants and purified compounds.

PubMed

Krettli, Antoniana Ursine

2009-02-01

Malaria is the most important parasitic disease and its control depends on specific chemotherapy, now complicated by Plasmodium falciparum that has become resistant to most commonly available antimalarials. Treatment of the disease requires quinine or drug combinations of artemisinin derivatives and other antimalarials. Further drug resistance is expected. New active compounds need to be discovered. To find new antimalarials from medicinal and randomly collected plants, crude extracts are screened against P. falciparum in cultures and in malaria animal models, following bioassays of purified fractions, and cytotoxicity tests. For antimalarial research, screening medicinal plants is more efficient than screening randomly chosen plants. Biomonitored fractionation allows selection of new active molecules identified as potential antimalarials in multidisciplinary projects in Brazil; no new molecule is available for human testing. The advantages of projects based on ethnopharmacology are discussed.

Worms taste bitter: ASH neurons, QUI-1, GPA-3 and ODR-3 mediate quinine avoidance in Caenorhabditis elegans

PubMed Central

Hilliard, Massimo A; Bergamasco, Carmela; Arbucci, Salvatore; Plasterk, Ronald HA; Bazzicalupo, Paolo

2004-01-01

An animal's ability to detect and avoid toxic compounds in the environment is crucial for survival. We show that the nematode Caenorhabditis elegans avoids many water-soluble substances that are toxic and that taste bitter to humans. We have used laser ablation and a genetic cell rescue strategy to identify sensory neurons involved in the avoidance of the bitter substance quinine, and found that ASH, a polymodal nociceptive neuron that senses many aversive stimuli, is the principal player in this response. Two G protein α subunits GPA-3 and ODR-3, expressed in ASH and in different, nonoverlapping sets of sensory neurons, are necessary for the response to quinine, although the effect of odr-3 can only be appreciated in the absence of gpa-3. We identified and cloned a new gene, qui-1, necessary for quinine and SDS avoidance. qui-1 codes for a novel protein with WD-40 domains and which is expressed in the avoidance sensory neurons ASH and ADL. PMID:14988722

Application of solid-phase microextraction in the investigation of protein binding of pharmaceuticals.

PubMed

Theodoridis, Georgios

2006-01-18

Protein-drug interactions of seven common pharmaceuticals were studied using solid-phase microextraction (SPME). SPME can be used in such investigations on the condition that no analyte depletion occurs. In multi-compartment systems (e.g. a proteinaceous matrix) only the free portion of the analyte is able to partition into the SPME fiber. In addition if no sample depletion occurs, the bound drug-free drug equilibria are not disturbed. In the present study seven pharmaceuticals (quinine, quinidine, naproxen, ciprofloxacin, haloperidol, paclitaxel and nortriptyline) were assayed by SPME. For quantitative purposes SPME was validated first in the absence of proteins. Calibration curves were constructed for each drug by HPLC-fluorescence and HPLC-UV analysis. SPME was combined to HPLC off-line, desorption occurring in HPLC inserts filled with 200 microL methanol. Binding of each drug to human serum albumin was studied independently. Experimental results were in agreement with literature data and ultrafiltration experiments, indicating the feasibility of the method for such bioanalytical purposes.

Impact of poor-quality medicines in the 'developing' world.

PubMed

Newton, Paul N; Green, Michael D; Fernández, Facundo M

2010-03-01

Since our ancestors began trading several millennia ago, counterfeit and substandard medicines have been a recurring problem, with history punctuated by crises in the supply of anti-microbials, such as fake cinchona bark in the 1600s and fake quinine in the 1800s. Unfortunately this problem persists, in particular afflicting unsuspecting patients in 'developing' countries. Poor-quality drugs are a vital (but neglected) public health problem. They contribute to a 'crevasse' between the enormous effort in therapeutic research and policy decisions and implementation of good-quality medicines. 2009 Elsevier Ltd. All rights reserved.

Amodiaquine induced agranulocytosis: inhibition of colony growth in bone marrow by antimalarial agents.

PubMed Central

Rhodes, E G; Ball, J; Franklin, I M

1986-01-01

Bone marrow was cultured in vitro for colonies of granulocytes and macrophages five months after a patient had recovered from amodiaquine induced agranulocytosis. The addition of amodiaquine, chloroquine, and sulfadoxine to the culture was followed by a dose dependent inhibition of colony growth in the patient's marrow but not in normal control bone marrow. Colony growth was, however, unaffected by proguanil, pyrimethamine, and quinine. These findings show that in vitro marrow culture may have important predictive value in some cases of drug induced agranulocytosis. PMID:3082409

Impact of poor-quality medicines in the ‘developing’ world

PubMed Central

Newton, Paul N.; Green, Michael D.; Fernández, Facundo M.

2010-01-01

Since our ancestors began trading several millennia ago, counterfeit and substandard medicines have been a recurring problem, with history punctuated by crises in the supply of anti-microbials, such as fake cinchona bark in the 1600s and fake quinine in the 1800s. Unfortunately this problem persists, in particular afflicting unsuspecting patients in ‘developing’ countries. Poor-quality drugs are a vital (but neglected) public health problem. They contribute to a ‘crevasse’ between the enormous effort in therapeutic research and policy decisions and implementation of good-quality medicines. PMID:20117849

Drugs and Alcohol in Civil Aviation Accident Pilot Fatalities from 2004-2008

DTIC Science & Technology

2011-09-01

Quinine 16 0.9 19 1.1 37 2.3 42 3.1 FDA 򒾅 Salicylatesβ 96 5.2 114 6.8 41 2.6 11 0.8 FDA 򒾅 Simethicone 0 0.0 0 0.0 0 0.0 1 0.1 FDA 1996... Simethicone 0 0.0 0 0.0 0 0.0 1 0.1 FDA 1996 Triprolidine 0 0.0 0 0.0 2 0.1 2 0.1 FDA 򒾅 β – Screening Cutoff Increased in 2002 μ - Public Law

Science in the service of colonial agro-industrialism: the case of cinchona cultivation in the Dutch and British East Indies, 1852-1900.

PubMed

Roersch van der Hoogte, Arjo; Pieters, Toine

2014-09-01

The isolation of quinine from cinchona bark in 1820 opened new possibilities for the mass-production and consumption of a popular medicine that was suitable for the treatment of intermittent (malarial) fevers and other diseases. As the 19th century European empires expanded in Africa and Asia, control of tropical diseases such as malaria was seen as crucial. Consequently, quinine and cinchona became a pivotal tool of British, French, German and Dutch empire-builders. This comparative study shows how the interplay between science, industry and government resulted in different historical trajectories for cinchona and quinine in the Dutch and British Empires during the second half of the 19th century. We argue that in the Dutch case the vectors of assemblage that provided the institutional and physical framework for communication, exchange and control represent an early example of commodification of colonial science. Furthermore, both historical trajectories show how the employment of the laboratory as a new device materialised within the colonial context of agricultural and industrial production of raw materials (cinchona bark), semi-finished product (quinine sulphate) and plant-based medicines like quinine. Hence, illustrating the 19th century transition from 'colonial botany' and 'green imperialism' to what we conceptualise as 'colonial agro-industrialism'. Copyright © 2014 Elsevier Ltd. All rights reserved.

Intake of Ethanol, Sodium Chloride, Sucrose, Citric Acid, and Quinine Hydrochloride Solutions by Mice: A Genetic Analysis

PubMed Central

Bachmanov, A. A.; Reed, D. R.; Tordoff, M. G.; Price, R. A.; Beauchamp, G. K.

2013-01-01

Mice of the 129/J (129) and C57BL/6ByJ (B6) strains and their reciprocal F1 and F2 hybrids were offered solutions of ethanol, sucrose, citric acid, quinine hydrochloride, and NaCI in two-bottle choice tests. Consistent with earlier work, the B6 mice drank more ethanol, sucrose, citric acid, and quinine hydrochloride solution and less NaCI solution than did 129 mice. Analyses of each generation’s means and distributions showed that intakes of ethanol, quinine, sucrose, and NaCI were influenced by a few genes. The mode of inheritance was additive in the case of ethanol and quinine, for sucrose the genotype of the 129 strain was recessive, and for NaCI it was dominant. Citric acid intake appeared to be influenced by many genes with small effects, with the 129 genotype dominant. Correlations of sucrose consumption with ethanol and citric acid consumption were found among mice of the F2 generation, and the genetically determined component of these correlations was stronger than the component related to environmental factors. The genetically determined correlation between sucrose and ethanol intakes is consistent with the hypothesis that the higher ethanol intake by B6 mice depends, in part, on higher hedonic attractiveness of its sweet taste component. PMID:8990535

Impact of retreatment with an artemisinin-based combination on malaria incidence and its potential selection of resistant strains: study protocol for a randomized controlled clinical trial

PubMed Central

2013-01-01

Background Artemisinin-based combination therapy is currently recommended by the World Health Organization as first-line treatment of uncomplicated malaria. Recommendations were adapted in 2010 regarding rescue treatment in case of treatment failure. Instead of quinine monotherapy, it should be combined with an antibiotic with antimalarial properties; alternatively, another artemisinin-based combination therapy may be used. However, for informing these policy changes, no clear evidence is yet available. The need to provide the policy makers with hard data on the appropriate rescue therapy is obvious. We hypothesize that the efficacy of the same artemisinin-based combination therapy used as rescue treatment is as efficacious as quinine + clindamycin or an alternative artemisinin-based combination therapy, without the risk of selecting drug resistant strains. Design We embed a randomized, open label, three-arm clinical trial in a longitudinal cohort design following up children with uncomplicated malaria until they are malaria parasite free for 4 weeks. The study is conducted in both the Democratic Republic of Congo and Uganda and performed in three steps. In the first step, the pre-randomized controlled trial (RCT) phase, children aged 12 to 59 months with uncomplicated malaria are treated with the recommended first-line drug and constitute a cohort that is passively followed up for 42 days. If the patients experience an uncomplicated malaria episode between days 14 and 42 of follow-up, they are randomized either to quinine + clindamycin, or an alternative artemisinin-based combination therapy, or the same first-line artemisinin-based combination therapy to be followed up for 28 additional days. If between days 14 and 28 the patients experience a recurrent parasitemia, they are retreated with the recommended first-line regimen and actively followed up for another 28 additional days (step three; post-RCT phase). The same methodology is followed for each subsequent failure. In any case, all patients without an infection at day 28 are classified as treatment successes and reach a study endpoint. The RCT phase allows the comparison of the safety and efficacy of three rescue treatments. The prolonged follow-up of all children until they are 28 days parasite-free allows us to assess epidemiological-, host- and parasite-related predictors for repeated malaria infection. Trial registration NCT01374581 and PACTR201203000351114 PMID:24059911

Halide (Cl(super -)) Quenching of Quinine Sulfate Fluorescence: A Time-Resolved Fluorescence Experiment for Physical Chemistry

ERIC Educational Resources Information Center

Gutow, Jonathan H.

2005-01-01

The time-resolved fluorescence experiment investigating the halide quenching of fluorescence from quinine sulfate in water is described. The objectives of the experiment include reinforcing student understanding of the kinetics of competing pathways, making connections with microscopic theories of kinetics through comparison of experimental and…

Bitter Taste Stimuli Induce Differential Neural Codes in Mouse Brain

PubMed Central

Wilson, David M.; Boughter, John D.; Lemon, Christian H.

2012-01-01

A growing literature suggests taste stimuli commonly classified as “bitter” induce heterogeneous neural and perceptual responses. Here, the central processing of bitter stimuli was studied in mice with genetically controlled bitter taste profiles. Using these mice removed genetic heterogeneity as a factor influencing gustatory neural codes for bitter stimuli. Electrophysiological activity (spikes) was recorded from single neurons in the nucleus tractus solitarius during oral delivery of taste solutions (26 total), including concentration series of the bitter tastants quinine, denatonium benzoate, cycloheximide, and sucrose octaacetate (SOA), presented to the whole mouth for 5 s. Seventy-nine neurons were sampled; in many cases multiple cells (2 to 5) were recorded from a mouse. Results showed bitter stimuli induced variable gustatory activity. For example, although some neurons responded robustly to quinine and cycloheximide, others displayed concentration-dependent activity (p<0.05) to quinine but not cycloheximide. Differential activity to bitter stimuli was observed across multiple neurons recorded from one animal in several mice. Across all cells, quinine and denatonium induced correlated spatial responses that differed (p<0.05) from those to cycloheximide and SOA. Modeling spatiotemporal neural ensemble activity revealed responses to quinine/denatonium and cycloheximide/SOA diverged during only an early, at least 1 s wide period of the taste response. Our findings highlight how temporal features of sensory processing contribute differences among bitter taste codes and build on data suggesting heterogeneity among “bitter” stimuli, data that challenge a strict monoguesia model for the bitter quality. PMID:22844505

Quinine Pharmacokinetics and Pharmacodynamics in Children with Malaria Caused by Plasmodium falciparum

PubMed Central

Le Jouan, M.; Jullien, V.; Tetanye, E.; Tran, A.; Rey, E.; Tréluyer, J.-M.; Tod, M.; Pons, G.

2005-01-01

The aim of the present study was to assess the pharmacokinetics and the efficacy of a shorter than usual 5-day quinine treatment given orally to children in Cameroon with malaria caused by Plasmodium falciparum. Quinine (8.3 mg of base per kg of body weight every 8 h) was administered as a 2% formiate salt syrup for 5 days to 30 children (age range, 0.55 to 6.7 years) with uncomplicated falciparum malaria (initial parasitemia, 1.4 × 103 to 1.8 × 105/μl). Quinine concentrations in plasma samples (five to nine per patient) were measured by liquid chromatography on days 1 to 3. Parasitemia was counted on days 0, 1, 2, 3, 4, 7, and 14. Pharmacokinetic and pharmacodynamic data were analyzed by population approaches by using NONMEM and WinBugs, respectively. The kinetics of quinine were best described by a one-compartment model with time-varying protein binding. Clearance and the volume of distribution were positively correlated with body weight and increased over time. Parasitemia was undetectable from day 3 to 14 in all children. The time to a 4-log reduction of the initial level of parasitemia (Ter) was related to the average quinine concentration from 0 to 72 h (Cav) as Ter = Tmin [1 + (C50/Cav)s], where sigmoidicity (s) is equal to 2, Tmin is the time to eradication at infinite Cav, and C50 is the value of Cav for which Ter is twice Tmin. The C50 distribution was unimodal, and all C50 values were less than 8 mg/liter, while Cav ranged from 5.9 to 18.3 mg/liter. The median (10th to 90th percentile) Ter was 47 h (range, 39 to 76 h). The efficacy of a 5-day treatment course should be evaluated in a larger clinical trial. PMID:16127036

A histidine-rich protein 2-based malaria drug sensitivity assay for field use.

PubMed

Noedl, Harald; Attlmayr, Bernhard; Wernsdorfer, Walther H; Kollaritsch, Herwig; Miller, Robert S

2004-12-01

With the spread of antimalarial drug resistance, simple and reliable tools for the assessment of antimalarial drug resistance, particularly in endemic regions and under field conditions, have become more important than ever before. We therefore developed a histidine-rich protein 2 (HRP2)-based drug sensitivity assay for testing of fresh isolates of Plasmodium falciparum in the field. In contrast to the HRP2 laboratory assay, the field assay uses a procedure that further simplifies the handling and culturing of malaria parasites by omitting centrifugation, washing, the use of serum, and dilution with uninfected red blood cells. A total of 40 fresh Plasmodium falciparum isolates were successfully tested for their susceptibility to dihydroartemisinin, mefloquine, quinine, and chloroquine (50% inhibitory concentration [IC50] = 3.43, 61.89, 326.75, and 185.31 nM, respectively). Results very closely matched those obtained with a modified World Health Organization schizont maturation assay (R2 = 0.96, P < 0.001; mean log difference at IC50 = 0.054).

Plants as antimalarial agents in Sub-Saharan Africa.

PubMed

Chinsembu, Kazhila C

2015-12-01

Although the burden of malaria is decreasing, parasite resistance to current antimalarial drugs and resistance to insecticides by vector mosquitoes threaten the prospects of malaria elimination in endemic areas. Corollary, there is a scientific departure to discover new antimalarial agents from nature. Because the two antimalarial drugs quinine and artemisinin were discovered through improved understanding of the indigenous knowledge of plants, bioprospecting Sub-Saharan Africa's enormous plant biodiversity may be a source of new and better drugs to treat malaria. This review analyses the medicinal plants used to manage malaria in Sub-Saharan Africa. Chemical compounds with antiplasmodial activity are described. In the Sub-Saharan African countries cited in this review, hundreds of plants are used as antimalarial remedies. While the number of plant species is not exhaustive, plants used in more than one country probably indicate better antimalarial efficacy and safety. The antiplasmodial data suggest an opportunity for inventing new antimalarial drugs from Sub-Saharan-African flora. Copyright © 2015 Elsevier B.V. All rights reserved.

Micro-RNA detection based on fluorescence resonance energy transfer of DNA-carbon quantum dots probes.

PubMed

Khakbaz, Faeze; Mahani, Mohamad

2017-04-15

Carbon quantum dots have been proposed as an effective platform for miRNA detection. Carbon dots were synthesized by citric acid. The synthesized dots were characterized by dynamic light scattering, UV-Vis spectrophotometry, spectrofluorimetry, transmission electron microscopy and FT-IR spectrophotometry. The fluorescence quantum yield of the synthesized dots was determined using quinine sulfate as the standard. The FAM-labeled single stranded DNA, as sensing element, was adsorbed on dots by π-π interaction. The quenching of the dots fluorescence due to fluorescence resonance energy transfer (FRET) was used for mir 9-1 detection. In the presence of the complementary miRNA, the FRET did not take place and the fluorescence was recovered. Copyright © 2017 Elsevier Inc. All rights reserved.

Sweet and bitter taste of ethanol in C57BL/6J and DBA2/J mouse strains.

PubMed

Blizard, David A

2007-01-01

Studies of inbred strains of rats and mice have suggested a positive association between strain variations in sweet taste and ethanol intake. However, strain associations by themselves are insufficient to support a functional link between taste and ethanol intake. We used conditioned taste aversion (CTA) to explore the sweet and bitter taste of ethanol and ability to detect sucrose, quinine and ethanol in C57BL/6J (B6) and DBA/2J (D2) mouse strains that are frequently used in alcohol research. The present study showed that C57BL/6J mice generalized taste aversions from sucrose and quinine solutions to 10% ethanol and, reciprocally, aversions to 10% ethanol generalized to each of these solutions presented separately. Only conditioned aversions to quinine generalized to ethanol in the DBA/2J strain but an aversion conditioned to ethanol did not generalize reciprocally to quinine. Thus, considering these two gustatory qualities, 10% ethanol tastes both sweet and bitter to B6 mice but only bitter to D2. Both strains were able to generalize taste aversions across different concentrations of the same compound. B6 were able to detect lower concentrations of quinine than D2 but both strains were able to detect sucrose and (in contrast to previous findings) ethanol at similar concentrations. The strain-dependent gustatory profiles for ethanol may make an important contribution to the understanding of the undoubtedly complex mechanisms influencing high ethanol preference of B6 and pronounced ethanol avoidance of D2 mice.

Cytochrome P450 induction by rifampicin in healthy subjects: determination using the Karolinska cocktail and the endogenous CYP3A4 marker 4beta-hydroxycholesterol.

PubMed

Kanebratt, K P; Diczfalusy, U; Bäckström, T; Sparve, E; Bredberg, E; Böttiger, Y; Andersson, T B; Bertilsson, L

2008-11-01

The Karolinska cocktail, comprising caffeine, losartan, omeprazole, and quinine, was given before and after administration of rifampicin (20, 100, or 500 mg daily) to measure induction of cytochrome P450 (P450) enzymes. Rifampicin was given for 14 days to eight healthy subjects (all of whom possessed at least one wild-type CYP2C9 and one wild-type CYP2C19 gene) in each dose group. 4beta-hydroxycholesterol was assessed as an endogenous marker of CYP3A4 induction. A fourfold induction of CYP3A4 was seen at the highest dose by both quinine:3'-hydroxyquinine and 4beta-hydroxycholesterol measurements (P < 0.001). CYP3A4 was also induced at the two lower doses of rifampicin when measured by these two markers (P < 0.01 or P < 0.001). CYP1A2, CYP2C9, and CYP2C19 were induced after 500 mg rifampicin daily (1.2-fold, P < 0.05; 1.4-fold, P < 0.05; and 4.2-fold, P < 0.01, respectively). In conclusion, we have shown that the Karolinska cocktail and 4beta-hydroxycholesterol can be used for an initial screening of the induction properties of a drug candidate.

Quantitative determination of major alkaloids in Cinchona bark by Supercritical Fluid Chromatography.

PubMed

Murauer, Adele; Ganzera, Markus

2018-06-15

Chinoline alkaloids found in Cinchona bark still play an important role in medicine, for example as antimalarial and antiarrhythmic drugs. For the first time Supercritical Fluid Chromatography has been utilized for their separation. Six respective derivatives (dihydroquinidine, dihydroquinine, quinidine, quinine, cinchonine and cinchonidine) could be resolved in less than 7 min, and three of them quantified in crude plant extracts. The optimum stationary phase showed to be an Acquity UPC 2 Torus DEA 1.7 μm column, the mobile phase comprised of CO 2 , acetonitrile, methanol and diethylamine. Method validation confirmed that the procedure is selective, accurate (recovery rates from 97.2% to 103.7%), precise (intra-day ≤2.2%, inter-day ≤3.0%) and linear (R 2  ≥ 0.999); at 275 nm the observed detection limits were always below 2.5 μg/ml. In all of the samples analyzed cinchonine dominated (1.87%-2.30%), followed by quinine and cinchonidine. Their total content ranged from 4.75% to 5.20%. These values are in good agreement with published data, so that due to unmatched speed and environmental friendly character SFC is definitely an excellent alternative for the analysis of these important natural products. Copyright © 2018 The Author(s). Published by Elsevier B.V. All rights reserved.

“A Spoonful of Sugar Helps the Medicine Go Down”: Bitter Masking by Sucrose Among Children and Adults

PubMed Central

Reed, Danielle R.; Mathew, Phoebe S.; Roberts, Kristi M.; Mansfield, Corrine J.

2015-01-01

Sweeteners are often added to liquid formulations of drugs but whether they merely make them better tasting or actually reduce the perception of bitterness remains unknown. In a group of children and adults, we determined whether adding sucrose to urea, caffeine, denatonium benzoate, propylthiouracil (PROP), and quinine would reduce their bitterness using a forced-choice method of paired comparisons. To better understand individual differences, adults also rated each solution using a more complex test (general Labeled Magnitude Scale [gLMS]) and were genotyped for the sweet taste receptor gene TAS1R3 and the bitter receptor TAS2R38. Sucrose suppressed the bitterness of each agent in children and adults. In adults, sucrose was effective in reducing the bitterness ratings from moderate to weak for all compounds tested, but those with the sensitive form of the sweet receptor reported greater reduction for caffeine and quinine. For PROP, sucrose was most effective for those who were genetically the most sensitive, although this did not attain statistical significance. Not only is the paired comparison method a valid tool to study how sucrose improves the taste of pediatric medicines among children but knowledge gleaned from basic research in bitter taste and how to alleviate it remains an important public health priority. PMID:25381313

Therapeutic Responses to Different Antimalarial Drugs in Vivax Malaria

PubMed Central

Pukrittayakamee, Sasithon; Chantra, Arun; Simpson, Julie A.; Vanijanonta, Sirivan; Clemens, Ralf; Looareesuwan, Sornchai; White, Nicholas J.

2000-01-01

The therapeutic responses to the eight most widely used antimalarial drugs were assessed in 207 adult patients with Plasmodium vivax malaria. This parasite does not cause marked sequestration, so parasite clearance can be used as a direct measure of antimalarial activity. The activities of these drugs in descending order were artesunate, artemether, chloroquine, mefloquine, quinine, halofantrine, primaquine, and pyrimethamine-sulfadoxine (PS). Therapeutic responses to PS were poor; parasitemias did not clear in 5 of the 12 PS-treated patients, whereas all the other patients made an initial recovery. Of 166 patients monitored for ≥28 days, 35% had reappearance of vivax malaria 11 to 65 days later and 7% developed falciparum malaria 5 to 21 days after the start of treatment. There were no significant differences in the times taken for vivax malaria reappearance among the different groups except for those given mefloquine and chloroquine, in which all vivax malaria reappearances developed >28 days after treatment, suggesting suppression of the first relapse by these slowly eliminated drugs. There was no evidence of chloroquine resistance. The antimalarial drugs vary considerably in their intrinsic activities and stage specificities of action. PMID:10817728

Discordant Temporal Evolution of Pfcrt and Pfmdr1 Genotypes and Plasmodium falciparum In Vitro Drug Susceptibility to 4-Aminoquinolines after Drug Policy Change in French Guiana

PubMed Central

Yrinesi, Joséphine; Ekala, Marie-Thérèse; Péneau, Julie; Volney, Béatrice; Berger, Franck; Bouchier, Christiane; Bertani, Stéphane; Musset, Lise; Meynard, Jean-Baptiste; Mercereau-Puijalon, Odile

2012-01-01

Analysis of the evolution of drug target genes under changing drug policy is needed to assist monitoring of Plasmodium falciparum drug resistance in the field. Here we genotype Pfcrt and Pfdmr1 of 700 isolates collected in French Guiana from 2000 (5 years after withdrawal of chloroquine) to 2008, i.e., the period when the artemether-lumefantrine combination was progressively introduced and mefloquine was abandoned. Gene sequencing showed fixation of the 7G8-type Pfcrt SMVNT resistance haplotype and near fixation of the NYCDY Pfdmr1 haplotype. Pfdmr1 gene copy number correlated with 50% inhibitory concentrations of mefloquine and halofantrine (r = 0.64 and 0.47, respectively, n = 547); its temporal changes paralleled changes in in vitro mefloquine susceptibility. However, the molecular parameters studied did not account for the regained in vitro susceptibility to chloroquine and showed a poor correlation with susceptibility to artemether, lumefantrine, or quinine. Identification of novel markers of resistance to these antimalarials is needed in this South American area. PMID:22232280

Trends in malaria case management following changes in the treatment policy to artemisinin combination therapy at the Mbakong Health Centre, Cameroon 2006-2012: a retrospective study.

PubMed

Ndong, Ignatius C; Reenen, Mari van; Boakye, Daniel A; Mbacham, Wilfred F; Grobler, Anne F

2015-10-01

National malaria treatment policies are devised to guide health professionals and to facilitate diagnosis and case management. Following the recommendations of the WHO, Cameroon changed its malaria treatment policy from monotherapy to artemisinin-based combination therapy (ACT) as the first-line treatment for uncomplicated malaria. We report an investigation into trends of case management following this change in policy. Data was collected retrospectively, through consultation and perusal of laboratory and prescription registers of the Mbakong Health Centre. Analysis of data was done using SPSS and SAS Statistics. Data presented herein demonstrate that from 2006 to 2012, a total of 2484 (58.7%) of the total prescriptions included an anti-malarial, 1989 (47.0%) included an antibiotic and 1935(45.7%) included an antipyretic. The anti-malarials prescribed were Anti-malaria combination therapy (ACT) - 1216 (47.6%), quinine 1044 (40.8%) or SP 296 (11.6%). Of the 1216 patients prescribed an ACT, 441(36.3%) had a positive malaria parasite confirmation, 746 (61.3%) were negative for plasmodium. Overall, 29 patients (2.4%) were treated either with an ACT without any test performed. Quinine intake was recorded in 566 (54.2%) patients positive for plasmodium. ACT prescription increased from 23% in 2007 to between 44 and 45% in 2008-2009. During this period there was a corresponding drop in the prescription of quinine from 38% in 2007 to 13% in 2009 (r=-0.43, p>0.05). Sulphadoxine-Pyrimethamine (SP) was restrictively prescribed to women of childbearing age (97.0%) after 2008. Antibiotics prescription dropped from 53.7% to 39.3% from 2010 to 2012. The odds of being prescribed an antibiotic was significantly higher in patients with a malaria negative result compared to malaria positive patients (OR=6.12, CI 4.74-7.91, p<0.00001). Overall, there is an over treatment of malaria, thus departing from the WHO guidelines of appropriate treatment. Although there is an overall increase in the prescription of ACT, less prescription of quinine and a noticeable restrain from prescription of SP to febrile cases, the old practice was still rampant. There is need for healthcare workers to adhere to guidelines in order to enhance the rational use of drugs to achieve appropriate treatment of uncomplicated malaria according to WHO guidelines. Copyright © 2015 Elsevier B.V. All rights reserved.

Property & Peace: Insurgency, Strategy and the Statute of Frauds

DTIC Science & Technology

2009-05-01

Colombia: Fragmented 125 quinine, ink, feathers, fur, flowers , gold, oil, poppy, sugar, cattle – all these saleable items and many others have...easily includes ink, leather, edible rodents, hardwoods, African palm oil, cigarettes, quinine, counterfeit monies, music CDs, bananas , etc. The smuggling...lesser resources spurring armed violence, not the least of which are bananas , coffee and African palm.122 Admitting many commonalities, each of these

Orexin-1 receptor blockade suppresses compulsive-like alcohol drinking in mice

PubMed Central

Lei, Kelly; Wegner, Scott A.; Yu, Ji-Hwan; Hopf, F. Woodward

2016-01-01

Addiction is promoted by pathological motivation for addictive substances, and, despite extensive efforts, alcohol use disorders (AUDs) continue to extract a very high social, physical, and economic toll. Compulsive drinking of alcohol, where consumption persists even when alcohol is paired with negative consequences, is considered a particular obstacle for treating AUDs. Aversion-resistant alcohol intake in rodents, e.g. where rodents drink even when alcohol is paired with the bitter tastant quinine, has been considered to model some compulsive aspects of human alcohol consumption. However, the critical mechanisms that drive compulsive-like drinking are only beginning to be identified. The neuropeptide orexin has been linked to high motivation for cocaine, preferred foods, and alcohol. Thus, we investigated the role of orexin receptors in compulsive-like alcohol drinking, where C57BL/6 mice had 2-hr daily access to 15% alcohol with or without quinine (100 µM). We found that systemic administration of the widely used selective orexin-1 receptor (OX1R) blocker, SB-334867 (SB), significantly reduced compulsive-like consumption at doses lower than those reported to reduce quinine-free alcohol intake. The dose of 3-mg/kg SB, in particular, suppressed only compulsive-like drinking. Furthermore, SB did not reduce concurrent water intake during the alcohol drinking sessions, and did not alter saccharin+quinine consumption. In addition, the OX2R antagonist TCS-OX2-29 (3 or 10 mg/kg) did not alter intake of alcohol with or without quinine. Together, our results suggest that OX1R signaling is particularly important for promoting compulsive-like alcohol drinking, and that OX1Rs might represent a novel therapy to counteract compulsive aspects of human AUDs. PMID:27523303

Alkaloid decomposition by DC pin-hole discharge in water solution

NASA Astrophysics Data System (ADS)

Klimova, Edita J.; Krcma, Frantisek; Jonisova, Lenka

2016-08-01

DC diaphragm discharge generated in a batch reactor was used to decompose two selected model alkaloids, caffeine and quinine in concentrations ranging from 10 to 50 ppm or 5 to 15 ppm, respectively. UV-vis spectrometry was utilized in evaluation of H2O2 production during the process as well as degradation of caffeine. Fluorescence spectrometry was used for quantification of quinine. High rates of decomposition were reached in both cases in the anode part of the reactor. On the other hand, up to four times lower decomposition was observed in the cathode part. Total removal efficiency gained up to 300 mg/kWh for caffeine and 210 mg/kWh for quinine. Contribution to the topical issue "6th Central European Symposium on Plasma Chemistry (CESPC-6)", edited by Nicolas Gherardi, Ester Marotta and Cristina Paradisi

Antimalarial Activity of New Water-Soluble Dihydroartemisinin Derivatives

DTIC Science & Technology

1987-11-01

No cross-resistance to the antimalarial agents mefloquine, chloroquine , pyrimethamine, sulfadoxine, and quinine was observed. In general, the new...a) Klayman, D. L. Science (Washington, D.C.) 1985, 228, Neitherin-2 exhibit cross-resistance to chloroquine and 108) . in, A. .; Klayman, D. L.; lch... chloroquine , py- (J = 3-4 Hz) and 9-H." Due to the close proximity to rimethamine, sulfadoxine, and quinine. several asymmetric carbon centers on the

A Catastrophic Consequence of Cramp.

PubMed

Htet, Zay Myo; Karim, Mahzuz

2018-01-01

Quinine has long been used for the treatment of conditions such as malaria and leg cramps, and is also present at low levels in some beverages; however, it can cause serious side effects. We describe a patient who developed severe haemolysis, thrombocytopaenia, and acute kidney injury following the ingestion of a single dose of quinine. This case demonstrates the importance of awareness of such potentially life-threatening consequences of exposure to this agent.

The number of taste buds is related to bitter taste sensitivity in layer and broiler chickens.

PubMed

Kudo, Ken-ichi; Shiraishi, Jun-ichi; Nishimura, Shotaro; Bungo, Takashi; Tabata, Shoji

2010-04-01

The relationship between taste sensitivity and the number of taste buds using a bitter tastant, quinine hydrochloride, was investigated in White Leghorn, Rhode Island Red, and broiler chickens. The White Leghorn and Rhode Island Red strains were able to perceive 2.0 mmol/L quinine hydrochloride, but the taste sensitivity of Rhode Island Red chickens was higher than that of White Leghorn chickens. Broiler chickens perceived 0.5 mmol/L quinine hydrochloride. The number of taste buds in the White Leghorn strain was the lowest, then the Rhode Island Red strain, with the number of taste buds highest in the broiler chickens. The number of taste buds was well correlated with bitter taste sensitivity. Therefore, we suggest that the number of taste buds is a vital factor in the perception of bitter taste and may be useful in selecting appropriate feeds for chickens.

Bioactive cinchona alkaloids from Remijia peruviana.

PubMed

Ruiz-Mesia, Lastenia; Ruiz-Mesía, Wilfredo; Reina, Matías; Martínez-Diaz, Rafael; de Inés, Concepción; Guadaño, Ana; González-Coloma, Azucena

2005-03-23

Three known Cinchona alkaloids of the quinine type, quinine (1), cupreine (2), cinchonine (3), and the possible artifact cinchonine-HCl (3-HCl), along with two new ones, acetylcupreine (4) and N-ethylquinine (5), have been isolated from the bark of Remijia peruviana (Rubiaceae). Their stereochemical structures were established by high resolution NMR spectroscopy. Alkaloids 2-4 had antifeedant effects on Leptinotarsa decemlineata with varying potencies. Compound 4 was cytotoxic to both insect Sf9 and mammalian CHO cells after 48 h of incubation, while 3-HCl had stronger and selective cytotoxicity to Sf9. Quinine 1 had a moderate to low effect on Trypanosoma cruzi. Tumoral cells were also affected by these alkaloids, with 4 and 3-HCl being the most cytotoxic to all the cell lines tested. Overall, the 8R, 9S configurations, as in 3 and 3-HCl, as well as the C-6'acetylated alkaloid 4, with an 8S, 9R configuration, showed stronger biological effects.

The crystal structure of halofantrine-ferriprotoporphyrin IX and the mechanism of action of arylmethanol antimalarials.

PubMed

de Villiers, Katherine A; Marques, Helder M; Egan, Timothy J

2008-08-01

The crystal structure of the complex formed between the antimalarial drug halofantrine and ferriprotoporphyrin IX (Fe(III)PPIX) has been determined by single crystal X-ray diffraction. The structure shows that halofantrine coordinates to the Fe(III) center through its alcohol functionality in addition to pi-stacking of the phenanthrene ring over the porphyrin. The length of the Fe(III)-O bond is consistent with an alkoxide and not an alcohol coordinating group. The iron porphyrin is five coordinate and monomeric. Changes in the electronic spectrum of Fe(III)PPIX upon addition of halofantrine base in acetonitrile solution are almost identical to those observed upon addition of quinidine free base in the same solvent. This suggests homologous binding. Molecular mechanics modeling of Fe(III)PPIX complexes of quinidine, quinine, 9-epiquinine and 9-epiquinidine based on this homology suggests that the antimalarially active quinidine and quinine can readily adopt conformations that permit formation of an intramolecular salt bridge between the protonated quinuclidine tertiary amino group and unprotonated heme propionate group, while the inactive epimers 9-epiquinidine and 9-epiquinine have to adopt high energy conformations in order to accommodate such salt bridge formation. We propose that salt bridge formation may interrupt formation of the hemozoin precursor dimer formed during the heme detoxification pathway and so account for the strong activity of the two active isomers.

Inhibition of phosphodiesterase-4 decreases ethanol intake in mice.

PubMed

Hu, Wei; Lu, Tina; Chen, Alan; Huang, Ying; Hansen, Rolf; Chandler, L Judson; Zhang, Han-Ting

2011-11-01

Cyclic AMP (cAMP)-protein kinase A signaling has been implicated in the regulation of ethanol consumption. Phosphodiesterase-4 (PDE4) specifically hydrolyzes cAMP and plays a critical role in controlling intracellular cAMP levels in the brain. However, the role of PDE4 in ethanol consumption remains unknown. The objective of this study is to examine whether PDE4 was involved in regulating ethanol intake. The two-bottle choice paradigm was used to assess intake of ethanol, sucrose, and quinine in C57BL/6J mice treated with the selective PDE4 inhibitor rolipram or Ro 20-1724; locomotor activity was also monitored using the open-field test in mice treated with rolipram. Administration (i.p.) of either rolipram (0.25 and 0.5 mg/kg) or Ro 20-1724 (10 mg/kg) reduced ethanol intake and preference by 60-80%, but did not alter total fluid intake. In contrast, rolipram even at the higher dose of 0.5 mg/kg was not able to affect intake of sucrose or quinine, alcohol-induced sedation, or blood ethanol elimination. At 0.5 mg/kg, rolipram did decrease locomotor activity, but the effect only lasted for approximately 40 min, which did not likely affect behavior of ethanol drinking. These results suggest that PDE4 is a novel target for drugs that reduce ethanol intake; PDE4 inhibitors may be used for treatment of alcohol dependence.

Antimalarial drug susceptibility and point mutations associated with drug resistance in 248 Plasmodium falciparum isolates imported from Comoros to Marseille, France in 2004 2006.

PubMed

Parola, Philippe; Pradines, Bruno; Simon, Fabrice; Carlotti, Marie-Paule; Minodier, Philippe; Ranjeva, Marie-Pierre; Badiaga, Sékéné; Bertaux, Lionel; Delmont, Jean; Morillon, Marc; Silai, Ramatou; Brouqui, Philippe; Parzy, Daniel

2007-09-01

A total of 248 Plasmodium falciparum isolates were sampled in travelers with malaria who came to Marseille, France from Comoros to investigate in vitro activities of antimalarial drugs and molecular markers of drug resistance. Of the 248 isolates, 126 were maintained in culture. Of these, 53% were resistant to chloroquine, and 3% had reduced susceptibility to quinine, mefloquine, and atovaquone; 1% had reduced susceptibility to halofantrine and dihydroartemisinin; 7% had reduced susceptibility to monodesethylamodiaquine; 37% had reduced susceptibility to cycloguanil; and none had reduced susceptibility to lumefantrine. Resistance-associated point mutations were screened in 207 isolates. No mutations in the cytochrome b gene were found. Of the 207 isolates, 119 (58%) had a mutation in the P. falciparum dihydrofolate reductase (Pfdhfr) gene at codon 108, 6 (5%) had mutations in both Pfdhfr codon 108 and the P. falciparum dihydropteroate synthase codon 437, and 115 (56%) had the chloroquine resistance-associated K76T mutation in the P. falciparum chloroquine resistance transporter gene. This study represents a unique opportunity to improve surveillance of P. falciparum drug resistance in Comoros with consequences for treatment and chemoprophylaxis guidelines.

Perinatal administration of a bitter tastant influences gene expression in chicken palate and duodenum.

PubMed

Cheled-Shoval, Shira L; Behrens, Maik; Meyerhof, Wolfgang; Niv, Masha Y; Uni, Zehava

2014-12-31

Bitter taste receptors (Tas2rs) and downstream effectors are responsible for mediating bitterness perception and regulation of food choice in mammals. Using RT-PCR, we demonstrated the expression of three Tas2rs and taste signal transduction molecules, α-gustducin, PLCβ2, and TRPM5, in the palate, tongue, and gastrointestinal tract sections in chicken. The bitter tastant quinine activates all three chicken Tas2rs in vitro as shown using calcium-imaging assays of transfected cells. Administration of quinine postnatally or perinatally (both pre- and posthatch) to chickens increased the expression of Tas2r genes in the palate by 6.45-fold (ggTas2r1 postnatal treatment), 4.86-fold (ggTas2r1 perinatal treatment), and 4.48-fold (ggTas2r7 postnatal treatment) compared to the genes' expression in the naı̈ve group respectively, and affected taste related gene expression in the duodenum. Whereas no-choice intake of quinine solution was not significantly lower than that of water in naı̈ve chicks, the treatment groups postnatal, prenatal, and perinatal showed significantly lower intake of quinine by 56.1, 47.7, and 50.2%, respectively, suggesting a possible trend toward sensitization. These results open new venues toward unraveling the formative stages shaping food intake and nutrition in chicken.

Use of microdose phenotyping to individualise dosing of patients.

PubMed

Hohmann, Nicolas; Haefeli, Walter E; Mikus, Gerd

2015-09-01

Administering the right amount of the right drug at the right time is a key mission of clinical medicine. This comprises dose adaptation according to a patient's intrinsic and extrinsic factors influencing drug disposition. Several biomarkers are available for dose adaptation; still, prediction of individual drug disposition may be improved. Phenotyping is the quantification of drug metabolism with probe substrates specific to drug-metabolising enzymes. This allows measurement of baseline metabolism and changes after modulation of drug metabolism. This article explores the concept of phenotyping using pharmacologically ineffective microdoses of probe substrates to obtain information on drug metabolism. Several probe drugs such as midazolam for cytochrome P450 3A have already been used, but validation of other microdosed probe drugs, analytical procedures and drug formulations still face some challenges that have to be overcome. Since microdosed probe drugs have no risk of adverse drug reactions or interference with therapy, more widespread use is possible. This allows drug-drug interaction data to be safely obtained during first-in-man studies, enhancing the clinical safety of human healthy volunteers and patients in clinical trials, and, most importantly, allows determination of the drug-metabolising phenotype in severely ill patients. With harmless probe drugs at hand quantifying drug metabolism and adapting the dose accordingly, a phenotyping-based dosing strategy could become reality, offering the possibility of individualised drug therapy with reduced adverse effects and fewer therapeutic failures.

Mesoporous silica nanocarriers encapsulated antimalarials with high therapeutic performance.

PubMed

Amolegbe, Saliu Alao; Hirano, Yui; Adebayo, Joseph Oluwatope; Ademowo, Olusegun George; Balogun, Elizabeth Abidemi; Obaleye, Joshua Ayoola; Krettli, Antoniana Ursine; Yu, Chengzhong; Hayami, Shinya

2018-02-15

The use of nanocarriers in drug delivery is a breakeven research and has received a clarion call in biomedicine globally. Herein, two newly nano-biomaterials: MCM-41 encapsulated quinine (MCM-41 ⊃ QN) (1) and 3-phenylpropyl silane functionalized MCM-41 loaded QN (pMCM-41 ⊃ QN) (2) were synthesized and well characterized. 1 and 2 along with our two already reported nano-antimalarial drugs (MCM-41 ⊃ ATS) (3) and 3-aminopropyl silane functionalized MCM-41 contained ATS (aMCM-41 ⊃ ATS) (4) were screened in vitro for their activity against P. falciparium W2 strain, cytotoxicity against BGM cells and in vivo for their activity against Plasmodium bergheiNK65. 1 has the highest antimalarial activity in vivo against P. berghei NK65, (ED 50 : < 0.0625 mg/kg body weight) and higher mean survival time compared to the other nano biomaterials or unencapsulated drugs at doses higher than 0.0625 mg/kg body weight. This encapsulation strategy of MCM-41 ⊃ QN (1) stands very useful and effective in delivering the drug to the target cells compared to other delivery systems and therefore, this encapsulated drug may be considered for rational drug design.

Relative to Quinine and Quinidine, Their 9-Epimers Exhibit Decreased Cytostatic Activity and Altered Heme Binding but Similar Cytocidal Activity versus Plasmodium falciparum

PubMed Central

Gorka, Alexander P.; Sherlach, Katy S.; de Dios, Angel C.

2013-01-01

The 9-epimers of quinine (QN) and quinidine (QD) are known to exhibit poor cytostatic potency against P. falciparum (Karle JM, Karle IL, Gerena L, Milhous WK, Antimicrob. Agents Chemother. 36:1538–1544, 1992). We synthesized 9-epi-QN (eQN) and 9-epi-QD (eQD) via Mitsunobu esterification-saponification and evaluated both cytostatic and cytocidal antimalarial activities. Relative to the cytostatic activity of QN and QD, we observed a large decrease in cytostatic activity (higher 50% inhibitory concentration [IC50s]) against QN-sensitive strain HB3, QN-resistant strain Dd2, and QN-hypersensitive strain K76I, consistent with previous work. However, we observed relatively small changes in cytocidal activity (the 50% lethal dose), similar to observations with chloroquine (CQ) analogues with a wide range of IC50s (see the accompanying paper [A. P. Gorka, J. N. Alumasa, K. S. Sherlach, L. M. Jacobs, K. B. Nickley, J. P. Brower, A. C. de Dios, and P. D. Roepe, Antimicrob. Agents Chemother. 57:356–364, 2013]). Compared to QN and QD, the 9-epimers had significantly reduced hemozoin inhibition efficiency and did not affect pH-dependent aggregation of ferriprotoporphyrin IX (FPIX) heme. Magnetic susceptibility measurements showed that the 9-epimers perturb FPIX monomer-dimer equilibrium in favor of monomer, and UV-visible (VIS) titrations showed that eQN and eQD bind monomer with similar affinity relative to QN and QD. However, unique ring proton shifts in the presence of zinc(II) protoporphyrin IX (ZnPIX) indicate that binding of the 9-epimers to monomeric heme is via a distinct geometry. We isolated eQN- and eQD-FPIX complexes formed under aqueous conditions and analyzed them by mass, fluorescence, and UV-VIS spectroscopies. The 9-epimers produced low-fluorescent adducts with a 2:1 stoichiometry (drug to FPIX) which did not survive electrospray ionization, in contrast to QN and QD complexes. The data offer important insight into the relevance of heme interactions as a drug target for cytostatic versus cytocidal dosages of quinoline antimalarial drugs and further elucidate a surprising structural diversity of quinoline antimalarial drug-heme complexes. PMID:23114754

Radical curative efficacy of tafenoquine combination regimens in Plasmodium cynomolgi-infected Rhesus monkeys (Macaca mulatta).

PubMed

Dow, Geoffrey S; Gettayacamin, Montip; Hansukjariya, Pranee; Imerbsin, Rawiwan; Komcharoen, Srawuth; Sattabongkot, Jetsumon; Kyle, Dennis; Milhous, Wilbur; Cozens, Simon; Kenworthy, David; Miller, Anne; Veazey, Jim; Ohrt, Colin

2011-07-29

Tafenoquine is an 8-aminoquinoline being developed for radical cure (blood and liver stage elimination) of Plasmodium vivax. During monotherapy treatment, the compound exhibits slow parasite and fever clearance times, and toxicity in glucose-6-phosphate dehydrogenase (G6PD) deficiency is a concern. Combination with other antimalarials may mitigate these concerns. In 2005, the radical curative efficacy of tafenoquine combinations was investigated in Plasmodium cynomolgi-infected naïve Indian-origin Rhesus monkeys. In the first cohort, groups of two monkeys were treated with a three-day regimen of tafenoquine at different doses alone and in combination with a three-day chloroquine regimen to determine the minimum curative dose (MCD). In the second cohort, the radical curative efficacy of a single-day regimen of tafenoquine-mefloquine was compared to that of two three-day regimens comprising tafenoquine at its MCD with chloroquine or artemether-lumefantrine in groups of six monkeys. In a final cohort, the efficacy of the MCD of tafenoquine against hypnozoites alone and in combination with chloroquine was investigated in groups of six monkeys after quinine pre-treatment to eliminate asexual parasites. Plasma tafenoquine, chloroquine and desethylchloroquine concentrations were determined by LC-MS in order to compare doses of the drugs to those used clinically in humans. The total MCD of tafenoquine required in combination regimens for radical cure was ten-fold lower (1.8 mg/kg versus 18 mg/kg) than for monotherapy. This regimen (1.8 mg/kg) was equally efficacious as monotherapy or in combination with chloroquine after quinine pre-treatment to eliminate asexual stages. The same dose of (1.8 mg/kg) was radically curative in combination with artemether-lumefantrine. Tafenoquine was also radically curative when combined with mefloquine. The MCD of tafenoquine monotherapy for radical cure (18 mg/kg) appears to be biologically equivalent to a 600-1200 mg dose in humans. At its MCD in combination with blood schizonticidal drugs (1.8 mg/kg), the maximum observed plasma concentrations were substantially lower than (20-84 versus 550-1,100 ng/ml) after administration of 1, 200 mg in clinical studies. Ten-fold lower clinical doses of tafenoquine than used in prior studies may be effective against P. vivax hypnozoites if the drug is deployed in combination with effective blood-schizonticidal drugs.

Radical curative efficacy of tafenoquine combination regimens in Plasmodium cynomolgi-infected Rhesus monkeys (Macaca mulatta)

PubMed Central

2011-01-01

Background Tafenoquine is an 8-aminoquinoline being developed for radical cure (blood and liver stage elimination) of Plasmodium vivax. During monotherapy treatment, the compound exhibits slow parasite and fever clearance times, and toxicity in glucose-6-phosphate dehydrogenase (G6PD) deficiency is a concern. Combination with other antimalarials may mitigate these concerns. Methods In 2005, the radical curative efficacy of tafenoquine combinations was investigated in Plasmodium cynomolgi-infected naïve Indian-origin Rhesus monkeys. In the first cohort, groups of two monkeys were treated with a three-day regimen of tafenoquine at different doses alone and in combination with a three-day chloroquine regimen to determine the minimum curative dose (MCD). In the second cohort, the radical curative efficacy of a single-day regimen of tafenoquine-mefloquine was compared to that of two three-day regimens comprising tafenoquine at its MCD with chloroquine or artemether-lumefantrine in groups of six monkeys. In a final cohort, the efficacy of the MCD of tafenoquine against hypnozoites alone and in combination with chloroquine was investigated in groups of six monkeys after quinine pre-treatment to eliminate asexual parasites. Plasma tafenoquine, chloroquine and desethylchloroquine concentrations were determined by LC-MS in order to compare doses of the drugs to those used clinically in humans. Results The total MCD of tafenoquine required in combination regimens for radical cure was ten-fold lower (1.8 mg/kg versus 18 mg/kg) than for monotherapy. This regimen (1.8 mg/kg) was equally efficacious as monotherapy or in combination with chloroquine after quinine pre-treatment to eliminate asexual stages. The same dose of (1.8 mg/kg) was radically curative in combination with artemether-lumefantrine. Tafenoquine was also radically curative when combined with mefloquine. The MCD of tafenoquine monotherapy for radical cure (18 mg/kg) appears to be biologically equivalent to a 600-1200 mg dose in humans. At its MCD in combination with blood schizonticidal drugs (1.8 mg/kg), the maximum observed plasma concentrations were substantially lower than (20-84 versus 550-1,100 ng/ml) after administration of 1, 200 mg in clinical studies. Conclusions Ten-fold lower clinical doses of tafenoquine than used in prior studies may be effective against P. vivax hypnozoites if the drug is deployed in combination with effective blood-schizonticidal drugs. PMID:21801400

Gustatory detection of tetrodotoxin and saxitoxin, and its competitive inhibition by quinine and strychnine in freshwater fishes.

PubMed

Hara, Toshiaki J

2011-01-01

Fish detect extremely low levels of marine toxins tetrodotoxin (TTX) and saxitoxin (STX) via the specialized gustatory receptor(s). Physiological and pharmacological studies show that receptor(s) for TTX and STX are distinct from those which detect feeding stimulant amino acids and bile acids, and that TTX and STX do not share the same receptor populations, while interacting with quinine and strychnine in a competitive fashion suggestive of an antidotal relationship.

Gustatory Detection of Tetrodotoxin and Saxitoxin, and Its Competitive Inhibition by Quinine and Strychnine in Freshwater Fishes

PubMed Central

Hara, Toshiaki J.

2011-01-01

Fish detect extremely low levels of marine toxins tetrodotoxin (TTX) and saxitoxin (STX) via the specialized gustatory receptor(s). Physiological and pharmacological studies show that receptor(s) for TTX and STX are distinct from those which detect feeding stimulant amino acids and bile acids, and that TTX and STX do not share the same receptor populations, while interacting with quinine and strychnine in a competitive fashion suggestive of an antidotal relationship. PMID:22163186

Access to artemisinin-based combination therapies and other anti-malarial drugs in Kinshasa.

PubMed

Nkoli Mandoko, P; Sinou, V; Moke Mbongi, D; Ngoyi Mumba, D; Kahunu Mesia, G; Losimba Likwela, J; Bi Shamamba Karhemere, S; Muepu Tshilolo, L; Tamfum Muyembe, J-J; Parzy, D

2018-06-01

Artemisinin-based combination therapies have been available since 2005 in the Democratic Republic of the Congo to treat malaria and to overcome the challenge of anti-malarial drug resistance as well as to improve access to effective treatments. The private sector is the primary distribution source for anti-malarial drugs and thus, has a key position among the supply chain actors for a rational and proper use of anti-malarial drugs. We aimed to assess access to nationally recommended anti-malarial drugs in private sector pharmacies of the capital-city of Kinshasa. We performed a cross-sectional survey of 404 pharmacies. Anti-malarial drugs were stocked in all surveyed pharmacies. Non-artemisinin-based anti-malarial therapies such as quinine or sulfadoxine-pyrimethamine, were the most frequently stocked drugs (93.8% of pharmacies). Artemisinin-based combination therapies were stocked in 88% of pharmacies. Artemether-lumefantrine combinations were the most frequently dispensed drugs (93% of pharmacies), but less than 3% were quality-assured products. Other non-officially recommended artemisinin-based therapies including oral monotherapies were widely available. Artemisinin-based combination therapies were widely available in the private pharmacies of Kinshasa. However, the private sector does not guarantee the use of nationally recommended anti-malarial drugs nor does it give priority to quality-assured anti-malarial drugs. These practices contribute to the risk of emergence and spread of resistance to anti-malarial drugs and to increasing treatment costs. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Investigation of sarizotan's impact on the pharmacokinetics of probe drugs for major cytochrome P450 isoenzymes: a combined cocktail trial.

PubMed

Krösser, Sonja; Neugebauer, Roland; Dolgos, Hugues; Fluck, Markus; Rost, Karl-Ludwig; Kovar, Andreas

2006-04-01

The 5HT(1A) receptor agonist sarizotan is in clinical development for the treatment of dyskinesia, a potentially disabling complication in Parkinson's disease. We investigated the effect of sarizotan on the clinical pharmacokinetics of probe drugs for cytochrome P450 (CYP) to evaluate the risk of CYP-related drug-drug interactions. This was a double-blind, randomised, two-period cross-over interaction study with repeated administration of 5 mg sarizotan HCl or placebo b.i.d. for 8 days in 18 healthy volunteers. On day 4, a single dose of 100 mg metoprolol (CYP2D6 probe) was administered. On day 8, single doses of 100 mg caffeine (CYP1A2 probe), 50 mg diclofenac (CYP2C9 probe), 100 mg mephenytoin (CYP2C19 probe) and 7.5 mg midazolam (CYP3A4 probe) were simultaneously applied. Pharmacokinetic parameters for probe drugs and their metabolites in plasma and urinary recovery were determined. Concentration-time profiles and pharmacokinetic parameters of all probes and their metabolites remained unchanged after co-administration of sarizotan, compared with placebo. Analysis of variance of the area under the plasma concentration-time curve for probe drugs/metabolites, metabolic ratios and urinary excretion resulted in 90% confidence intervals within the acceptance range (0.8-1.25), indicating the absence of drug-drug interactions. At a dose higher than that intended for clinical use (1 mg b.i.d.), sarizotan had no effect on the metabolism and pharmacokinetics of specific probe drugs for CYP isoenzymes 1A2, 2C19, 2C9, 2D6 and 3A4. Pharmacokinetic interactions with co-administered drugs metabolised by these CYP isoforms are not expected, and dose adjustment of co-administered CYP substrates is not necessary.

Bitter-sensitive gustatory receptor neuron responds to chemically diverse insect repellents in the common malaria mosquito Anopheles quadrimaculatus

NASA Astrophysics Data System (ADS)

Sparks, Jackson T.; Dickens, Joseph C.

2016-06-01

Female mosquitoes feed on blood from animal hosts to obtain nutritional resources used for egg production. These contacts facilitate the spread of harmful human diseases. Chemical repellents are used to disrupt mosquito host-seeking and blood-feeding behaviors; however, little is known about the gustatory sensitivity of mosquitoes to known repellents. Here, we recorded electrical responses from gustatory receptor neurons (GRNs) housed within the labellar sensilla of female Anopheles quadrimaculatus to N,N-diethyl-3-methylbenzamide (DEET), picaridin, IR3535, 2-undecanone, p-menthane-3,8-diol, geraniol, trans-2-hexen-1-ol, quinine, and quinidine. A bitter-sensitive GRN responded to all tested repellents and quinine, a known feeding deterrent. Responses of the bitter-sensitive neuron to quinine and an isomer, quinidine, did not differ. Delayed bursts of electrical activity were observed in response to continuous stimulation with synthetic repellents at high concentrations. Electrophysiological recordings from bitter-sensitive GRNs associated with mosquito gustatory sensilla represent a convenient model to evaluate candidate repellents.

Bitter-sensitive gustatory receptor neuron responds to chemically diverse insect repellents in the common malaria mosquito Anopheles quadrimaculatus.

PubMed

Sparks, Jackson T; Dickens, Joseph C

2016-06-01

Female mosquitoes feed on blood from animal hosts to obtain nutritional resources used for egg production. These contacts facilitate the spread of harmful human diseases. Chemical repellents are used to disrupt mosquito host-seeking and blood-feeding behaviors; however, little is known about the gustatory sensitivity of mosquitoes to known repellents. Here, we recorded electrical responses from gustatory receptor neurons (GRNs) housed within the labellar sensilla of female Anopheles quadrimaculatus to N,N-diethyl-3-methylbenzamide (DEET), picaridin, IR3535, 2-undecanone, p-menthane-3,8-diol, geraniol, trans-2-hexen-1-ol, quinine, and quinidine. A bitter-sensitive GRN responded to all tested repellents and quinine, a known feeding deterrent. Responses of the bitter-sensitive neuron to quinine and an isomer, quinidine, did not differ. Delayed bursts of electrical activity were observed in response to continuous stimulation with synthetic repellents at high concentrations. Electrophysiological recordings from bitter-sensitive GRNs associated with mosquito gustatory sensilla represent a convenient model to evaluate candidate repellents.

Stimulus-Dependent Effects of Temperature on Bitter Taste in Humans

PubMed Central

Andrew, Kendra

2017-01-01

This study investigated the effects of temperature on bitter taste in humans. The experiments were conducted within the context of current understanding of the neurobiology of bitter taste and recent evidence of stimulus-dependent effects of temperature on sweet taste. In the first experiment, the bitterness of caffeine and quinine sampled with the tongue tip was assessed at 4 different temperatures (10°, 21°, 30°, and 37 °C) following pre-exposure to the same solution or to water for 0, 3, or 10 s. The results showed that initial bitterness (0-s pre-exposure) followed an inverted U-shaped function of temperature for both stimuli, but the differences across temperature were statistically significant only for quinine. Conversely, temperature significantly affected adaptation to the bitterness of quinine but not caffeine. A second experiment used the same procedure to test 2 additional stimuli, naringin and denatonium benzoate. Temperature significantly affected the initial bitterness of both stimuli but had no effect on adaptation to either stimulus. These results confirm that like sweet taste, temperature affects bitter taste sensitivity and adaptation in stimulus-dependent ways. However, the thermal effect on quinine adaptation, which increased with warming, was opposite to what had been found previously for adaptation to sweetness. The implications of these results are discussed in relation to findings from prior studies of temperature and bitter taste in humans and the possible neurobiological mechanisms of gustatory thermal sensitivity. PMID:28119357

Evaluation of selected antiprotozoal drugs in the Babesia microti-hamster model.

PubMed Central

Marley, S E; Eberhard, M L; Steurer, F J; Ellis, W L; McGreevy, P B; Ruebush, T K

1997-01-01

The presently used therapy for Babesia microti infections, a combination of quinine and clindamycin, does not always result in parasitologic cures. To identify possible alternative chemotherapeutic agents for such infections, we screened, in the hamster-B. microti system, 12 antiprotozoal drugs that have either recently been released for human use or were in experimental stages of development at the Walter Reed Army Institute of Research for the treatment of malaria and leishmaniasis. Several well-recognized antimalarial drugs, such as mefloquine, halofantrine, artesunate, and artelenic acid, exhibited little or no effect on parasitemia. Two 8-aminoquinolines, WR006026 [8-(6-diethylaminohexylamino)-6-methoxy-4-methylquinoline dihydrochloride] and WR238605 [8-[(4-amino-1-methylbutyl)amino]-2,6-dimethoxy-4-methyl-5 -(3-trifluoromethylphenoxy-7) quinoline succinate], produced clearance of patent parasitemia. Furthermore, blood from infected hamsters treated with WR238605 via an intramuscular injection failed to infect naive hamsters on subpassage, thus producing a parasitologic cure. These two compounds merit further screening in other systems and may prove useful in treating human babesiosis. PMID:8980761

In vitro activity of tafenoquine alone and in combination with artemisinin against Plasmodium falciparum.

PubMed

Ramharter, Michael; Noedl, Harald; Thimasarn, Krongthong; Wiedermann, Gerhard; Wernsdorfer, Gunther; Wernsdorfer, Walther H

2002-07-01

Emergence and spread of drug-resistant falciparum malaria has created an urgent demand for alternative therapeutic agents. This study was conducted to assess the in vitro blood schizontocidal activity of tafenoquine, the most advanced candidate drug of the 8-aminoquinolines, and of its 1:1 combination with artemisinin in fresh isolates of Plasmodium falciparum in an area with multi-drug resistance, measuring the inhibition of schizont maturation. In 43 successfully tested parasite isolates, the mean effective concentrations (ECs) of tafenoquine were 209 nmol/L for the EC50, and 1,414 nmol/L for the EC90. Tafenoquine showed no significant activity relationships with mefloquine, artemisinin, and chloroquine. With quinine, a highly significant activity relationship was observed at the EC50, but not at the EC90. The EC50, and EC90 of the tafenoquine-artemisinin combination were 15.9 nmol/L and 84.3 nmol/L. The combination was synergistic. Tafenoquine appears to be a promising candidate for treating multidrug-resistant falciparum malaria, especially in combination with artemisinin derivatives.

Characterization of "Yaa Chud" Medicine on the Thailand-Myanmar border: selecting for drug-resistant malaria and threatening public health.

PubMed

Newton, Paul N; Hampton, Christina Y; Alter-Hall, Krystyn; Teerwarakulpana, Thanongsak; Prakongpan, Sompol; Ruangveerayuth, Ronnatrai; White, Nicholas J; Day, Nicholas P J; Tudino, Mabel B; Mancuso, Natalia; Fernández, Facundo M

2008-11-01

Multidrug-resistant Plasmodium falciparum malaria is a severe public health problem on the Thailand-Myanmar border. Many villagers buy packets of 4-5 mixed medicines ("yaa chud") from shops without medical assessment as their first-line malaria treatment. In 2000-2001 a local researcher purchased 50 yaa chud from 44 shops around Mae Sot, Thailand and Myawaddy, Myanmar (Burma), for his wife who was said to be pregnant with fever and drowsiness. The tablets/capsules were provisionally identified by appearance and active ingredients determined in a subset by using mass and atomic spectrometry. The most frequently detected active ingredients were acetaminophen (22%), chlorpheniramine (13.4%), chloroquine (12.6%), tetracycline/doxycycline (11.4%), and quinine (5.1%). Only seven bags contained potentially curative medicine for malaria. A total of 82% of the bags contained medicines contraindicated in pregnancy. Inappropriate, ineffective antimalarial drugs on the Thailand-Myanmar border are likely to increase malaria morbidity, mortality and health costs and engender the emergence and spread of antimalarial drug resistance.

In vivo performance of a microelectrode neural probe with integrated drug delivery

PubMed Central

Rohatgi, Pratik; Langhals, Nicholas B.; Kipke, Daryl R.; Patil, Parag G.

2014-01-01

Object The availability of sophisticated neural probes is a key prerequisite in the development of future brain machine interfaces (BMI). In this study, we developed and validated a neural probe design capable of simultaneous drug delivery and electrophysiology recordings in vivo. Focal drug delivery has promise to dramatically extend the recording lives of neural probes, a limiting factor to clinical adoption of BMI technology. Methods To form the multifunctional neural probe, we affixed a 16-channel microfabricated silicon electrode array to a fused silica catheter. Three experiments were conducted to characterize the performance of the device. Experiment 1 examines cellular damage from probe insertion and the drug distribution in tissue. Experiment 2 measures the effects of saline infusions delivered through the probe on concurrent electrophysiology. Experiment 3 demonstrates that a physiologically relevant amount of drug can be delivered in a controlled fashion. For these experiments, Hoechst and propidium iodide were used to assess insertion trauma and the tissue distribution of the infusate. Artificial cerebral spinal fluid and tetrodotoxin were injected to determine the efficacy of drug delivery. Results The newly developed multifunctional neural probes were successfully inserted into rat cortex and were able to deliver fluids and drugs that resulted in the expected electrophysiological and histological responses. The damage from insertion of the device into brain tissue was substantially less than the volume of drug dispersion in tissue. Electrophysiological activity, including both individual spikes as well as local field potentials, was successfully recorded with this device during real-time drug delivery. No significant changes were seen in response to delivery of artificial cerebral spinal fluid as a control experiment, whereas delivery of tetrodotoxin produced the expected result of suppressing all spiking activity in the vicinity of the catheter outlet. Conclusions Multifunctional neural probes such as the ones developed and validated within this study have great potential to help further understand the design space and criteria for the next generation of neural probe technology. By incorporating integrated drug delivery functionality into the probes, new treatment options for neurological disorders and regenerative neural interfaces utilizing localized and feedback controlled delivery of drugs can be realized in the near future. PMID:19569896

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

Intravenous artesunate plus Artemisnin based Combination Therapy (ACT) or intravenous quinine plus ACT for treatment of severe malaria in Ugandan children: a randomized controlled clinical trial.

PubMed

Byakika-Kibwika, Pauline; Achan, Jane; Lamorde, Mohammed; Karera-Gonahasa, Carine; Kiragga, Agnes N; Mayanja-Kizza, Harriet; Kiwanuka, Noah; Nsobya, Sam; Talisuna, Ambrose O; Merry, Concepta

2017-12-28

Severe malaria is a medical emergency associated with high mortality. Adequate treatment requires initial parenteral therapy for fast parasite clearance followed by longer acting oral antimalarial drugs for cure and prevention of recrudescence. In a randomized controlled clinical trial, we evaluated the 42-day parasitological outcomes of severe malaria treatment with intravenous artesunate (AS) or intravenous quinine (QNN) followed by oral artemisinin based combination therapy (ACT) in children living in a high malaria transmission setting in Eastern Uganda. We enrolled 300 participants and all were included in the intention to treat analysis. Baseline characteristics were similar across treatment arms. The median and interquartile range for number of days from baseline to parasite clearance was significantly lower among participants who received intravenous AS (2 (1-2) vs 3 (2-3), P < 0.001). Overall, 63.3% (178/281) of the participants had unadjusted parasitological treatment failure over the 42-day follow-up period. Molecular genotyping to distinguish re-infection from recrudescence was performed in a sample of 127 of the 178 participants, of whom majority 93 (73.2%) had re-infection and 34 (26.8%) had recrudescence. The 42 day risk of recrudescence did not differ with ACT administered. Adverse events were of mild to moderate severity and consistent with malaria symptoms. In this high transmission setting, we observed adequate initial treatment outcomes followed by very high rates of malaria re-infection post severe malaria treatment. The impact of recurrent antimalarial treatment on the long term efficacy of antimalarial regimens needs to be investigated and surveillance mechanisms for resistance markers established since recurrent malaria infections are likely to be exposed to sub-therapeutic drug concentrations. More strategies for prevention of recurrent malaria infections in the most at risk populations are needed. The study was registered with the Pan African Clinical Trial Registry ( PACTR201110000321348 ).

21 CFR 870.1915 - Thermodilution probe.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Thermodilution probe. 870.1915 Section 870.1915 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CARDIOVASCULAR DEVICES Cardiovascular Diagnostic Devices § 870.1915 Thermodilution probe...

Understanding Unlicensed Drug Vendor Practices Related to Childhood Malaria in One Rural District of Uganda: An Exploratory Study

PubMed Central

Sekiwunga, Richard

2018-01-01

This study investigated unlicensed drug outlets' practices for the management of malaria in the rural district of Butaleja, Uganda. A qualitative design using semistructured interviews was used. Interviews were recorded, translated, transcribed, and analyzed using thematic analysis. A total of 75 vendors, representing 85% of the outlets in the study area, were interviewed. Most of the vendors were associated with a drug shop type of outfit. About three-quarters reported having completed some level of postsecondary education, but just one-tenth of the vendors had qualifications that made them eligible to apply for a license to operate a drug shop. While most outlets stocked at least one type of antimalarial, only about one-quarter stocked an artemisinin-based combination therapy (ACT), one-quarter expressed a preference for ACTs, and less than one-tenth attested to firmly adhering to the national malaria treatment guidelines on dispensing ACTs as the first-line option. In contrast, nine out of 10 vendors stocked quinine and well over a third stocked antimalarials no longer recommended, such as chloroquine and sulphadoxine-pyrimethamine. Given the ongoing gap between the national malaria policy and unlicensed drug outlet practices, this study calls for greater engagement of unlicensed vendors to improve the management of childhood malaria. PMID:29623095

Understanding Unlicensed Drug Vendor Practices Related to Childhood Malaria in One Rural District of Uganda: An Exploratory Study.

PubMed

Liow, Eric; Kassam, Rosemin; Sekiwunga, Richard

2018-01-01

This study investigated unlicensed drug outlets' practices for the management of malaria in the rural district of Butaleja, Uganda. A qualitative design using semistructured interviews was used. Interviews were recorded, translated, transcribed, and analyzed using thematic analysis. A total of 75 vendors, representing 85% of the outlets in the study area, were interviewed. Most of the vendors were associated with a drug shop type of outfit. About three-quarters reported having completed some level of postsecondary education, but just one-tenth of the vendors had qualifications that made them eligible to apply for a license to operate a drug shop. While most outlets stocked at least one type of antimalarial, only about one-quarter stocked an artemisinin-based combination therapy (ACT), one-quarter expressed a preference for ACTs, and less than one-tenth attested to firmly adhering to the national malaria treatment guidelines on dispensing ACTs as the first-line option. In contrast, nine out of 10 vendors stocked quinine and well over a third stocked antimalarials no longer recommended, such as chloroquine and sulphadoxine-pyrimethamine. Given the ongoing gap between the national malaria policy and unlicensed drug outlet practices, this study calls for greater engagement of unlicensed vendors to improve the management of childhood malaria.

Multidrug resistance: prospects for clinical management.

PubMed

Mansouri, A; Henle, K J; Nagle, W A

1992-01-01

Clinical success in the treatment of tumors with chemotherapy has significantly improved over the past several years. However, treatment failures due to drug resistance of cancer cells has remained a major problem. The classical form of multiple drug resistance is perhaps also the most common type of drug resistance, and represents the overexpression of a transmembrane glycoprotein pump (P-170) that mediates the efflux of a spectrum of structurally and functionally unrelated drugs. Here, we discuss recent evidence that support the concept that the total phenomenon of multiple drug resistance (MDR) involves several other mechanisms in addition to that underlying "classical" MDR. These include the action of other energy-dependent membrane efflux pumps, elevated levels of GSH for drug conjugation and detoxification to facilitate export, enhanced DNA repair facility, gene amplification and oncogene activation. The combination of mechanisms used by any particular cell line is variable and suggests that many of these mechanisms are independent. Successful reversal of drug resistance appears to require the identification of relevant operative resistance mechanisms. An example is the competitive inhibition of P-170 with verapamil, quinine and tamoxifen. A broadly successful strategy for killing drug-resistant cancer cells, however, could be based on either selective energy depletion of cancer cells or the permeabilization of tumor cells with an effective bypass of efflux pumps, since many mechanisms of drug resistance entail the energy-dependent export of toxins. The latter approach may be achieved via membrane lipid modifications or the introduction of membrane pores by biological or physical (electroporation) means.

First-trimester artemisinin derivatives and quinine treatments and the risk of adverse pregnancy outcomes in Africa and Asia: A meta-analysis of observational studies.

PubMed

Dellicour, Stephanie; Sevene, Esperança; McGready, Rose; Tinto, Halidou; Mosha, Dominic; Manyando, Christine; Rulisa, Stephen; Desai, Meghna; Ouma, Peter; Oneko, Martina; Vala, Anifa; Rupérez, Maria; Macete, Eusébio; Menéndez, Clara; Nakanabo-Diallo, Seydou; Kazienga, Adama; Valéa, Innocent; Calip, Gregory; Augusto, Orvalho; Genton, Blaise; Njunju, Eric M; Moore, Kerryn A; d'Alessandro, Umberto; Nosten, Francois; Ter Kuile, Feiko; Stergachis, Andy

2017-05-01

Animal embryotoxicity data, and the scarcity of safety data in human pregnancies, have prevented artemisinin derivatives from being recommended for malaria treatment in the first trimester except in lifesaving circumstances. We conducted a meta-analysis of prospective observational studies comparing the risk of miscarriage, stillbirth, and major congenital anomaly (primary outcomes) among first-trimester pregnancies treated with artemisinin derivatives versus quinine or no antimalarial treatment. Electronic databases including Medline, Embase, and Malaria in Pregnancy Library were searched, and investigators contacted. Five studies involving 30,618 pregnancies were included; four from sub-Saharan Africa (n = 6,666 pregnancies, six sites) and one from Thailand (n = 23,952). Antimalarial exposures were ascertained by self-report or active detection and confirmed by prescriptions, clinic cards, and outpatient registers. Cox proportional hazards models, accounting for time under observation and gestational age at enrollment, were used to calculate hazard ratios. Individual participant data (IPD) meta-analysis was used to combine the African studies, and the results were then combined with those from Thailand using aggregated data meta-analysis with a random effects model. There was no difference in the risk of miscarriage associated with the use of artemisinins anytime during the first trimester (n = 37/671) compared with quinine (n = 96/945; adjusted hazard ratio [aHR] = 0.73 [95% CI 0.44, 1.21], I2 = 0%, p = 0.228), in the risk of stillbirth (artemisinins, n = 10/654; quinine, n = 11/615; aHR = 0.29 [95% CI 0.08-1.02], p = 0.053), or in the risk of miscarriage and stillbirth combined (pregnancy loss) (aHR = 0.58 [95% CI 0.36-1.02], p = 0.099). The corresponding risks of miscarriage, stillbirth, and pregnancy loss in a sensitivity analysis restricted to artemisinin exposures during the embryo sensitive period (6-12 wk gestation) were as follows: aHR = 1.04 (95% CI 0.54-2.01), I2 = 0%, p = 0.910; aHR = 0.73 (95% CI 0.26-2.06), p = 0.551; and aHR = 0.98 (95% CI 0.52-2.04), p = 0.603. The prevalence of major congenital anomalies was similar for first-trimester artemisinin (1.5% [95% CI 0.6%-3.5%]) and quinine exposures (1.2% [95% CI 0.6%-2.4%]). Key limitations of the study include the inability to control for confounding by indication in the African studies, the paucity of data on potential confounders, the limited statistical power to detect differences in congenital anomalies, and the lack of assessment of cardiovascular defects in newborns. Compared to quinine, artemisinin treatment in the first trimester was not associated with an increased risk of miscarriage or stillbirth. While the data are limited, they indicate no difference in the prevalence of major congenital anomalies between treatment groups. The benefits of 3-d artemisinin combination therapy regimens to treat malaria in early pregnancy are likely to outweigh the adverse outcomes of partially treated malaria, which can occur with oral quinine because of the known poor adherence to 7-d regimens. PROSPERO CRD42015032371.

Reprint of "Characterisation and modelling of the thermorheological properties of pharmaceutical polymers and their blends using capillary rheometry: Implications for hot melt processing of dosage forms".

PubMed

Jones, David S; Margetson, Daniel N; McAllister, Mark S; Andrews, Gavin P

2015-12-30

Given the growing interest in thermal processing methods, this study describes the use of an advanced rheological technique, capillary rheometry, to accurately determine the thermorheological properties of two pharmaceutical polymers, Eudragit E100 (E100) and hydroxypropylcellulose JF (HPC) and their blends, both in the presence and absence of a model therapeutic agent (quinine, as the base and hydrochloride salt). Furthermore, the glass transition temperatures (Tg) of the cooled extrudates produced using capillary rheometry were characterised using Dynamic Mechanical Thermal Analysis (DMTA) thereby enabling correlations to be drawn between the information derived from capillary rheometry and the glass transition properties of the extrudates. The shear viscosities of E100 and HPC (and their blends) decreased as functions of increasing temperature and shear rates, with the shear viscosity of E100 being significantly greater than that of HPC at all temperatures and shear rates. All platforms were readily processed at shear rates relevant to extrusion (approximately 200-300s(-1)) and injection moulding (approximately 900s(-1)). Quinine base was observed to lower the shear viscosities of E100 and E100/HPC blends during processing and the Tg of extrudates, indicative of plasticisation at processing temperatures and when cooled (i.e. in the solid state). Quinine hydrochloride (20% w/w) increased the shear viscosities of E100 and HPC and their blends during processing and did not affect the Tg of the parent polymer. However, the shear viscosities of these systems were not prohibitive to processing at shear rates relevant to extrusion and injection moulding. As the ratio of E100:HPC increased within the polymer blends the effects of quinine base on the lowering of both shear viscosity and Tg of the polymer blends increased, reflecting the greater solubility of quinine within E100. In conclusion, this study has highlighted the importance of capillary rheometry in identifying processing conditions, polymer miscibility and plasticisation phenomena. Copyright © 2015. Published by Elsevier B.V.

Characterisation and modelling of the thermorheological properties of pharmaceutical polymers and their blends using capillary rheometry: Implications for hot melt processing of dosage forms.

PubMed

Jones, David S; Margetson, Daniel N; McAllister, Mark S; Andrews, Gavin P

2015-09-30

Given the growing interest in thermal processing methods, this study describes the use of an advanced rheological technique, capillary rheometry, to accurately determine the thermorheological properties of two pharmaceutical polymers, Eudragit E100 (E100) and hydroxypropylcellulose JF (HPC) and their blends, both in the presence and absence of a model therapeutic agent (quinine, as the base and hydrochloride salt). Furthermore, the glass transition temperatures (Tg) of the cooled extrudates produced using capillary rheometry were characterised using Dynamic Mechanical Thermal Analysis (DMTA) thereby enabling correlations to be drawn between the information derived from capillary rheometry and the glass transition properties of the extrudates. The shear viscosities of E100 and HPC (and their blends) decreased as functions of increasing temperature and shear rates, with the shear viscosity of E100 being significantly greater than that of HPC at all temperatures and shear rates. All platforms were readily processed at shear rates relevant to extrusion (approximately 200-300 s(-1)) and injection moulding (approximately 900 s(-1)). Quinine base was observed to lower the shear viscosities of E100 and E100/HPC blends during processing and the Tg of extrudates, indicative of plasticisation at processing temperatures and when cooled (i.e. in the solid state). Quinine hydrochloride (20% w/w) increased the shear viscosities of E100 and HPC and their blends during processing and did not affect the Tg of the parent polymer. However, the shear viscosities of these systems were not prohibitive to processing at shear rates relevant to extrusion and injection moulding. As the ratio of E100:HPC increased within the polymer blends the effects of quinine base on the lowering of both shear viscosity and Tg of the polymer blends increased, reflecting the greater solubility of quinine within E100. In conclusion, this study has highlighted the importance of capillary rheometry in identifying processing conditions, polymer miscibility and plasticisation phenomena. Copyright © 2015. Published by Elsevier B.V.

Bitter-sweet processing in larval Drosophila.

PubMed

König, Christian; Schleyer, Michael; Leibiger, Judith; El-Keredy, Amira; Gerber, Bertram

2014-07-01

"Sweet-" and "bitter-" tasting substances distinctively support attractive and aversive choice behavior, respectively, and therefore are thought to be processed by distinct pathways. Interestingly, electrophysiological recordings in adult Drosophila suggest that bitter and salty tastants, in addition to activating bitter, salt, or bitter/salt sensory neurons, can also inhibit sweet-sensory neurons. However, the behavioral significance of such a potential for combinatorial coding is little understood. Using larval Drosophila as a study case, we find that the preference towards fructose is inhibited when assayed in the background of the bitter tastant quinine. When testing the influence of quinine on the preference to other, equally preferred sweet tastants, we find that these sweet tastants differ in their susceptibility to be inhibited by quinine. Such stimulus specificity argues that the inhibitory effect of quinine is not due to general effects on locomotion or nausea. In turn, not all bitter tastants have the same potency to inhibit sweet preference; notably, their inhibitory potency is not determined by the strength of the avoidance of them. Likewise, equally avoided concentrations of sodium chloride differ in their potency to inhibit sugar preference. Furthermore, Gr33a-Gal4-positive neurons, while being necessary for bitter avoidance, are dispensable for inhibition of the sweet pathway. Thus, interactions across taste modalities are behaviorally significant and, as we discuss, arguably diverse in mechanism. These results suggest that the coding of tastants and the organization of gustatory behavior may be more combinatorial than is generally acknowledged. © The Author 2014. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Electrophysiological Responses of Gustatory Receptor Neurons on the Labella of the Common Malaria Mosquito, Anopheles quadrimaculatus (Diptera: Culicidae).

PubMed

Sparks, Jackson T; Dickens, Joseph C

2016-05-11

We recorded electrical responses from sensory cells associated with gustatory sensilla on the labella of female Anopheles quadrimaculatus Say to salt, sucrose, quinine (a feeding deterrent), and the insect repellent, N,N-diethyl-3-methylbenzamide (DEET). A salt-sensitive cell responded to increasing concentrations of sodium chloride. A second cell was activated by increasing sucrose concentrations, while quinine, DEET, or a mixture of quinine + DEET elicited spike activity from a third cell, an apparent bitter- or deterrent-sensitive cell. Both quinine and DEET suppressed activity of the sugar-sensitive cell; sucrose suppressed activity of the bitter- or deterrent-sensitive cell. These results demonstrate separate gustatory pathways for a feeding stimulant and aversive contact cues mediated through distinct sensory inputs on the labellum. This sensory appendage may serve as a useful target to disrupt feeding behavior in this and other anopheline species, which transmit diseases like malaria to human populations. Published by Oxford University Press on behalf of Entomological Society of America 2016. This work is written by US Government employees and is in the public domain in the United States.

Rapid and green analytical method for the determination of quinoline alkaloids from Cinchona succirubra based on Microwave-Integrated Extraction and Leaching (MIEL) prior to high performance liquid chromatography.

PubMed

Fabiano-Tixier, Anne-Sylvie; Elomri, Abdelhakim; Blanckaert, Axelle; Seguin, Elisabeth; Petitcolas, Emmanuel; Chemat, Farid

2011-01-01

Quinas contains several compounds, such as quinoline alkaloids, principally quinine, quinidine, cinchonine and cichonidine. Identified from barks of Cinchona, quinine is still commonly used to treat human malaria. Microwave-Integrated Extraction and Leaching (MIEL) is proposed for the extraction of quinoline alkaloids from bark of Cinchona succirubra. The process is performed in four steps, which ensures complete, rapid and accurate extraction of the samples. Optimal conditions for extraction were obtained using a response surface methodology reached from a central composite design. The MIEL extraction has been compared with a conventional technique soxhlet extraction. The extracts of quinoline alkaloids from C. succirubra obtained by these two different methods were compared by HPLC. The extracts obtained by MIEL in 32 min were quantitatively (yield) and qualitatively (quinine, quinidine, cinchonine, cinchonidine) similar to those obtained by conventional Soxhlet extraction in 3 hours. MIEL is a green technology that serves as a good alternative for the extraction of Cinchona alkaloids.

Rapid and Green Analytical Method for the Determination of Quinoline Alkaloids from Cinchona succirubra Based on Microwave-Integrated Extraction and Leaching (MIEL) Prior to High Performance Liquid Chromatography

PubMed Central

Fabiano-Tixier, Anne-Sylvie; Elomri, Abdelhakim; Blanckaert, Axelle; Seguin, Elisabeth; Petitcolas, Emmanuel; Chemat, Farid

2011-01-01

Quinas contains several compounds, such as quinoline alkaloids, principally quinine, quinidine, cinchonine and cichonidine. Identified from barks of Cinchona, quinine is still commonly used to treat human malaria. Microwave-Integrated Extraction and Leaching (MIEL) is proposed for the extraction of quinoline alkaloids from bark of Cinchona succirubra. The process is performed in four steps, which ensures complete, rapid and accurate extraction of the samples. Optimal conditions for extraction were obtained using a response surface methodology reached from a central composite design. The MIEL extraction has been compared with a conventional technique soxhlet extraction. The extracts of quinoline alkaloids from C. succirubra obtained by these two different methods were compared by HPLC. The extracts obtained by MIEL in 32 min were quantitatively (yield) and qualitatively (quinine, quinidine, cinchonine, cinchonidine) similar to those obtained by conventional Soxhlet extraction in 3 hours. MIEL is a green technology that serves as a good alternative for the extraction of Cinchona alkaloids. PMID:22174637

Biologically active quinoline and quinazoline alkaloids part I.

PubMed

Shang, Xiao-Fei; Morris-Natschke, Susan L; Liu, Ying-Qian; Guo, Xiao; Xu, Xiao-Shan; Goto, Masuo; Li, Jun-Cai; Yang, Guan-Zhou; Lee, Kuo-Hsiung

2018-05-01

Quinoline and quinazoline alkaloids, two important classes of N-based heterocyclic compounds, have attracted tremendous attention from researchers worldwide since the 19th century. Over the past 200 years, many compounds from these two classes were isolated from natural sources, and most of them and their modified analogs possess significant bioactivities. Quinine and camptothecin are two of the most famous and important quinoline alkaloids, and their discoveries opened new areas in antimalarial and anticancer drug development, respectively. In this review, we survey the literature on bioactive alkaloids from these two classes and highlight research achievements prior to the year 2008 (Part I). Over 200 molecules with a broad range of bioactivities, including antitumor, antimalarial, antibacterial and antifungal, antiparasitic and insecticidal, antiviral, antiplatelet, anti-inflammatory, herbicidal, antioxidant and other activities, were reviewed. This survey should provide new clues or possibilities for the discovery of new and better drugs from the original naturally occurring quinoline and quinazoline alkaloids. © 2017 Wiley Periodicals, Inc.

Identification of Compounds with Efficacy against Malaria Parasites from Common North American Plants.

PubMed

Cai, Shengxin; Risinger, April L; Nair, Shalini; Peng, Jiangnan; Anderson, Timothy J C; Du, Lin; Powell, Douglas R; Mooberry, Susan L; Cichewicz, Robert H

2016-03-25

Some of the most valuable antimalarial compounds, including quinine and artemisinin, originated from plants. While these drugs have served important roles over many years for the treatment of malaria, drug resistance has become a widespread problem. Therefore, a critical need exists to identify new compounds that have efficacy against drug-resistant malaria strains. In the current study, extracts prepared from plants readily obtained from local sources were screened for activity against Plasmodium falciparum. Bioassay-guided fractionation was used to identify 18 compounds from five plant species. These compounds included eight lupane triterpenes (1-8), four kaempferol 3-O-rhamnosides (10-13), four kaempferol 3-O-glucosides (14-17), and the known compounds amentoflavone and knipholone. These compounds were tested for their efficacy against multi-drug-resistant malaria parasites and counterscreened against HeLa cells to measure their antimalarial selectivity. Most notably, one of the new lupane triterpenes (3) isolated from the supercritical extract of Buxus sempervirens, the common boxwood, showed activity against both drug-sensitive and -resistant malaria strains at a concentration that was 75-fold more selective for the drug-resistant malaria parasites as compared to HeLa cells. This study demonstrates that new antimalarial compounds with efficacy against drug-resistant strains can be identified from native and introduced plant species in the United States, which traditionally have received scant investigation compared to more heavily explored tropical and semitropical botanical resources from around the world.

Retail supply of malaria-related drugs in rural Tanzania: risks and opportunities.

PubMed

Goodman, Catherine; Kachur, S Patrick; Abdulla, Salim; Mwageni, Eleuther; Nyoni, Joyce; Schellenberg, Joanna A; Mills, Anne; Bloland, Peter

2004-06-01

To characterize availability of fever and malaria medicines within the retail sector in rural Tanzania, assess the likely public health implications, and identify opportunities for policy interventions to increase the coverage of effective treatment. A census of retailers selling drugs was undertaken in the areas under demographic surveillance in four Tanzanian districts, using a structured questionnaire. Drugs were stocked by two types of retailer: a large number of general retailers (n = 675) and a relatively small number of drug shops (n = 43). Almost all outlets stocked antipyretics/painkillers. One-third of general retailers stocking drugs had antimalarials, usually chloroquine alone. Almost all drug shops stocked antimalarials (98%): nearly all had chloroquine, 42% stocked quinine, 37% sulphadoxine-pyrimethamine and 30% amodiaquine. A large number of antimalarial brands were available. Population ratios indicate the relative accessibility of retail drug providers compared with health facilities. Drug shop staff generally travelled long distances to buy from drugs wholesalers or pharmacies. General retailers bought mainly from local general wholesalers, with a few general wholesalers accounting for a high proportion of all sources cited. Drugs were widely available from a large number of retail outlets. Potential negative implications include provision of ineffective drugs, confusion over brand names, uncontrolled use of antimalarials, and the availability of components of potential combination therapy regimens as monotherapies. On the other hand, this active and highly accessible retail market provides opportunities for improving the coverage of effective antimalarial treatment. Interventions targeted at all drug retailers are likely to be costly to deliver and difficult to sustain, but two promising points for targeted intervention are drug shops and selected general wholesalers. Retail quality may also be improved through consumer education, and modification of the chemical quality, packaging and price of products entering the retail distribution chain.

Helplessness in the tail suspension test is associated with an increase in ethanol intake and its rewarding effect in female mice.

PubMed

Pelloux, Yann; Hagues, Guillaume; Costentin, Jean; Duterte-Boucher, Dominique

2005-03-01

Depression is frequently observed in drug abusers. However, depression may be a primary factor of predisposition to drug abuse or a consequence of drug abuse. The aim of this study was to analyze the influence of a preexisting depressive-like state/helplessness on subsequent alcohol responsiveness in mice. Male and female CD1 mice were selected according to their immobility time in the tail suspension test, and only mice with "high immobility" and "low immobility" time were retained. Using a two-bottle free-choice paradigm, these mice were given continuous access to tap water or solutions of ethanol (3-20% v/v), quinine (12.5-50 mg/liter), or sucrose (1-4% w/v). In female mice, rewarding and aversive effects of ethanol (1.5 and 3 g/kg, intraperitoneally) were also investigated using the conditioned place preference and the conditioned taste aversion paradigms. Female mice were more immobile and drank more ethanol than male mice. No striking sex difference was observed in quinine consumption. Sucrose intake was higher in female than in male mice, whatever the solution concentration. At the 4% concentrated solution, a sucrose-induced increase in daily fluid intake was observed only in female mice. Female mice with high immobility time (HI) consumed more ethanol at the highest concentration than female mice with low immobility time (LI), whereas no difference was observed between HI and LI male mice. Moreover, whereas LI female mice failed to express place conditioning induced by the 3-g/kg dose of ethanol, HI female mice were strongly responsive to the rewarding effect of this high ethanol dose. Ethanol dose-dependently induced a conditioned taste aversion with a similar magnitude in both LI and HI female mice. The findings indicate that female CD1 mice tend to drink greater amounts of ethanol or sucrose solutions than male CD1 mice, suggesting that female mice may be a better model of excessive alcohol intake. Furthermore, no relationship was found between immobility scores and ethanol consumption in male mice. On the contrary, within female mice, HI mice consumed higher amounts of ethanol than LI mice probably because they experienced greater rewarding effects of ethanol. The present results support the hypothesis that depressive-like responses may predispose to ethanol abuse in female mice.

Rectal artemisinins for malaria: a review of efficacy and safety from individual patient data in clinical studies

PubMed Central

Gomes, Melba; Ribeiro, Isabela; Warsame, Marian; Karunajeewa, Harin; Petzold, Max

2008-01-01

Background Rectal administration of artemisinin derivatives has potential for early treatment for severe malaria in remote settings where injectable antimalarial therapy may not be feasible. Preparations available include artesunate, artemisinin, artemether and dihydroartemisinin. However each may have different pharmacokinetic properties and more information is needed to determine optimal dose and comparative efficacy with each another and with conventional parenteral treatments for severe malaria. Methods Individual patient data from 1167 patients in 15 clinical trials of rectal artemisinin derivative therapy (artesunate, artemisinin and artemether) were pooled in order to compare the rapidity of clearance of Plasmodium falciparum parasitaemia and the incidence of reported adverse events with each treatment. Data from patients who received comparator treatment (parenteral artemisinin derivative or quinine) were also included. Primary endpoints included percentage reductions in parasitaemia at 12 and 24 hours. A parasite reduction of >90% at 24 hours was defined as parasitological success. Results Artemisinin and artesunate treatment cleared parasites more rapidly than parenteral quinine during the first 24 hours of treatment. A single higher dose of rectal artesunate treatment was five times more likely to achieve >90% parasite reductions at 24 hours than were multiple lower doses of rectal artesunate, or a single lower dose administration of rectal artemether. Conclusion Artemisinin and artesunate suppositories rapidly eliminate parasites and appear to be safe. There are less data on artemether and dihydroartemisinin suppositories. The more rapid parasite clearance of single high-dose regimens suggests that achieving immediate high drug concentrations may be the optimal strategy. PMID:18373841

Atorvastatin as a potential anti-malarial drug: in vitro synergy in combinational therapy with quinine against Plasmodium falciparum.

PubMed

Parquet, Véronique; Henry, Maud; Wurtz, Nathalie; Dormoi, Jerome; Briolant, Sébastien; Gil, Marine; Baret, Eric; Amalvict, Rémy; Rogier, Christophe; Pradines, Bruno

2010-05-25

Quinine (QN) remains the first line anti-malarial drug for the treatment of complicated malaria in Europe and Africa. The emergence of QN resistance has been documented. QN resistance is not yet a significant problem, but there is an urgent need to discover partners for use in combination with QN. The aim of the study was to assess the in vitro potentiating effects of atorvastatin (AVA), a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, in combination with QN against Plasmodium falciparum and to evaluate whether the effects of AVA could be associated with gene copy number or mutations in genes involved in QN resistance, such as pfcrt, pfmdr1, pfmrp and pfnhe. The susceptibilities to combination of AVA with QN were assessed against 21 parasite strains using the in vitro isotopic microtest. Genotypes and gene copy number were assessed for pfcrt, pfmdr1, pfmdr2, pfmrp genes. In addition, the number of DNNND, DDNHNDNHNN repeats in pfnhe-1 ms4760 and the ms4760 profile were determined for each strains of P. falciparum. AVA demonstrated synergistic effects in combination with QN against 21 P. falciparum strains. The QN IC50 was reduced by 5% (0% to 15%; 95%CI: 1%-8%), 10% (3% to 23%; 95%CI: 7%-14%) and 22% (14% to 40%; 95%CI: 19%-25%) in presence of AVA at concentrations of 0.1, 0.5 and 1.0 microM, respectively. These reductions were all significant (p < 0.009). The reduction in the QN IC50 in presence of AVA was not significantly correlated with the QN IC50 (r = 0.22, P = 0.3288) or the AVA IC50 (r = 0.03, P = 0.8946). The synergistic effect of AVA in combination with QN was not significantly associated with polymorphisms in the pfcrt, pfmdr1, pfmrp, and pfnhe-1 genes that could be involved in QN resistance. The synergistic effect of AVA on QN responses was not significantly associated with pfmdr1 copy number (P = 0.0428). The synergistic effect of AVA in combination with QN was found to be unrelated to mutations occurring in transport protein genes involved in QN drug resistance. The different mechanisms of drug uptake and/or mode of action for AVA compared to the other anti-malarial drugs, as well as the AVA-mediated synergy of the anti-malarial effect of QN, suggests that AVA will be a good candidate for combinatorial malaria treatment. All of these observations support calls for both an in vivo evaluation with pharmacokinetic component and clinical trials of AVA as an anti-malarial therapy.

Atorvastatin as a potential anti-malarial drug: in vitro synergy in combinational therapy with quinine against Plasmodium falciparum

PubMed Central

2010-01-01

Background Quinine (QN) remains the first line anti-malarial drug for the treatment of complicated malaria in Europe and Africa. The emergence of QN resistance has been documented. QN resistance is not yet a significant problem, but there is an urgent need to discover partners for use in combination with QN. The aim of the study was to assess the in vitro potentiating effects of atorvastatin (AVA), a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, in combination with QN against Plasmodium falciparum and to evaluate whether the effects of AVA could be associated with gene copy number or mutations in genes involved in QN resistance, such as pfcrt, pfmdr1, pfmrp and pfnhe. Methods The susceptibilities to combination of AVA with QN were assessed against 21 parasite strains using the in vitro isotopic microtest. Genotypes and gene copy number were assessed for pfcrt, pfmdr1, pfmdr2, pfmrp genes. In addition, the number of DNNND, DDNHNDNHNN repeats in pfnhe-1 ms4760 and the ms4760 profile were determined for each strains of P. falciparum. Results AVA demonstrated synergistic effects in combination with QN against 21 P. falciparum strains. The QN IC50 was reduced by 5% (0% to 15%; 95%CI: 1%-8%), 10% (3% to 23%; 95%CI: 7%-14%) and 22% (14% to 40%; 95%CI: 19%-25%) in presence of AVA at concentrations of 0.1, 0.5 and 1.0 μM, respectively. These reductions were all significant (p < 0.009). The reduction in the QN IC50 in presence of AVA was not significantly correlated with the QN IC50 (r = 0.22, P = 0.3288) or the AVA IC50 (r = 0.03, P = 0.8946). The synergistic effect of AVA in combination with QN was not significantly associated with polymorphisms in the pfcrt, pfmdr1, pfmrp, and pfnhe-1 genes that could be involved in QN resistance. The synergistic effect of AVA on QN responses was not significantly associated with pfmdr1 copy number (P = 0.0428). Conclusion The synergistic effect of AVA in combination with QN was found to be unrelated to mutations occurring in transport protein genes involved in QN drug resistance. The different mechanisms of drug uptake and/or mode of action for AVA compared to the other anti-malarial drugs, as well as the AVA-mediated synergy of the anti-malarial effect of QN, suggests that AVA will be a good candidate for combinatorial malaria treatment. All of these observations support calls for both an in vivo evaluation with pharmacokinetic component and clinical trials of AVA as an anti-malarial therapy. PMID:20497586

The microculture tetrazolium assay (MTA): another colorimetric method of testing Plasmodium falciparum chemosensitivity.

PubMed

Delhaes, L; Lazaro, J E; Gay, F; Thellier, M; Danis, M

1999-01-01

Malarial lactate dehydrogenase (LDH), which uses 3-acetyl pyridine adenine dinucleotide as coenzyme in a reaction leading to the formation of pyruvate from L-lactate, may be used to study the susceptibility of Plasmodium falciparum to a drug in vitro. Several methods to determine the activity of this enzyme are available. One, the colorimetric method of Makler and colleagues, was modified slightly, by using sodium-2,3-bis-[2-methoxy-4-nitro-5-sulphophenyl]-2H-tetrazolium-5 - carboxanilide (XTT) and following the reaction by measuring the optical density at 450 nm. Using two, culture-adapted strains of P. falciparum, this LDH assay was compared with the unmodified Makler's assay and with the isotopic microtest based on the incorporation of tritium-labelled hypoxanthine. Fresh, clinical P. falciparum isolates were also tested in the presence of several drugs, including chloroquine, mefloquine, quinine, halofantrine, atovaquone and qinghaosu derivatives. The results of the three assays were correlated for all the drugs tested except atovaquone. The two enzymatic assays are non-radioactive, rapid, reliable, inexpensive to perform and semi-automatic. However, they do require an initial parasitaemia of 2% with a haematocrit of 1.8%.

A non-radiolabelled ferriprotoporphyrin IX biomineralisation inhibition test for the high throughput screening of antimalarial compounds.

PubMed

Deharo, E; García, R N; Oporto, P; Gimenez, A; Sauvain, M; Jullian, V; Ginsburg, H

2002-04-01

Intraerythrocytic malaria parasites produce large amounts of toxic ferriprotoporphyrin IX (FP) during their digestion of host cell haemoglobin. The inhibition of biomineralisation of FP to haemozoin (or beta-haematin) by antimalarial drugs underlies their mode of action. We have developed an in vitro microassay for testing the inhibition of biomineralisation by drugs. It is based on the detection by optical density measurement of solubilised beta-haematin remaining after contact with drugs. The assay uses a 192-microM haemin chloride solution in dimethyl sulfoxide, 96-well filtration microplates as well as normal microplates; it lasts 18-24h and requires a spectrophotometer. We determined by this assay the IC(50) of chloroquine phosphate (28microM) and quinine base (324microM) and showed that unlike previous methods it is insensitive to inorganic anions. We also determined the activity of synthetic dyes and plant extract to determinate the interference of coloured compounds on the accuracy of the test. We found that methylene blue, thionine (IC(50) 38 and 87microM, respectively), and an extract of plants that contains quinoline derivatives, inhibited the biomineralisation of FP regardless of their intrinsic colour.

CRISPR-Cas9-modified pfmdr1 protects Plasmodium falciparum asexual blood stages and gametocytes against a class of piperazine-containing compounds but potentiates artemisinin-based combination therapy partner drugs.

PubMed

Ng, Caroline L; Siciliano, Giulia; Lee, Marcus C S; de Almeida, Mariana J; Corey, Victoria C; Bopp, Selina E; Bertuccini, Lucia; Wittlin, Sergio; Kasdin, Rachel G; Le Bihan, Amélie; Clozel, Martine; Winzeler, Elizabeth A; Alano, Pietro; Fidock, David A

2016-08-01

Emerging resistance to first-line antimalarial combination therapies threatens malaria treatment and the global elimination campaign. Improved therapeutic strategies are required to protect existing drugs and enhance treatment efficacy. We report that the piperazine-containing compound ACT-451840 exhibits single-digit nanomolar inhibition of the Plasmodium falciparum asexual blood stages and transmissible gametocyte forms. Genome sequence analyses of in vitro-derived ACT-451840-resistant parasites revealed single nucleotide polymorphisms in pfmdr1, which encodes a digestive vacuole membrane-bound ATP-binding cassette transporter known to alter P. falciparum susceptibility to multiple first-line antimalarials. CRISPR-Cas9 based gene editing confirmed that PfMDR1 point mutations mediated ACT-451840 resistance. Resistant parasites demonstrated increased susceptibility to the clinical drugs lumefantrine, mefloquine, quinine and amodiaquine. Stage V gametocytes harboring Cas9-introduced pfmdr1 mutations also acquired ACT-451840 resistance. These findings reveal that PfMDR1 mutations can impart resistance to compounds active against asexual blood stages and mature gametocytes. Exploiting PfMDR1 resistance mechanisms provides new opportunities for developing disease-relieving and transmission-blocking antimalarials. © 2016 John Wiley & Sons Ltd.

Advances in the Treatment of Malaria

PubMed Central

Castelli, Francesco; Tomasoni, Lina Rachele; Matteelli, Alberto

2012-01-01

Malaria still claims a heavy toll of deaths and disabilities even at the beginning of the third millennium. The inappropriate sequential use of drug monotherapy in the past has facilitated the spread of drug-resistant P. falciparum, and to a lesser extend P. vivax, strains in most of the malaria endemic areas, rendering most anti-malarial ineffective. In the last decade, a new combination strategy based on artemisinin derivatives (ACT) has become the standard of treatment for most P. falciparum malaria infections. This strategy could prevent the selection of resistant strains by rapidly decreasing the parasitic burden (by the artemisinin derivative, mostly artesunate) and exposing the residual parasite to effective concentrations of the partner drug. The widespread use of this strategy is somehow constrained by cost and by the inappropriate use of artemisinin, with possible impact on resistance, as already sporadically observed in South East Asia. Parenteral artesunate has now become the standard of care for severe malaria, even if quinine still retains its value in case artesunate is not immediately available. The appropriateness of pre-referral use of suppository artesunate is under close monitoring, while waiting for an effective anti-malarial vaccine to be made available. PMID:23170193

A rational regulatory approach for positron emission tomography imaging probes: from "first in man" to NDA approval and reimbursement.

PubMed

Barrio, Jorge R; Marcus, Carol S; Hung, Joseph C; Keppler, Jennifer S

2004-01-01

We propose a new regulatory approach for positron emission tomography (PET) molecular imaging probes, essential tools in today's medicine. Even though the focus of this paper is on positron-emitting labeled probes, it is also justified to extend this proposed regulatory approach to other diagnostic nuclear medicine radiopharmaceuticals. Key aspects of this proposal include: (1) PET molecular imaging probes would be placed in a "no significant risk" category, similar to that category for devices in current Food and Drug Administration (FDA) regulations, based on overwhelming scientific evidence that demonstrates their faultless safety profile; (2) the FDA-sanctioned Radioactive Drug Research Committee (RDRC) will oversee all diagnostic research with these probes. The newly defined RDRC should approve "first in man" use; supervise a broader spectrum of diagnostic research protocols, including those looking to demonstrate initial efficacy, as well as multicenter clinical trials and the use of molecular imaging probes as a screening tool in drug discovery. The current investigational new drug (IND) mechanism is thus eliminated for these diagnostic probes; (3) when a molecular imaging probe has demonstrated diagnostic efficacy, FDA approval (i.e., NDA) will be sought. The review will be done by a newly constituted Radioactive Drug Advisory Committee (RDAC) composed of experts chosen by the professional societies, who would provide a binding assessment of the adequacy of the safety and efficacy data. When the RDAC recommends its diagnostic use on scientific and medical grounds, the molecular imaging probe becomes FDA approved. After a molecular imaging probe is approved for a diagnostic indication, the existing mechanism to seek reimbursement will be utilized; and (4) the FDA would retain its direct oversight function for traditional manufacturers engaged in commercial distribution of the approved diagnostic molecular imaging probes (i.e., under NDA) to monitor compliance with existing US Pharmacopeia (USP) requirements. With abbreviated and more appropriate regulations, new PET molecular imaging probes for diagnostic use would be then rapidly incorporated into the mainstream diagnostic medicine. Equally importantly, this approach would facilitate the use of molecular imaging in drug discovery and development, which would substantially reduce the costs and time required to bring new therapeutic drugs to market.

Interaction of chloroquine and its analogues with heme: An isothermal titration calorimetric study.

PubMed

Bachhawat, K; Thomas, C J; Surolia, N; Surolia, A

2000-10-05

Quinoline-containing drugs such as chloroquine and quinine have had a long and successful history in antimalarial chemotherapy. Identification of ferriprotoporphyrin IX ([Fe(III)PPIX], haematin) as the drug receptors for these antimalarials called for investigations of the binding affinity, mode of interaction, and the conditions affecting the interaction. The parameters obtained are significant in recent times with the emergence of chloroquine resistant strains of the malaria parasites. This has underlined the need to unravel the molecular mechanism of their action so as to meet the requirement of an alternative to the existing antimalarial drugs. The isothermal titration calorimetric studies on the interaction of chloroquine with haematin lead us to propose an altered mode of binding. The initial recognition is ionic in nature mediated by the propionyl group of haematin with the quaternary nitrogen on CQ. This ionic interaction induces a conformational change, such as to favour binding of subsequent CQ molecules. On the contrary, conditions emulating the cytosolic environment (pH 7.4 and 150 mM salt) reveal the hydrophobic force to be the sole contributor driving the interaction. Interaction of a carefully selected panel of quinoline antimalarial drugs with monomeric ferriprotoporphyrin IX has also been investigated at pH 5.6 mimicking the acidic environment prevalent in the food vacuoles of parasite, the center of drug activity, which are consistent with their antimalarial activity. Copyright 2000 Academic Press.

Delay discounting of oral morphine and sweetened juice rewards in dependent and non-dependent rats.

PubMed

Harvey-Lewis, Colin; Perdrizet, Johnna; Franklin, Keith B J

2014-07-01

Opioid-dependent humans are reported to show accelerated delay discounting of opioid rewards when compared to monetary rewards. It has been suggested that this may reflect a difference in discounting of consumable and non-consumable goods not specific to dependent individuals. Here, we evaluate the discounting of similar morphine and non-morphine oral rewards in dependent and non-dependent rats We first tested the analgesic and rewarding effects of our morphine solution. In a second experiment, we assigned rats randomly to either dependent or non-dependent groups that, 30 min after daily testing, received 30 mg/kg subcutaneous dose of morphine, or saline, respectively. Delay discounting of drug-free reward was examined prior to initiation of the dosing regimen. We tested discounting of the morphine reward in half the rats and retested the discounting of the drug-free reward in the other half. All tests were run 22.5 h after the daily maintenance dose. Rats preferred the morphine cocktail to the drug-free solution and consumed enough to induce significant analgesia. The control quinine solution did not produce these effects. Dependent rats discounted morphine rewards more rapidly than before dependence and when compared to discounting drug-free rewards. In non-dependent rats both reward types were discounted similarly. These results show that morphine dependence increases impulsiveness specifically towards a drug reward while morphine experience without dependence does not.

MTBDRplus and MTBDRsl Assays: Absence of Wild-Type Probe Hybridization and Implications for Detection of Drug-Resistant Tuberculosis

PubMed Central

Georghiou, Sophia B.; Catanzaro, Donald; Rodrigues, Camilla; Crudu, Valeriu; Victor, Thomas C.; Garfein, Richard S.; Catanzaro, Antonino; Rodwell, Timothy C.

2016-01-01

Accurate identification of drug-resistant Mycobacterium tuberculosis is imperative for effective treatment and subsequent reduction in disease transmission. Line probe assays rapidly detect mutations associated with resistance and wild-type sequences associated with susceptibility. Examination of molecular-level performance is necessary for improved assay result interpretation and for continued diagnostic development. Using data collected from a large, multisite diagnostic study, probe hybridization results from line probe assays, MTBDRplus and MTBDRsl, were compared to those of sequencing, and the diagnostic performance of each individual mutation and wild-type probe was assessed. Line probe assay results classified as resistant due to the absence of wild-type probe hybridization were compared to those of sequencing to determine if novel mutations were inhibiting wild-type probe hybridization. The contribution of absent wild-type probe hybridization to the detection of drug resistance was assessed via comparison to a phenotypic reference standard. In our study, mutation probes demonstrated significantly higher specificities than wild-type probes and wild-type probes demonstrated marginally higher sensitivities than mutation probes, an ideal combination for detecting the presence of resistance conferring mutations while yielding the fewest number of false-positive results. The absence of wild-type probe hybridization without mutation probe hybridization was determined to be primarily the result of failure of mutation probe hybridization and not the result of novel or rare mutations. Compared to phenotypic culture-based drug susceptibility testing, the absence of wild-type probe hybridization without mutation probe hybridization significantly contributed to the detection of phenotypic rifampin and fluoroquinolone resistance with negligible increases in false-positive results. PMID:26763971

Identifying mechanism-of-action targets for drugs and probes

PubMed Central

Gregori-Puigjané, Elisabet; Setola, Vincent; Hert, Jérôme; Crews, Brenda A.; Irwin, John J.; Lounkine, Eugen; Marnett, Lawrence; Roth, Bryan L.; Shoichet, Brian K.

2012-01-01

Notwithstanding their key roles in therapy and as biological probes, 7% of approved drugs are purported to have no known primary target, and up to 18% lack a well-defined mechanism of action. Using a chemoinformatics approach, we sought to “de-orphanize” drugs that lack primary targets. Surprisingly, targets could be easily predicted for many: Whereas these targets were not known to us nor to the common databases, most could be confirmed by literature search, leaving only 13 Food and Drug Administration—approved drugs with unknown targets; the number of drugs without molecular targets likely is far fewer than reported. The number of worldwide drugs without reasonable molecular targets similarly dropped, from 352 (25%) to 44 (4%). Nevertheless, there remained at least seven drugs for which reasonable mechanism-of-action targets were unknown but could be predicted, including the antitussives clemastine, cloperastine, and nepinalone; the antiemetic benzquinamide; the muscle relaxant cyclobenzaprine; the analgesic nefopam; and the immunomodulator lobenzarit. For each, predicted targets were confirmed experimentally, with affinities within their physiological concentration ranges. Turning this question on its head, we next asked which drugs were specific enough to act as chemical probes. Over 100 drugs met the standard criteria for probes, and 40 did so by more stringent criteria. A chemical information approach to drug-target association can guide therapeutic development and reveal applications to probe biology, a focus of much current interest. PMID:22711801

UK malaria treatment guidelines 2016.

PubMed

Lalloo, David G; Shingadia, Delane; Bell, David J; Beeching, Nicholas J; Whitty, Christopher J M; Chiodini, Peter L

2016-06-01

1.Malaria is the tropical disease most commonly imported into the UK, with 1300-1800 cases reported each year, and 2-11 deaths. 2. Approximately three quarters of reported malaria cases in the UK are caused by Plasmodium falciparum, which is capable of invading a high proportion of red blood cells and rapidly leading to severe or life-threatening multi-organ disease. 3. Most non-falciparum malaria cases are caused by Plasmodium vivax; a few cases are caused by the other species of plasmodium: Plasmodium ovale, Plasmodium malariae or Plasmodium knowlesi. 4. Mixed infections with more than one species of parasite can occur; they commonly involve P. falciparum with the attendant risks of severe malaria. 5. There are no typical clinical features of malaria; even fever is not invariably present. Malaria in children (and sometimes in adults) may present with misleading symptoms such as gastrointestinal features, sore throat or lower respiratory complaints. 6. A diagnosis of malaria must always be sought in a feverish or sick child or adult who has visited malaria-endemic areas. Specific country information on malaria can be found at http://travelhealthpro.org.uk/. P. falciparum infection rarely presents more than six months after exposure but presentation of other species can occur more than a year after exposure. 7. Management of malaria depends on awareness of the diagnosis and on performing the correct diagnostic tests: the diagnosis cannot be excluded until more than one blood specimen has been examined. Other travel related infections, especially viral haemorrhagic fevers, should also be considered. 8. The optimum diagnostic procedure is examination of thick and thin blood films by an expert to detect and speciate the malarial parasites. P. falciparum and P. vivax (depending upon the product) malaria can be diagnosed almost as accurately using rapid diagnostic tests (RDTs) which detect plasmodial antigens. RDTs for other Plasmodium species are not as reliable. 9. Most patients treated for P. falciparum malaria should be admitted to hospital for at least 24 h as patients can deteriorate suddenly, especially early in the course of treatment. In specialised units seeing large numbers of patients, outpatient treatment may be considered if specific protocols for patient selection and follow up are in place. 10. Uncomplicated P. falciparum malaria should be treated with an artemisinin combination therapy (Grade 1A). Artemether-lumefantrine (Riamet(®)) is the drug of choice (Grade 2C) and dihydroartemisinin-piperaquine (Eurartesim(®)) is an alternative. Quinine or atovaquone-proguanil (Malarone(®)) can be used if an ACT is not available. Quinine is highly effective but poorly-tolerated in prolonged treatment and should be used in combination with an additional drug, usually oral doxycycline. 11. Severe falciparum malaria, or infections complicated by a relatively high parasite count (more than 2% of red blood cells parasitized) should be treated with intravenous therapy until the patient is well enough to continue with oral treatment. Severe malaria is a rare complication of P. vivax or P. knowlesi infection and also requires parenteral therapy. 12. The treatment of choice for severe or complicated malaria in adults and children is intravenous artesunate (Grade 1A). Intravenous artesunate is unlicensed in the EU but is available in many centres. The alternative is intravenous quinine, which should be started immediately if artesunate is not available (Grade 1A). Patients treated with intravenous quinine require careful monitoring for hypoglycemia. 13. Patients with severe or complicated malaria should be managed in a high-dependency or intensive care environment. They may require haemodynamic support and management of: acute respiratory distress syndrome, disseminated intravascular coagulation, acute kidney injury, seizures, and severe intercurrent infections including Gram-negative bacteraemia/septicaemia. 14. Children with severe malaria should also be treated with empirical broad spectrum antibiotics until bacterial infection can be excluded (Grade 1B). 15. Haemolysis occurs in approximately 10-15% patients following intravenous artesunate treatment. Haemoglobin concentrations should be checked approximately 14 days following treatment in those treated with IV artemisinins (Grade 2C). 16. Falciparum malaria in pregnancy is more likely to be complicated: the placenta contains high levels of parasites, stillbirth or early delivery may occur and diagnosis can be difficult if parasites are concentrated in the placenta and scanty in the blood. 17. Uncomplicated falciparum malaria in the second and third trimester of pregnancy should be treated with artemether-lumefantrine (Grade 2B). Uncomplicated falciparum malaria in the first trimester of pregnancy should usually be treated with quinine and clindamycin but specialist advice should be sought. Severe malaria in any trimester of pregnancy should be treated as for any other patient with artesunate preferred over quinine (Grade 1C). 18. Children with uncomplicated malaria should be treated with an ACT (artemether-lumefantrine or dihydroartemisinin-piperaquine) as first line treatment (Grade 1A). Quinine with doxycycline or clindamycin, or atovaquone-proguanil at appropriate doses for weight can also be used. Doxycycline should not be given to children under 12 years. 19. Either an oral ACT or chloroquine can be used for the treatment of non-falciparum malaria. An oral ACT is preferred for a mixed infection, if there is uncertainty about the infecting species, or for P. vivax infection from areas where chloroquine resistance is common (Grade 1B). 20. Dormant parasites (hypnozoites) persist in the liver after treatment of P. vivax or P. ovale infection: the only currently effective drug for eradication of hypnozoites is primaquine (1A). Primaquine is more effective at preventing relapse if taken at the same time as chloroquine (Grade 1C). 21. Primaquine should be avoided or given with caution under expert supervision in patients with Glucose-6-phosphate dehydrogenase deficiency (G6PD), in whom it may cause severe haemolysis. 22. Primaquine (for eradication of P. vivax or P. ovale hypnozoites) is contraindicated in pregnancy and when breastfeeding (until the G6PD status of child is known); after initial treatment for these infections a pregnant woman should take weekly chloroquine prophylaxis until after delivery or cessation of breastfeeding when hypnozoite eradication can be considered. 23. An acute attack of malaria does not confer protection from future attacks: individuals who have had malaria should take effective anti-mosquito precautions and chemoprophylaxis during future visits to endemic areas. Copyright © 2016 The British Infection Association. Published by Elsevier Ltd. All rights reserved.

Quinine (Cinchona) and the incurable malaria: India c. 1900-1930s.

PubMed

Muraleedharan, V R

2000-06-01

The early decades of this century witnessed significant developments in the approaches to control of malaria in British India. These included both large-scale preventive measures and curative treatment methods (often referred to as "cinchona" or "quinine" policy). This paper identifies a number of factors that constrained the colonial government's capacity to control malaria through effective cinchona policy. The ideal of achieving "self-sufficiency" and having an efficient form of treatment and distribution within the reach of the masses in India (as originally intended in late 1850s) was far from being achieved. Both government's policy and medical profession seemed to have contributed equally to this failure.

The analytical measurement of fluorescein, quinine and trace metal concentrations in solution using single bubble sonoluminescence

NASA Astrophysics Data System (ADS)

Wallace, P.; McCallum, K.; Barnard, C. L. R.; Clement, C.; Marshall, J.; Carroll, J.

2007-03-01

A single bubble was generated and levitated in a high-intensity sound field within a spherical flask excited in its fundamental mode. Under optimum experimental conditions the bubble was observed to emit light in the form of short flashes. This phenomenon is known as single bubble sonoluminescence (SBSL). Using this process, the emitted light from the bubble was monitored when solutions containing fluorescein, quinine and sodium, potassium and copper salts were placed in the cell. The results obtained indicated that reproducible signals related directly to the concentration of the species present in solution could be achieved using single bubble sonoluminescence. The results for the molecular species were compared with those obtained by fluorescence spectroscopy and, in the case of quinine, parallel determinations of concentration in a test solution were performed with consistent results. SBSL signals were also observed to exhibit a linear correlation with the concentration of several trace metal salts introduced to the solution in the measurement cell. However, it was not possible to demonstrate that the SBSL signals were derived from stimulated atomic emission or fluorescence, and it was concluded that the effect may result from an indirect effect involving the bubble excitation mechanism.

In vivo Raman measurement of levofloxacin lactate in blood using a nanoparticle-coated optical fiber probe

PubMed Central

Liu, Shupeng; Rong, Ming; Zhang, Heng; Chen, Na; Pang, Fufei; Chen, Zhenyi; Wang, Tingyun; Yan, Jianshe

2016-01-01

Monitoring drug concentrations in vivo is very useful for adjusting a drug dosage during treatment and for drug research. Specifically, cutting-edge “on-line” drug research relies on knowing how drugs are metabolized or how they interact with the blood in real-time. Thus, this study explored performing in vivo Raman measurements of the model drug levofloxacin lactate in the blood using a nanoparticle-coated optical fiber probe (optical fiber nano-probe). The results show that we were able to measure real-time changes in the blood concentration of levofloxacin lactate, suggesting that this technique could be helpful for performing drug analyses and drug monitoring in a clinical setting without repeatedly withdrawing blood from patients. PMID:27231590

Efficacy and safety evaluation of a novel trioxaquine in the management of cerebral malaria in a mouse model.

PubMed

Odhiambo, Onyango C; Wamakima, Hannah N; Magoma, Gabriel N; Kirira, Peter G; Malala, Bonface J; Kimani, Francis T; Muregi, Francis W

2017-07-03

The emergence of multidrug-resistant strains of Plasmodium falciparum poses a great threat of increased fatalities in cases of cerebral and other forms of severe malaria infections in which parenteral artesunate monotherapy is the current drug of choice. The study aimed to investigate in a mouse model of human cerebral malaria whether a trioxaquine chemically synthesized by covalent linking of a 4,7-dichloroquinoline pharmacophore to artesunate through a recent drug development approach termed 'covalent bitherapy' could improve the curative outcomes in cerebral malaria infections. Human cerebral malaria rodent model, the C57BL/6 male mice were infected intraperitoneally (ip) with Plasmodium berghei ANKA and intravenously (iv) treated with the trioxaquine from day 8 post-infection (pi) at 12.5 and 25 mg/kg, respectively, twice a day for 3 days. Treatments with the trioxaquine precursors (artesunate and 4,7-dichloroquine), and quinine were also included as controls. In vivo safety evaluation for the trioxaquine was done according to Organization for Economic Co-operation and Development (OECD) guidelines 423, where female Swiss albino mice were orally administered with either 300 or 2000 mg/kg of the trioxaquine and monitored for signs of severity, and or mortality for 14 days post-treatment. The trioxaquine showed a potent and a rapid antiplasmodial activity with 80% parasite clearance in the first 24 h for the two dosages used. Long-term parasitaemia monitoring showed a total parasite clearance as the treated mice survived beyond 60 days post-treatment, with no recrudescence observed. Artesunate treated mice showed recrudescence 8 days post-treatment, with all mice in this group succumbing to the infection. Also, 4,7-dichloroquinoline and quinine did not show any significant parasitaemia suppression in the first 24 h post-treatment, with the animals succumbing to the infection. Covalent bitherapy proves to be a viable source of urgently needed new anti-malarials for management of cerebral malaria, and this polypharmacology approach could be a potential strategy to protect artesunate from parasite resistance and in potentially improving clinical outcomes in severe forms of malaria infections.

Significant Divergence in Sensitivity to Antimalarial Drugs between Neighboring Plasmodium falciparum Populations along the Eastern Border of Myanmar

PubMed Central

Zeng, Weilin; Bai, Yao; Wang, Meilian; Wang, Zenglei; Deng, Shuang; Ruan, Yonghua; Feng, Shi; Yang, Zhaoqing

2016-01-01

ABSTRACT Malaria parasites in different areas where malaria is endemic display different levels of resistance to antimalarial drugs as the result of varied drug use histories. To provide updated knowledge of drug sensitivities during the malaria elimination phase in Southeast Asia, an epicenter of multidrug resistance, we determined in vitro susceptibilities of culture-adapted Plasmodium falciparum isolates from two eastern border regions (Wa and Kachin) of Myanmar to 10 drugs. Despite their close proximity, the Kachin parasites displayed higher 50% inhibitory concentrations than the Wa parasites to chloroquine, piperaquine, naphthoquine, mefloquine, quinine, pyrimethamine, pyronaridine, lumefantrine, and dihydroartemisinin. Genotyping of genes associated with drug resistance also showed significant differences in the prevalence rates of mutant alleles between the two regions. Particularly, major pfdhfr mutations mediating pyrimethamine resistance and the pfdhps A437G mutation had significantly higher frequencies in the Kachin parasites (P < 0.005). Moreover, when pfdhfr and pfdhps were considered together, the wild-type allele was found only in the Wa samples (22.6%). In addition, the pfmdr1 Y184F mutation reached 38.7% in the Kachin parasites, compared to 9.7% in the Wa parasites, whereas N86Y was only detected in the Wa parasites, at 22.6%. Furthermore, the F446I mutation and all mutations in the propeller domain of the PfK13 gene were significantly more frequent in the Kachin parasites. Collectively, this work demonstrates that even in spatially closely separated regions, parasites can exhibit drastic differences in drug sensitivities and genetic makeups underlying drug resistance, which may reflect regionally different drug histories and genetic drift of these isolated parasite populations. PMID:27919892

21 CFR 886.4350 - Manual ophthalmic surgical instrument.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Manual ophthalmic surgical instrument. 886.4350 Section 886.4350 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES... suturing needle, lachrymal probe, trabeculotomy probe, cornea-sclera punch, ophthalmic retractor...

Effect of Ketoconazole, a Cytochrome P450 Inhibitor, on the Efficacy of Quinine and Halofantrine against Schistosoma mansoni in Mice

PubMed Central

Sabra, Abdel-Nasser Abdel-Aal; Hammam, Olfat Ali; El-Lakkany, Naglaa Mohamed

2013-01-01

The fear that schistosomes will become resistant to praziquantel (PZQ) motivates the search for alternatives to treat schistosomiasis. The antimalarials quinine (QN) and halofantrine (HF) possess moderate antischistosomal properties. The major metabolic pathway of QN and HF is through cytochrome P450 (CYP) 3A4. Accordingly, this study investigates the effects of CYP3A4 inhibitor, ketoconazole (KTZ), on the antischistosomal potential of these quinolines against Schistosoma mansoni infection by evaluating parasitological, histopathological, and biochemical parameters. Mice were classified into 7 groups: uninfected untreated (I), infected untreated (II), infected treated orally with PZQ (1,000 mg/kg) (III), QN (400 mg/kg) (IV), KTZ (10 mg/kg)+QN as group IV (V), HF (400 mg/kg) (VI), and KTZ (as group V)+HF (as group VI) (VII). KTZ plus QN or HF produced more inhibition (P<0.05) in hepatic CYP450 (85.7% and 83.8%) and CYT b5 (75.5% and 73.5%) activities, respectively, than in groups treated with QN or HF alone. This was accompanied with more reduction in female (89.0% and 79.3%), total worms (81.4% and 70.3%), and eggs burden (hepatic; 83.8%, 66.0% and intestinal; 68%, 64.5%), respectively, and encountering the granulomatous reaction to parasite eggs trapped in the liver. QN and HF significantly (P<0.05) elevated malondialdehyde levels when used alone or with KTZ. Meanwhile, KTZ plus QN or HF restored serum levels of ALT, albumin, and reduced hepatic glutathione (KTZ+HF) to their control values. KTZ enhanced the therapeutic antischistosomal potential of QN and HF over each drug alone. Moreover, the effect of KTZ+QN was more evident than KTZ+HF. PMID:23710083

Effect of genetic polymorphism on the inhibition of dopamine formation from p-tyramine catalyzed by brain cytochrome P450 2D6.

PubMed

Niwa, Toshiro; Shizuku, Marina; Yamano, Kaori

2017-04-15

The inhibitory effects of steroid hormones, including glucocorticoids such as cortisol, and related compounds on dopamine formation from p-tyramine, catalyzed by cytochrome P450 (CYP) 2D6.2 (Arg296Cys, Ser486Thr) and CYP2D6.10 (Pro34Ser, Ser486Thr) were compared with the effects of those catalyzed by CYP2D6.1 (wild type), to investigate the effect of a CYP2D6 polymorphism on neuroactive amine metabolism in the brain. Inhibition constants (K i ) or 50% inhibitory concentrations of six steroid hormones (cortisol, cortisone, corticosterone, dehydroepiandrosterone, progesterone, and pregnenolone) and quinidine and quinine-typical potent inhibitors of the human CYP2D6 and rat CYP2D subfamily, respectively-toward dopamine formation catalyzed by CYP2D6.1, CYP2D6.2, and CYP2D6.10 expressed in recombinant Escherichia coli were compared. Although most steroid hormones had no or minor inhibitory effects on the dopamine formation by all CYP2D6 variants, progesterone inhibited the metabolism and K i value against CYP2D6.10 was approximately twice that for CYP2D6.1 and CYP2D6.2. Quinidine exhibited stronger inhibition than quinine; however, these two compounds inhibited the CYP2D6.10-mediated reaction more weakly than the CYP2D6.1 and CYP2D6.2 reactions. These results suggest that CYP2D6 polymorphism would affect drug interaction through dopamine formation in the brain. Copyright © 2017 Elsevier Inc. All rights reserved.

Further characterization of an aversive learning task in Drosophila melanogaster: intensity of the stimulus, relearning, and use of rutabaga mutants.

PubMed

Perisse, Emmanuel; Portelli, Geoffrey; Le Goas, Solène; Teste, Elsa; Le Bourg, Eric

2007-11-01

Various learning tasks have been described in Drosophila melanogaster, flies being either tested in groups or at the individual level. Le Bourg and Buecher (Anim Learn Behav 33:330-341, 2002) have designed a task at the individual level: photopositive flies crossing a T-maze learn to prefer the dark exit when the lighted one is associated with the presence of aversive stimuli (humidity and quinine). Previous studies have reported various results (e.g. no effect of age) and the present article further characterizes this task by studying the possible effects of: (1) the intensity of the stimuli (quantity of water or concentration of quinine), (2) various delays between two learning sessions on the learning score at the second session, (3) the rutabaga learning mutation on the learning score. More concentrated quinine solutions increased learning scores but the quantity of water had no effect. Learning scores at the second session were higher with shorter delays between the two learning sessions and retrograde amnesia could decrease this memory score. rutabaga mutants showed learning deficits as in experiments testing groups of flies. This learning task could particularly be used to verify whether learning mutants isolated after experiments testing flies in groups display similar deficits when tested at the individual level.

Fluorescence calibration method for single-particle aerosol fluorescence instruments

NASA Astrophysics Data System (ADS)

Shipley Robinson, Ellis; Gao, Ru-Shan; Schwarz, Joshua P.; Fahey, David W.; Perring, Anne E.

2017-05-01

Real-time, single-particle fluorescence instruments used to detect atmospheric bioaerosol particles are increasingly common, yet no standard fluorescence calibration method exists for this technique. This gap limits the utility of these instruments as quantitative tools and complicates comparisons between different measurement campaigns. To address this need, we have developed a method to produce size-selected particles with a known mass of fluorophore, which we use to calibrate the fluorescence detection of a Wideband Integrated Bioaerosol Sensor (WIBS-4A). We use mixed tryptophan-ammonium sulfate particles to calibrate one detector (FL1; excitation = 280 nm, emission = 310-400 nm) and pure quinine particles to calibrate the other (FL2; excitation = 280 nm, emission = 420-650 nm). The relationship between fluorescence and mass for the mixed tryptophan-ammonium sulfate particles is linear, while that for the pure quinine particles is nonlinear, likely indicating that not all of the quinine mass contributes to the observed fluorescence. Nonetheless, both materials produce a repeatable response between observed fluorescence and particle mass. This procedure allows users to set the detector gains to achieve a known absolute response, calculate the limits of detection for a given instrument, improve the repeatability of the instrumental setup, and facilitate intercomparisons between different instruments. We recommend calibration of single-particle fluorescence instruments using these methods.

Functional mechanotransduction is required for cisplatin-induced hair cell death in the zebrafish lateral line.

PubMed

Thomas, Andrew J; Hailey, Dale W; Stawicki, Tamara M; Wu, Patricia; Coffin, Allison B; Rubel, Edwin W; Raible, David W; Simon, Julian A; Ou, Henry C

2013-03-06

Cisplatin, one of the most commonly used anticancer drugs, is known to cause inner ear hair cell damage and hearing loss. Despite much investigation into mechanisms of cisplatin-induced hair cell death, little is known about the mechanism whereby cisplatin is selectively toxic to hair cells. Using hair cells of the zebrafish lateral line, we found that chemical inhibition of mechanotransduction with quinine and EGTA protected against cisplatin-induced hair cell death. Furthermore, we found that the zebrafish mutants mariner (myo7aa) and sputnik (cad23) that lack functional mechanotransduction were resistant to cisplatin-induced hair cell death. Using a fluorescent analog of cisplatin, we found that chemical or genetic inhibition of mechanotransduction prevented its uptake. These findings demonstrate that cisplatin-induced hair cell death is dependent on functional mechanotransduction in the zebrafish lateral line.

21 CFR 892.1320 - Nuclear uptake probe.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Nuclear uptake probe. 892.1320 Section 892.1320 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED..., signal analysis and display equipment, patient and equipment supports, component parts, and accessories...

21 CFR 892.1320 - Nuclear uptake probe.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Nuclear uptake probe. 892.1320 Section 892.1320 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED..., signal analysis and display equipment, patient and equipment supports, component parts, and accessories...

21 CFR 892.1320 - Nuclear uptake probe.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Nuclear uptake probe. 892.1320 Section 892.1320 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED..., signal analysis and display equipment, patient and equipment supports, component parts, and accessories...

21 CFR 870.2120 - Extravascular blood flow probe.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Extravascular blood flow probe. 870.2120 Section 870.2120 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CARDIOVASCULAR DEVICES Cardiovascular Monitoring Devices § 870.2120 Extravascular...

Photoaffinity labeling in target- and binding-site identification

PubMed Central

Smith, Ewan; Collins, Ian

2015-01-01

Photoaffinity labeling (PAL) using a chemical probe to covalently bind its target in response to activation by light has become a frequently used tool in drug discovery for identifying new drug targets and molecular interactions, and for probing the location and structure of binding sites. Methods to identify the specific target proteins of hit molecules from phenotypic screens are highly valuable in early drug discovery. In this review, we summarize the principles of PAL including probe design and experimental techniques for in vitro and live cell investigations. We emphasize the need to optimize and validate probes and highlight examples of the successful application of PAL across multiple disease areas. PMID:25686004

48 CFR 25.104 - Nonavailable articles.

Code of Federal Regulations, 2013 CFR

2013-10-01

.... Bananas. Bauxite. Beef, corned, canned. Beef extract. Bephenium hydroxynapthoate. Bismuth. Books, trade..., or cast bars. Pyrethrum flowers. Quartz crystals. Quebracho. Quinidine. Quinine. Rabbit fur felt...

48 CFR 25.104 - Nonavailable articles.

Code of Federal Regulations, 2011 CFR

2011-10-01

.... Bananas. Bauxite. Beef, corned, canned. Beef extract. Bephenium hydroxynapthoate. Bismuth. Books, trade..., or cast bars. Pyrethrum flowers. Quartz crystals. Quebracho. Quinidine. Quinine. Rabbit fur felt...

48 CFR 25.104 - Nonavailable articles.

Code of Federal Regulations, 2014 CFR

2014-10-01

.... Bananas. Bauxite. Beef, corned, canned. Beef extract. Bephenium hydroxynapthoate. Bismuth. Books, trade..., or cast bars. Pyrethrum flowers. Quartz crystals. Quebracho. Quinidine. Quinine. Rabbit fur felt...

48 CFR 25.104 - Nonavailable articles.

Code of Federal Regulations, 2012 CFR

2012-10-01

.... Bananas. Bauxite. Beef, corned, canned. Beef extract. Bephenium hydroxynapthoate. Bismuth. Books, trade..., or cast bars. Pyrethrum flowers. Quartz crystals. Quebracho. Quinidine. Quinine. Rabbit fur felt...

48 CFR 25.104 - Nonavailable articles.

Code of Federal Regulations, 2010 CFR

2010-10-01

.... Bananas. Bauxite. Beef, corned, canned. Beef extract. Bephenium hydroxynapthoate. Bismuth. Books, trade..., or cast bars. Pyrethrum flowers. Quartz crystals. Quebracho. Quinidine. Quinine. Rabbit fur felt...

Determination of Dacarbazine Φ-Order Photokinetics, Quantum Yields, and Potential for Actinometry.

PubMed

Maafi, Mounir; Lee, Lok-Yan

2015-10-01

The characterization of drugs' photodegradation kinetics is more accurately achieved by means of the recently developed Φ-order kinetics than by the zero-, first-, and/or second-order classical treatments. The photodegradation of anti-cancer dacarbazine (DBZ) in ethanol has been investigated and found to obey Φ-order kinetics when subjected to continuous and monochromatic irradiation of various wavelengths. Its photochemical efficiency was proven to be wavelength dependent in the 220-350 nm range, undergoing a 50-fold increase. Albeit this variation was well defined by a sigmoid pattern, the overall photoreactivity of DBZ was proven to depend also on the contributions of reactants and experimental attributes. The usefulness of DBZ to serve as a drug-actinometer has been investigated using the mathematical framework of Φ-order kinetics. It has been shown that DBZ in ethanol can represent a good candidate for reliable actinometry in the range 270-350 nm. A detailed and easy-to-implement procedure has been proposed for DBZ actinometry. This procedure could advantageously be implemented prior to the determination of the photodegradation quantum yields. This approach might be found useful for the development of many drug actinometers as alternatives to quinine hydrochloride. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.

Investigating unlicensed retail drug vendors' preparedness and knowledge about malaria: An exploratory study in rural Uganda.

PubMed

Liow, Eric; Kassam, Rosemin; Sekiwunga, Richard

2017-10-01

Despite major efforts to increase the uptake of preventive measures and timely use of the first line antimalarial treatment artemisinin-based combination therapies (ACT), Uganda continues to fall short of meeting its national malaria control targets. One of the challenges has been scaling up effective measures in rural and remote areas where the unlicensed private retail sector remains the first point of contact and a common source of treatment. The current paper discusses unlicensed vendors' (1) training related to malaria case management for children aged five and under, and (2) knowledge related to the cause of malaria, preventive measures, common signs, and symptoms, diagnostic procedures, and best treatment options. A qualitative study using semi-structured interviews was conducted in the rural district of Butaleja, Uganda in 2011. All 88 unlicensed drug outlets enumerated in the study area were visited by six locally recruited research assistants, with one vendor from each outlet invited to participate. The transcripts were analyzed using acceptable qualitative research protocols. About half of the 75 vendors interviewed had received some sort of formal training on malaria at a post-secondary institution, although only 6.7% had qualifications which met licensure requirements. The study found widespread misconceptions relating to the cause, as well as prevention and treatment of malaria. A large majority of the vendors relied primarily on non-specific symptoms and limited physical exams for diagnoses, with less than one-tenth of the vendors recognizing that rapid or microscopic blood testing was necessary to confirm a clinical diagnosis of malaria. While most recognized mosquitoes as the primary vector for malaria, over two-fifths of the vendors held misconceptions about the factors that could increase the risk of malaria, and nearly a third believed that malaria could not be prevented. With respect to acute case management, three-quarters viewed as the best option a medicine other than the government's first-line antimalarial, artemisinin-based combination therapies (ACT). Almost three-fifths specified quinine as their preferred option, with about one-fifth recommending quinine injection. Findings from this study confirm significant gaps in unlicensed vendors' knowledge related to malaria. With increased utilization of unlicensed drug outlets in rural and remote settings such as Butaleja, findings from this study strongly supports the need to implement strategies to improve the quality of care delivered at these outlet. Copyright © 2017 Elsevier B.V. All rights reserved.

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

Hirode, Mitsuhiro; Ono, Atsushi; Miyagishima, Toshikazu

We have constructed a large-scale transcriptome database of rat liver treated with various drugs. In an effort to identify a biomarker for diagnosis of hepatic phospholipidosis, we extracted 78 probe sets of rat hepatic genes from data of 5 drugs, amiodarone, amitriptyline, clomipramine, imipramine, and ketoconazole, which actually induced this phenotype. Principal component analysis (PCA) using these probes clearly separated dose- and time-dependent clusters of treated groups from their controls. Moreover, 6 drugs (chloramphenicol, chlorpromazine, gentamicin, perhexiline, promethazine, and tamoxifen), which were reported to cause phospholipidosis but judged as negative by histopathological examination, were designated as positive by PCA usingmore » these probe sets. Eight drugs (carbon tetrachloride, coumarin, tetracycline, metformin, hydroxyzine, diltiazem, 2-bromoethylamine, and ethionamide), which showed phospholipidosis-like vacuolar formation in the histopathology, could be distinguished from the typical drugs causing phospholipidosis. Moreover, the possible induction of phospholipidosis was predictable by the expression of these genes 24 h after single administration in some of the drugs. We conclude that these identified 78 probe sets could be useful for diagnosis of phospholipidosis, and that toxicogenomics would be a promising approach for prediction of this type of toxicity.« less

[Progress on studies of impact on CYP450 enzymes activity of traditional Chinese medicine by Cocktail probe substrates approach].

PubMed

Du, Xi; He, Xin; Huang, Yu-Hong; Li, Zi-Qiang

2016-12-01

Cocktail probe substrates approach is a fast, sensitive and high through put method to determine cytochrome P450 enzymes activity. It has been widely used to screen early drug development, analyze drug metabolism types and confirm the metabolism pathways, study drug-drug interactions, optimize clinical regimen, evaluate post marketing drugs and help liver/kidney pathological studies. This article reviewed characteristics of Cocktail probe substrates, focused on the application to traditional Chinese medicine to CYP450 system as follows: the metabolic pathway research of Chinese herb active ingredients; processing way and compatibility of medical herbs affect CYP450; find out the metabolic characteristic of Chinese patent medicine, study in pharmacy of national minority; do research in liver protective effect of traditional Chinese medicine and evaluate traditional Chinese medicine syndromes in animal models. This article make a summary of existing research results and also make a comparison of cocktail probe substrates approach application to western medicine and Chinese medicine. Copyright© by the Chinese Pharmaceutical Association.

Turn-off fluorescence sensor for the detection of ferric ion in water using green synthesized N-doped carbon dots and its bio-imaging.

PubMed

Edison, Thomas Nesakumar Jebakumar Immanuel; Atchudan, Raji; Shim, Jae-Jin; Kalimuthu, Senthilkumar; Ahn, Byeong-Cheol; Lee, Yong Rok

2016-05-01

This paper reports turn-off fluorescence sensor for Fe(3+) ion in water using fluorescent N-doped carbon dots as a probe. A simple and efficient hydrothermal carbonization of Prunus avium fruit extract for the synthesis of fluorescent nitrogen-doped carbon dots (N-CDs) is described. This green approach proceeds quickly and provides good quality N-CDs. The mean size of synthesized N-CDs was approximately 7nm calculated from the high-resolution transmission electron microscopic images. X-ray photoelectron spectroscopy and Fourier transform infrared spectroscopy revealed the presence of -OH, -NH2, -COOH, and -CO functional groups over the surface of CDs. The N-CDs showed excellent fluorescent properties, and emitted blue fluorescence at 411nm upon excitation at 310nm. The calculated quantum yield of the synthesized N-CDs is 13% against quinine sulfate as a reference fluorophore. The synthesized N-CDs were used as a fluorescent probe towards the selective and sensitive detection of biologically important Fe(3+) ions in water by fluorescence spectroscopy and for bio-imaging of MDA-MB-231 cells. The limit of detection (LOD) and the Stern-Volmer quenching constant for the synthesized N-CDs were 0.96μM and 2.0958×10(3)M of Fe(3+) ions. The green synthesized N-CDs are efficiently used as a promising candidate for the detection of Fe(3+) ions and bio-imaging. Copyright © 2016 Elsevier B.V. All rights reserved.

Investigation of Drug-Induced Hepatotoxicity and Its Remediation Pathway with Reaction-Based Fluorescent Probes.

PubMed

Cheng, Dan; Xu, Wang; Yuan, Lin; Zhang, Xiaobing

2017-07-18

Drug-induced liver injury (DILI) is considered a serious problem related to public health, due to its unpredictability and acute response. The level of peroxynitrite (ONOO - ) generated in liver has long been regarded as a biomarker for the prediction and measurement of DILI. Herein we present two reaction-based fluorescent probes (Naph-ONOO - and Rhod-ONOO - ) for ONOO - through a novel and universally applicable mechanism: ONOO - -mediated deprotection of α-keto caged fluorophores. Among them, Rhod-ONOO - can selectively accumulate and react in mitochondria, one of the main sources of ONOO - , with a substantial lower nanomolar sensitivity of 43 nM. The superior selectivity and sensitivity of two probes enable real-time imaging of peroxynitrite generation in lipopolysaccharide-stimulated live cells, with a remarkable difference from cells doped with other interfering reactive oxygen species, in either one- or two-photon imaging modes. More importantly, we elucidated the drug-induced hepatotoxicity pathway with Rhod-ONOO - and revealed that CYP450/CYP2E1-mediated enzymatic metabolism of acetaminophen leads to ONOO - generation in liver cells. This is the first time to showcase the drug-induced hepatotoxicity pathways by use of a small-molecule fluorescent probe. We hence conclude that fluorescent probes can engender a deeper understanding of reactive species and their pathological revelations. The reaction-based fluorescent probes will be a potentially useful chemical tool to assay drug-induced hepatotoxicity.

Endophytic Colletrotrichum spp. from Cinchona calisaya wedd. and it's potential quinine production as antibacterial and antimalaria

NASA Astrophysics Data System (ADS)

Radiastuti, Nani; Mutea, Dalli; Sumarlin, La Ode

2017-02-01

An endophytic fungus is microorganisms that live inside plant tissues without harming its host and is capable of producing the same secondary metabolites as its host plant. The endophytic fungus is very diverse and important group of microorganisms. The objectives of the study are to identify endophyte Colletotrichum spp. using ITS rDNA analyze, alkaloid cinchona and antibacterial characteristics. Phylogenetic analysis of ITS rDNA regions and morphology are used to identify the species. The Chloroform extracts of filtrate were analyzed using the High Pressure Liquid Chromatography (HPLC) to determine the production of quinine. There were 13 isolates of Colletotrichum spp as endophytes with associated with Cinchona calisaya Wedd. from fruit (6 isolates), leaf (5 isolates), twig (1 isolate) and root (1 isolate). This is the first report as endophytes are associated with C. calisaya. Based on ITS phylogenetic analysis are introduced of 7 strains Colletotrichum sp, 1 strain closely with C. aegnigma, 2 strains closely C. cordylinicola, 1 strains C arxii, 2 strains nested C. karstii. The Colletotrichum sp. M1 (leaf), M3 (bark), M8 (fruit) and C. karstii M5 (fruit) are potential alkaloid quinine. Five strains of Colletotrichum spp. have antibacterial activity are selected against Staphylococcus aureus and nine Colletotrichum spp. against Escherichia coli. The endophyte identification of Colletotrichum species needs another gene other than ITS rDNA.

Postnatal development of bitter taste avoidance behavior in mice is associated with ACTIN-dependent localization of bitter taste receptors to the microvilli of taste cells.

PubMed

Yamashita, Atsuko; Kondo, Kaori; Kunishima, Yoshimi; Iseki, Sachiko; Kondo, Takashi; Ota, Masato S

2018-01-22

Bitter taste avoidance behavior (BAB) plays a fundamental role in the avoidance of toxic substances with a bitter taste. However, the molecular basis underlying the development of BAB is unknown. To study critical developmental events by which taste buds turn into functional organs with BAB, we investigated the early phase development of BAB in postnatal mice in response to bitter-tasting compounds, such as quinine and thiamine. Postnatal mice started to exhibit BAB for thiamine and quinine at postnatal day 5 (PD5) and PD7, respectively. Histological analyses of taste buds revealed the formation of microvilli in the taste pores starting at PD5 and the localization of type 2 taste receptor 119 (TAS2R119) at the microvilli at PD6. Treatment of the tongue epithelium with cytochalasin D (CytD), which disturbs ACTIN polymerization in the microvilli, resulted in the loss of TAS2R119 localization at the microvilli and the loss of BAB for quinine and thiamine. The release of ATP from the circumvallate papillae tissue due to taste stimuli was also declined following CytD treatment. These results suggest that the localization of TAS2R119 at the microvilli of taste pores is critical for the initiation of BAB. Copyright © 2017 Elsevier Inc. All rights reserved.

GWAS of human bitter taste perception identifies new loci and reveals additional complexity of bitter taste genetics.

PubMed

Ledda, Mirko; Kutalik, Zoltán; Souza Destito, Maria C; Souza, Milena M; Cirillo, Cintia A; Zamboni, Amabilene; Martin, Nathalie; Morya, Edgard; Sameshima, Koichi; Beckmann, Jacques S; le Coutre, Johannes; Bergmann, Sven; Genick, Ulrich K

2014-01-01

Human perception of bitterness displays pronounced interindividual variation. This phenotypic variation is mirrored by equally pronounced genetic variation in the family of bitter taste receptor genes. To better understand the effects of common genetic variations on human bitter taste perception, we conducted a genome-wide association study on a discovery panel of 504 subjects and a validation panel of 104 subjects from the general population of São Paulo in Brazil. Correction for general taste-sensitivity allowed us to identify a SNP in the cluster of bitter taste receptors on chr12 (10.88- 11.24 Mb, build 36.1) significantly associated (best SNP: rs2708377, P = 5.31 × 10(-13), r(2) = 8.9%, β = -0.12, s.e. = 0.016) with the perceived bitterness of caffeine. This association overlaps with-but is statistically distinct from-the previously identified SNP rs10772420 influencing the perception of quinine bitterness that falls in the same bitter taste cluster. We replicated this association to quinine perception (P = 4.97 × 10(-37), r(2) = 23.2%, β = 0.25, s.e. = 0.020) and additionally found the effect of this genetic locus to be concentration specific with a strong impact on the perception of low, but no impact on the perception of high concentrations of quinine. Our study, thus, furthers our understanding of the complex genetic architecture of bitter taste perception.

Caffeine Bitterness is Related to Daily Caffeine Intake and Bitter Receptor mRNA Abundance in Human Taste Tissue

PubMed Central

Lipchock, Sarah V.; Spielman, Andrew I.; Mennella, Julie A.; Mansfield, Corrine J.; Hwang, Liang-Dar; Douglas, Jennifer E.; Reed, Danielle R.

2018-01-01

We investigated whether the abundance of bitter receptor mRNA expression from human taste papillae is related to an individual’s perceptual ratings of bitter intensity and habitual intake of bitter drinks. Ratings of the bitterness of caffeine and quinine and three other bitter stimuli (urea, propylthiouracil, and denatonium benzoate) were compared with relative taste papilla mRNA abundance of bitter receptors that respond to the corresponding bitter stimuli in cell-based assays (TAS2R4, TAS2R10, TAS2R38, TAS2R43, and TAS2R46). We calculated caffeine and quinine intake from a food frequency questionnaire. The bitterness of caffeine was related to the abundance of the combined mRNA expression of these known receptors, r = 0.47, p = .05, and self-reported daily caffeine intake, t(18) = 2.78, p = .012. The results of linear modeling indicated that 47% of the variance among subjects in the rating of caffeine bitterness was accounted for by these two factors (habitual caffeine intake and taste receptor mRNA abundance). We observed no such relationships for quinine but consumption of its primary dietary form (tonic water) was uncommon. Overall, diet and TAS2R gene expression in taste papillae are related to individual differences in caffeine perception. PMID:28118781

Malaria and pregnancy: the perspective in Pakistan.

PubMed

Bhatti, Maqsood A; Azharuddin, Muhammad; Bhatti, Samreen; Islam, Muhammad; Khan, Muhammad Aslam

2007-01-01

To study the effects of malaria on pregnancy outcome. A case control study conducted on patients identified by ICD-9 coding system of the hospital medical records. Demographic and clinical data recorded on standardized data sheet and analyzed using SPSS 11.5 software. Of the total patients, 67.4% were multigravid and 32.6% were primigravid with 78.6% of patients having platelets < 150,000. Mean haemoglobin was 9.4 gm/dl in patients and 12.2 gm/dl in controls. Plasmodium Vivax was accounted for 55.8%, P. Falciparum for 41.9%, and P. Ovale 2.3% of infections. In all, 48.8% of patients received oral Chloroquine, 16.3% oral Quinine, 30.3% intravenous Quinine, 20.9% of patients received combination treatment with IV Clindamycin, and one each patient received oral Artemether or oral halofantrine. Two patients had an abortion. One of the following complications including, threatened abortion, preterm labour, ARDS or Cerebral malaria, was observed in one patient each. Mean weight of babies born to cases was 2.8 kg (range 1.4-3.8) and of control babies was 3.2 kg (range 2.5-4.0 kg). No congenital malformations were reported. Plasmodium falciparum sp, moderate parasitic load, haemoglobin < 10 gm/dL, platelet count < 50,000/mm3 and IV quinine with loading dose of 20 mg/kg are identified as few of the potential risk factors for poor outcome in pregnancy.

Quinine

MedlinePlus

... not been shown to be effective for this purpose, and may cause serious or life-threatening side ... to your pharmacist or contact your local garbage/recycling department to learn about take-back programs in ...

In vitro inhibition of Plasmodium falciparum by substances isolated from Amazonian antimalarial plants.

PubMed

de Andrade-Neto, Valter F; Pohlit, Adrian M; Pinto, Ana Cristina S; Silva, Ellen Cristina C; Nogueira, Karla L; Melo, Márcia R S; Henrique, Marycleuma C; Amorim, Rodrigo C N; Silva, Luis Francisco R; Costa, Mônica R F; Nunomura, Rita C S; Nunomura, Sergio M; Alecrim, Wilson D; Alecrim, M das Graças C; Chaves, F Célio M; Vieira, Pedro Paulo R

2007-06-01

In the present study, a quassinoid, neosergeolide, isolated from the roots and stems of Picrolemma sprucei (Simaroubaceae), the indole alkaloids ellipticine and aspidocarpine, isolated from the bark of Aspidosperma vargasii and A. desmanthum (Apocynaceae), respectively, and 4-nerolidylcatechol, isolated from the roots of Pothomorphe peltata (Piperaceae), all presented significant in vitro inhibition (more active than quinine and chloroquine) of the multi-drug resistant K1 strain of Plasmodium falciparum. Neosergeolide presented activity in the nanomolar range. This is the first report on the antimalarial activity of these known, natural compounds. This is also the first report on the isolation of aspidocarpine from A. desmanthum. These compounds are good candidates for pre-clinical tests as novel lead structures with the aim of finding new antimalarial prototypes and lend support to the traditional use of the plants from which these compounds are derived.

Functional mechanotransduction is required for cisplatin-induced hair cell death in the zebrafish lateral line

PubMed Central

Thomas, Andrew J.; Hailey, Dale W.; Stawicki, Tamara M.; Wu, Patricia; Coffin, Allison B.; Rubel, Edwin W.; Raible, David W.; Simon, Julian A.; Ou, Henry C.

2013-01-01

Cisplatin, one of the most commonly used anti-cancer drugs, is known to cause inner ear hair cell damage and hearing loss. Despite much investigation into mechanisms of cisplatin-induced hair cell death, little is known about the mechanism whereby cisplatin is selectively toxic to hair cells. Using hair cells of the zebrafish lateral line, we found that chemical inhibition of mechanotransduction with quinine and EGTA protected against cisplatin-induced hair cell death. Furthermore, we found that the zebrafish mutants mariner (myo7aa) and sputnik (cad23) that lack functional mechanotransduction were resistant to cisplatin-induced hair cell death. Using a fluorescent analogue of cisplatin, we found that chemical or genetic inhibition of mechanotransduction prevented its uptake. These findings demonstrate that cisplatin-induced hair cell death is dependent on functional mechanotransduction in the zebrafish lateral line. PMID:23467357

The Multifactorial Epidemiology of Blackwater Fever.

PubMed

Shanks, G Dennis

2017-12-01

Blackwater fever is a massive hemolytic event usually occurring in the context of repeated falciparum malaria infections and intermittent quinine use. Its etiology is poorly understood, and it is rarely seen today. Historical epidemiological observations from the 20th century demonstrated variable patterns in prisoners in Andaman Islands, refugees in Macedonia, canal workers in Panama, expatriates in Rhodesia, and Second World War soldiers. Rates of blackwater fever per 1,000 malaria cases varied over two orders of magnitude. Islands, such as the Andaman Islands and New Guinea, had lower blackwater fever rates than continental areas. During the Second World War, blackwater fever rates in British soldiers in West Africa and Australian soldiers in New Guinea differed by a factor of 40 despite similar treatment regimens and falciparum malaria transmission risks. Blackwater fever is a complex interaction between host erythrocyte, falciparum malaria, and antimalarial drugs which remains poorly understood.

Dapsone Topical

MedlinePlus

... as phenytoin (Dilantin, Phenytek); antimalarial medications such as chloroquine (Aralen), primaquine, and quinine (Qualaquin); dapsone (by mouth); ... and the laboratory.Do not let anyone else use your medication. Ask your pharmacist any questions you ...

Application of intracerebral microdialysis to study regional distribution kinetics of drugs in rat brain.

PubMed Central

de Lange, E. C.; Bouw, M. R.; Mandema, J. W.; Danhof, M.; de Boer, A. G.; Breimer, D. D.

1995-01-01

1. The purpose of the present study was to determine whether intracerebral microdialysis can be used for the assessment of local differences in drug concentrations within the brain. 2. Two transversal microdialysis probes were implanted in parallel into the frontal cortex of male Wistar rats, and used as a local infusion and detection device respectively. Within one rat, three different concentrations of atenolol or acetaminophen were infused in randomized order. By means of the detection probe, concentration-time profiles of the drug in the brain were measured at interprobe distances between 1 and 2 mm. 3. Drug concentrations were found to be dependent on the drug as well as on the interprobe distance. It was found that the outflow concentration from the detection probe decreased with increasing lateral spacing between the probes and this decay was much steeper for acetaminophen than for atenolol. A model was developed which allows estimation of kbp/Deff (transfer coefficient from brain to blood/effective diffusion coefficient in brain extracellular fluid), which was considerably larger for the more lipohilic drug, acetaminophen. In addition, in vivo recovery values for both drugs were determined. 4. The results show that intracerebral microdialysis is able to detect local differences in drug concentrations following infusion into the brain. Furthermore, the potential use of intracerebral microdialysis to obtain pharmacokinetic parameters of drug distribution in brain by means of monitoring local concentrations of drugs in time is demonstrated. PMID:8581296

Artemisinin-resistant Plasmodium falciparum malaria

PubMed Central

Fairhurst, Rick M.; Dondorp, Arjen M.

2016-01-01

For more than five decades, Southeast Asia (SEA) has been fertile ground for the emergence of drug-resistant Plasmodium falciparum malaria. After generating parasites resistant to chloroquine, sulfadoxine, pyrimethamine, quinine, and mefloquine, this region has now spawned parasites resistant to artemisinins – the world's most potent antimalarial drugs. In areas where artemisinin resistance is prevalent, artemisinin combination therapies (ACTs) – the first-line treatments for malaria – are failing fast. This worrisome development threatens to make malaria practically untreatable in SEA, and threatens to compromise global endeavors to eliminate this disease. A recent series of clinical, in-vitro, genomics, and transcriptomics studies in SEA have defined in-vivo and in-vitro phenotypes of artemisinin resistance; identified its causal genetic determinant; explored its molecular mechanism; and assessed its clinical impact. Specifically, these studies have established that artemisinin resistance manifests as slow parasite clearance in patients and increased survival of early ring-stage parasites in vitro; is caused by single nucleotide polymorphisms in the parasite's ‘K13’ gene; is associated with an upregulated “unfolded protein response” pathway that may antagonize the pro-oxidant activity of artemisinins; and selects for partner drug resistance that rapidly leads to ACT failures. In SEA, clinical studies are urgently needed to monitor ACT efficacy where K13 mutations are prevalent; test whether new combinations of currently-available drugs cure ACT failures; and advance new antimalarial compounds through preclinical pipelines and into clinical trials. Intensifying these efforts should help to forestall the spread of artemisinin and partner drug resistance from SEA to Sub-Saharan Africa, where the world's malaria transmission, morbidity, and mortality rates are highest. PMID:27337450

Artemisinin-Resistant Plasmodium falciparum Malaria.

PubMed

Fairhurst, Rick M; Dondorp, Arjen M

2016-06-01

For more than five decades, Southeast Asia (SEA) has been fertile ground for the emergence of drug-resistant Plasmodium falciparum malaria. After generating parasites resistant to chloroquine, sulfadoxine, pyrimethamine, quinine, and mefloquine, this region has now spawned parasites resistant to artemisinins, the world's most potent antimalarial drugs. In areas where artemisinin resistance is prevalent, artemisinin combination therapies (ACTs)-the first-line treatments for malaria-are failing fast. This worrisome development threatens to make malaria practically untreatable in SEA, and threatens to compromise global endeavors to eliminate this disease. A recent series of clinical, in vitro, genomics, and transcriptomics studies in SEA have defined in vivo and in vitro phenotypes of artemisinin resistance, identified its causal genetic determinant, explored its molecular mechanism, and assessed its clinical impact. Specifically, these studies have established that artemisinin resistance manifests as slow parasite clearance in patients and increased survival of early-ring-stage parasites in vitro; is caused by single nucleotide polymorphisms in the parasite's K13 gene, is associated with an upregulated "unfolded protein response" pathway that may antagonize the pro-oxidant activity of artemisinins, and selects for partner drug resistance that rapidly leads to ACT failures. In SEA, clinical studies are urgently needed to monitor ACT efficacy where K13 mutations are prevalent, test whether new combinations of currently available drugs cure ACT failures, and advance new antimalarial compounds through preclinical pipelines and into clinical trials. Intensifying these efforts should help to forestall the spread of artemisinin and partner drug resistance from SEA to sub-Saharan Africa, where the world's malaria transmission, morbidity, and mortality rates are highest.

In vitro and in vivo efficacy of drugs against the protozoan parasite Azumiobodo hoyamushi that causes soft tunic syndrome in the edible ascidian Halocynthia roretzi (Drasche).

PubMed

Park, K H; Zeon, S-R; Lee, J-G; Choi, S-H; Shin, Y K; Park, K-I

2014-04-01

It was discovered recently that infection by a protozoan parasite, Azumiobodo hoyamushi, is the most probable cause for soft tunic syndrome in an edible ascidian, Halocynthia roretzi (Drasche). In an attempt to develop measures to eradicate the causative parasite, various drugs were tested for efficacy in vitro and in vivo. Of the 20 antiprotozoal drugs having different action mechanisms, five were found potent (24-h EC50  < 10 mg L(-1) ) in their parasite-killing effects: formalin, H2 O2 , bithionol, ClO2 and bronopol. Moderately potent drugs (10 < 24-h EC50  < 100 mg L(-1) ) were quinine, fumagillin, amphotericin B, ketoconazole, povidone-iodine, chloramine-T and benzalkonium chloride. Seven compounds, metronidazole, albendazole, paromomycin, nalidixic acid, sulfamonomethoxine, KMnO4 , potassium monopersulphate and citric acid, exhibited EC50  > 100 mg L(-1) . When ascidians were artificially infected with A. hoyamushi, treated using 40 mg L(-1) formalin, bronopol, ClO2 , or H2 O2 for 1 h and then monitored for 24 h, very low mortality was observed. However, the number of surviving parasite cells in the ascidian tunic tissues was significantly reduced by treating with 40 mg L(-1) formalin or ClO2 for 1 h. The data suggest that we might be able to develop a disinfection measure using a treatment regimen involving commonly available drugs. © 2013 John Wiley & Sons Ltd.

Drugs in Development for Malaria.

PubMed

Ashley, Elizabeth A; Phyo, Aung Pyae

2018-05-25

The last two decades have seen a surge in antimalarial drug development with product development partnerships taking a leading role. Resistance of Plasmodium falciparum to the artemisinin derivatives, piperaquine and mefloquine in Southeast Asia means new antimalarials are needed with some urgency. There are at least 13 agents in clinical development. Most of these are blood schizonticides for the treatment of uncomplicated falciparum malaria, under evaluation either singly or as part of two-drug combinations. Leading candidates progressing through the pipeline are artefenomel-ferroquine and lumefantrine-KAF156, both in Phase 2b. Treatment of severe malaria continues to rely on two parenteral drugs with ancient forebears: artesunate and quinine, with sevuparin being evaluated as an adjuvant therapy. Tafenoquine is under review by stringent regulatory authorities for approval as a single-dose treatment for Plasmodium vivax relapse prevention. This represents an advance over standard 14-day primaquine regimens; however, the risk of acute haemolytic anaemia in patients with glucose-6-phosphate dehydrogenase deficiency remains. For disease prevention, several of the newer agents show potential but are unlikely to be recommended for use in the main target groups of pregnant women and young children for some years. Latest predictions are that the malaria burden will continue to be high in the coming decades. This fact, coupled with the repeated loss of antimalarials to resistance, indicates that new antimalarials will be needed for years to come. Failure of the artemisinin-based combinations in Southeast Asia has stimulated a reappraisal of current approaches to combination therapy for malaria with incorporation of three or more drugs in a single treatment under consideration.

Fetal alcohol exposure reduces responsiveness of taste nerves and trigeminal chemosensory neurons to ethanol and its flavor components.

PubMed

Glendinning, John I; Tang, Joyce; Morales Allende, Ana Paula; Bryant, Bruce P; Youngentob, Lisa; Youngentob, Steven L

2017-08-01

Fetal alcohol exposure (FAE) leads to increased intake of ethanol in adolescent rats and humans. We asked whether these behavioral changes may be mediated in part by changes in responsiveness of the peripheral taste and oral trigeminal systems. We exposed the experimental rats to ethanol in utero by administering ethanol to dams through a liquid diet; we exposed the control rats to an isocaloric and isonutritive liquid diet. To assess taste responsiveness, we recorded responses of the chorda tympani (CT) and glossopharyngeal (GL) nerves to lingual stimulation with ethanol, quinine, sucrose, and NaCl. To assess trigeminal responsiveness, we measured changes in calcium levels of isolated trigeminal ganglion (TG) neurons during stimulation with ethanol, capsaicin, mustard oil, and KCl. Compared with adolescent control rats, the adolescent experimental rats exhibited diminished CT nerve responses to ethanol, quinine, and sucrose and GL nerve responses to quinine and sucrose. The reductions in taste responsiveness persisted into adulthood for quinine but not for any of the other stimuli. Adolescent experimental rats also exhibited reduced TG neuron responses to ethanol, capsaicin, and mustard oil. The lack of change in responsiveness of the taste nerves to NaCl and the TG neurons to KCl indicates that FAE altered only a subset of the response pathways within each chemosensory system. We propose that FAE reprograms development of the peripheral taste and trigeminal systems in ways that reduce their responsiveness to ethanol and surrogates for its pleasant (i.e., sweet) and unpleasant (i.e., bitterness, oral burning) flavor attributes. NEW & NOTEWORTHY Pregnant mothers are advised to avoid alcohol. This is because even small amounts of alcohol can alter fetal brain development and increase the risk of adolescent alcohol abuse. We asked how fetal alcohol exposure (FAE) produces the latter effect in adolescent rats by measuring responsiveness of taste nerves and trigeminal chemosensory neurons. We found that FAE substantially reduced taste and trigeminal responsiveness to ethanol and its flavor components. Copyright © 2017 the American Physiological Society.

21 CFR 870.2120 - Extravascular blood flow probe.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Extravascular blood flow probe. 870.2120 Section... blood flow probe. (a) Identification. An extravascular blood flow probe is an extravascular ultrasonic or electromagnetic probe used in conjunction with a blood flowmeter to measure blood flow in a...

21 CFR 870.2120 - Extravascular blood flow probe.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Extravascular blood flow probe. 870.2120 Section... blood flow probe. (a) Identification. An extravascular blood flow probe is an extravascular ultrasonic or electromagnetic probe used in conjunction with a blood flowmeter to measure blood flow in a...

21 CFR 870.2120 - Extravascular blood flow probe.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Extravascular blood flow probe. 870.2120 Section... blood flow probe. (a) Identification. An extravascular blood flow probe is an extravascular ultrasonic or electromagnetic probe used in conjunction with a blood flowmeter to measure blood flow in a...

21 CFR 870.2120 - Extravascular blood flow probe.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Extravascular blood flow probe. 870.2120 Section... blood flow probe. (a) Identification. An extravascular blood flow probe is an extravascular ultrasonic or electromagnetic probe used in conjunction with a blood flowmeter to measure blood flow in a...

The Impact of Chemical Probes in Drug Discovery: A Pharmaceutical Industry Perspective.

PubMed

Garbaccio, Robert M; Parmee, Emma R

2016-01-21

Chemical probes represent an important component of both academic and pharmaceutical drug discovery research. As a complement to prior reviews that have defined this scientific field, we aim to provide an industry perspective on the value of having high-quality chemical probes throughout the course of preclinical research. By studying examples from the internal Merck pipeline, we recognize that these probes require significant collaborative investment to realize their potential impact in clarifying the tractability and translation of a given therapeutic target. This perspective concludes with recommendations for chemical probe discovery aimed toward maximizing their potential to identify targets that result in the successful delivery of novel therapeutics. Copyright © 2016 Elsevier Ltd. All rights reserved.

Bitter taste and nicotine preference: evidence for sex differences in rats.

PubMed

Nesil, Tanseli; Kanit, Lutfiye; Pogun, Sakire

2015-01-01

Nicotine affects sensory pathways and an interaction between taste and nicotine preference is likely. In addition to pharmacologic effects, orosensory factors are important in nicotine dependence. Recent evidence suggests a link between taste (notably bitter) receptor genes and nicotine addiction. To explore the possible interaction between taste and nicotine preference in rats, including sex as a factor. Adult male and female Sprague Dawley rats (n = 82) were used in free choice oral intake experiments. In Experiment 1 rats received water from one bottle and one of the taste substances (quinine, sucrose, or saccharine) from the other bottle for 12 days. Following a wash-out period, Experiment 2a was initiated in the same rats. Rats received water from one bottle and nicotine (10 and 20 mg/l) from the other for 12 days. In Experiment 2b, nicotine exposure was continued for four more weeks. Liquid intake and weight were measured at four-day (Experiments 1 and 2a) and one week (Experiment 2b) periods. In female rats, quinine and subsequent nicotine intake were positively correlated and quinine intake and weight gain were negatively correlated. No association was depicted between nicotine consumption and sweet tastants in either female or male animals. The results suggest that bitter taste and nicotine preference are related, but only in female rats. This finding is parallel to observations in human smokers. Our study may be a preliminary step in the search for common genes that underlie nicotine dependence and taste preference.

Single neurons in the nucleus of the solitary tract respond selectively to bitter taste stimuli.

PubMed

Geran, Laura C; Travers, Susan P

2006-11-01

Molecular data suggest that receptors for all bitter ligands are coexpressed in the same taste receptor cells (TRCs), whereas physiological results indicate that individual TRCs respond to only a subset of bitter stimuli. It is also unclear to what extent bitter-responsive neurons are stimulated by nonbitter stimuli. To explore these issues, single neuron responses were recorded from the rat nucleus of the solitary tract (NST) during whole mouth stimulation with a variety of bitter compounds: 10 microM cycloheximide, 7 mM propylthiouracil, 10 mM denatonium benzoate, and 3 mM quinine hydrochloride at intensities matched for behavioral effectiveness. Stimuli representing the remaining putative taste qualities were also tested. Particular emphasis was given to activating taste receptors in the foliate papillae innervated by the quinine-sensitive glossopharyngeal nerve. This method revealed a novel population of bitter-best (B-best) cells with foliate receptive fields and significant selectivity for bitter tastants. Across all neurons, multidimensional scaling depicted bitter stimuli as loosely clustered yet clearly distinct from nonbitter tastants. When neurons with posterior receptive fields were analyzed alone, bitter stimuli formed a tighter cluster. Nevertheless, responses to bitter stimuli were variable across B-best neurons, with cycloheximide the most, and quinine the least frequent optimal stimulus. These results indicate heterogeneity for the processing of ionic and nonionic bitter tastants, which is dependent on receptive field. Further, they suggest that neurons selective for bitter substances could contribute to taste coding.

GWAS of human bitter taste perception identifies new loci and reveals additional complexity of bitter taste genetics

PubMed Central

Ledda, Mirko; Kutalik, Zoltán; Souza Destito, Maria C.; Souza, Milena M.; Cirillo, Cintia A.; Zamboni, Amabilene; Martin, Nathalie; Morya, Edgard; Sameshima, Koichi; Beckmann, Jacques S.; le Coutre, Johannes; Bergmann, Sven; Genick, Ulrich K.

2014-01-01

Human perception of bitterness displays pronounced interindividual variation. This phenotypic variation is mirrored by equally pronounced genetic variation in the family of bitter taste receptor genes. To better understand the effects of common genetic variations on human bitter taste perception, we conducted a genome-wide association study on a discovery panel of 504 subjects and a validation panel of 104 subjects from the general population of São Paulo in Brazil. Correction for general taste-sensitivity allowed us to identify a SNP in the cluster of bitter taste receptors on chr12 (10.88– 11.24 Mb, build 36.1) significantly associated (best SNP: rs2708377, P = 5.31 × 10−13, r2 = 8.9%, β = −0.12, s.e. = 0.016) with the perceived bitterness of caffeine. This association overlaps with—but is statistically distinct from—the previously identified SNP rs10772420 influencing the perception of quinine bitterness that falls in the same bitter taste cluster. We replicated this association to quinine perception (P = 4.97 × 10−37, r2 = 23.2%, β = 0.25, s.e. = 0.020) and additionally found the effect of this genetic locus to be concentration specific with a strong impact on the perception of low, but no impact on the perception of high concentrations of quinine. Our study, thus, furthers our understanding of the complex genetic architecture of bitter taste perception. PMID:23966204

Boron nitride nanotubes as vehicles for intracellular delivery of fluorescent drugs and probes.

PubMed

Niskanen, Jukka; Zhang, Issan; Xue, Yanming; Golberg, Dmitri; Maysinger, Dusica; Winnik, Françoise M

2016-01-01

To evaluate the response of cells to boron nitride nanotubes (BNNTs) carrying fluorescent probes or drugs in their inner channel by assessment of the cellular localization of the fluorescent cargo, evaluation of the in vitro release and biological activity of a drug (curcumin) loaded in BNNTs. Cells treated with curcumin-loaded BNNTs and stimulated with lipopolysaccharide were assessed for nitric oxide release and stimulation of IL-6 and TNF-α. The cellular trafficking of two cell-permeant dyes and a non-cell-permeant dye loaded within BNNTs was imaged. BNNTs loaded with up to 13 wt% fluorophores were internalized by cells and controlled release of curcumin triggered cellular pathways associated with the known anti-inflammatory effects of the drug. The overall findings indicate that BNNTs can function as nanocarriers of biologically relevant probes/drugs allowing one to examine/control their local intracellular localization and biochemical effects, leading the way to applications as intracellular nanosensors.

Artemisinin activity-based probes identify multiple molecular targets within the asexual stage of the malaria parasites Plasmodium falciparum 3D7

PubMed Central

Ismail, Hanafy M.; Barton, Victoria; Phanchana, Matthew; Charoensutthivarakul, Sitthivut; Wong, Michael H. L.; Hemingway, Janet; Biagini, Giancarlo A.; O’Neill, Paul M.; Ward, Stephen A.

2016-01-01

The artemisinin (ART)-based antimalarials have contributed significantly to reducing global malaria deaths over the past decade, but we still do not know how they kill parasites. To gain greater insight into the potential mechanisms of ART drug action, we developed a suite of ART activity-based protein profiling probes to identify parasite protein drug targets in situ. Probes were designed to retain biological activity and alkylate the molecular target(s) of Plasmodium falciparum 3D7 parasites in situ. Proteins tagged with the ART probe can then be isolated using click chemistry before identification by liquid chromatography–MS/MS. Using these probes, we define an ART proteome that shows alkylated targets in the glycolytic, hemoglobin degradation, antioxidant defense, and protein synthesis pathways, processes essential for parasite survival. This work reveals the pleiotropic nature of the biological functions targeted by this important class of antimalarial drugs. PMID:26858419

21 CFR 882.4725 - Radiofrequency lesion probe.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Radiofrequency lesion probe. 882.4725 Section 882...) MEDICAL DEVICES NEUROLOGICAL DEVICES Neurological Surgical Devices § 882.4725 Radiofrequency lesion probe. (a) Identification. A radiofrequency lesion probe is a device connected to a radiofrequency (RF...

21 CFR 882.4725 - Radiofrequency lesion probe.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Radiofrequency lesion probe. 882.4725 Section 882...) MEDICAL DEVICES NEUROLOGICAL DEVICES Neurological Surgical Devices § 882.4725 Radiofrequency lesion probe. (a) Identification. A radiofrequency lesion probe is a device connected to a radiofrequency (RF...

21 CFR 870.1915 - Thermodilution probe.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Thermodilution probe. 870.1915 Section 870.1915...) MEDICAL DEVICES CARDIOVASCULAR DEVICES Cardiovascular Diagnostic Devices § 870.1915 Thermodilution probe. (a) Identification. A thermodilution probe is a device that monitors cardiac output by use of...

21 CFR 882.4725 - Radiofrequency lesion probe.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Radiofrequency lesion probe. 882.4725 Section 882...) MEDICAL DEVICES NEUROLOGICAL DEVICES Neurological Surgical Devices § 882.4725 Radiofrequency lesion probe. (a) Identification. A radiofrequency lesion probe is a device connected to a radiofrequency (RF...

21 CFR 870.1915 - Thermodilution probe.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Thermodilution probe. 870.1915 Section 870.1915...) MEDICAL DEVICES CARDIOVASCULAR DEVICES Cardiovascular Diagnostic Devices § 870.1915 Thermodilution probe. (a) Identification. A thermodilution probe is a device that monitors cardiac output by use of...

21 CFR 870.1915 - Thermodilution probe.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Thermodilution probe. 870.1915 Section 870.1915...) MEDICAL DEVICES CARDIOVASCULAR DEVICES Cardiovascular Diagnostic Devices § 870.1915 Thermodilution probe. (a) Identification. A thermodilution probe is a device that monitors cardiac output by use of...

21 CFR 882.4725 - Radiofrequency lesion probe.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Radiofrequency lesion probe. 882.4725 Section 882...) MEDICAL DEVICES NEUROLOGICAL DEVICES Neurological Surgical Devices § 882.4725 Radiofrequency lesion probe. (a) Identification. A radiofrequency lesion probe is a device connected to a radiofrequency (RF...

21 CFR 870.1915 - Thermodilution probe.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Thermodilution probe. 870.1915 Section 870.1915...) MEDICAL DEVICES CARDIOVASCULAR DEVICES Cardiovascular Diagnostic Devices § 870.1915 Thermodilution probe. (a) Identification. A thermodilution probe is a device that monitors cardiac output by use of...

21 CFR 882.4725 - Radiofrequency lesion probe.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Radiofrequency lesion probe. 882.4725 Section 882...) MEDICAL DEVICES NEUROLOGICAL DEVICES Neurological Surgical Devices § 882.4725 Radiofrequency lesion probe. (a) Identification. A radiofrequency lesion probe is a device connected to a radiofrequency (RF...

Open access chemical probes for epigenetic targets

PubMed Central

Brown, Peter J; Müller, Susanne

2015-01-01

Background High attrition rates in drug discovery call for new approaches to improve target validation. Academia is filling gaps, but often lacks the experience and resources of the pharmaceutical industry resulting in poorly characterized tool compounds. Discussion The SGC has established an open access chemical probe consortium, currently encompassing ten pharmaceutical companies. One of its mandates is to create well-characterized inhibitors (chemical probes) for epigenetic targets to enable new biology and target validation for drug development. Conclusion Epigenetic probe compounds have proven to be very valuable and have not only spurred a plethora of novel biological findings, but also provided starting points for clinical trials. These probes have proven to be critical complementation to traditional genetic targeting strategies and provided sometimes surprising results. PMID:26397018

Microneedle arrays for biosensing and drug delivery

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

Wang, Joseph; Windmiller, Joshua Ray; Narayan, Roger

Methods, structures, and systems are disclosed for biosensing and drug delivery techniques. In one aspect, a^ device for detecting an analyte and/or releasing a biochemical into a biological fluid can include an array of hollowed needles, in which each needle includes a protruded needle structure including an exterior wall forming a hollow interior and an opening at a terminal end of the protruded needle structure that exposes the hollow interior, and a probe inside the exterior wall to interact with one or more chemical or biological substances that come in contact with the probe via the opening to produce amore » probe sensing signal, and an array of wires that are coupled to probes of the array of hollowed needles, respectively, each wire being electrically conductive to transmit the probe sensing signal produced by a respective probe.« less

Microneedle arrays for biosensing and drug delivery

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

Wang, Joseph; Windmiller, Joshua Ray; Narayan, Roger

Methods, structures, and systems are disclosed for biosensing and drug delivery techniques. In one aspect, a device for detecting an analyte and/or releasing a biochemical into a biological fluid can include an array of hollowed needles, in which each needle includes a protruded needle structure including an exterior wall forming a hollow interior and an opening at a terminal end of the protruded needle structure that exposes the hollow interior, and a probe inside the exterior wall to interact with one or more chemical or biological substances that come in contact with the probe via the opening to produce amore » probe sensing signal, and an array of wires that are coupled to probes of the array of hollowed needles, respectively, each wire being electrically conductive to transmit the probe sensing signal produced by a respective probe.« less

Validation of a microdose probe drug cocktail for clinical drug interaction assessments for drug transporters and CYP3A.

PubMed

Prueksaritanont, T; Tatosian, D A; Chu, X; Railkar, R; Evers, R; Chavez-Eng, C; Lutz, R; Zeng, W; Yabut, J; Chan, G H; Cai, X; Latham, A H; Hehman, J; Stypinski, D; Brejda, J; Zhou, C; Thornton, B; Bateman, K P; Fraser, I; Stoch, S A

2017-04-01

A microdose cocktail containing midazolam, dabigatran etexilate, pitavastatin, rosuvastatin, and atorvastatin has been established to allow simultaneous assessment of a perpetrator impact on the most common drug metabolizing enzyme, cytochrome P450 (CYP)3A, and the major transporters organic anion-transporting polypeptides (OATP)1B, breast cancer resistance protein (BCRP), and MDR1 P-glycoprotein (P-gp). The clinical utility of these microdose cocktail probe substrates was qualified by conducting clinical drug interaction studies with three inhibitors with different in vitro inhibitory profiles (rifampin, itraconazole, and clarithromycin). Generally, the pharmacokinetic profiles of the probe substrates, in the absence and presence of the inhibitors, were comparable to their reported corresponding pharmacological doses, and/or in agreement with theoretical expectations. The exception was dabigatran, which resulted in an approximately twofold higher magnitude for microdose compared to conventional dosing, and, thus, can be used to flag a worst-case scenario for P-gp. Broader application of the microdose cocktail will facilitate a more comprehensive understanding of the roles of drug transporters in drug disposition and drug interactions. © 2016 American Society for Clinical Pharmacology and Therapeutics.

A polyspecific drug/proton antiporter mediates diphenhydramine and clonidine transport at the mouse blood-retinal barrier

PubMed Central

Chapy, Hélène; André, Pascal; Declèves, Xavier; Scherrmann, Jean-Michel; Cisternino, Salvatore

2015-01-01

Background and Purpose Transporters at the blood-retinal barrier (BRB), as at the blood–brain barrier (BBB), regulate the distribution of compounds into the neural parenchyma. However, the expression of BRB transporters and their quantitative impact in vivo are still poorly understood. Experimental Approach Clonidine and diphenhydramine are substrates of a novel BBB drug/proton-antiporter. We evaluated their transport at the BRB by in situ carotid perfusion in wild-type or knocked-out mice for Oct1-3 (Slc22a1-3). Key Results At pharmacological exposure levels, carrier-mediated BRB influx was 2 and 12 times greater than the passive diffusion rate for clonidine and diphenhydramine, respectively. Functional identification demonstrated the involvement of a high-capacity potassium- and sodium-independent proton-antiporter that shared the features of the previously characterized clonidine, diphenhydramine and cocaine BBB transporter. The functional characterization suggests that SLC transporters Oct1-3, Mate1 (Slc47a1) and Octn1-2 (Slc22a4-5) are not involved. Melanin/retinal toxic drugs like antimalarials (amodiaquine, quinine), quinidine and tricyclic antidepressants (imipramine) acted as inhibitors of this proton-antiporter. The endogenous indole derivative tryptamine inhibited the transporter, unlike 5-HT (serotonin), dopamine or L-DOPA. Trans-stimulation experiments with [3H]-clonidine at the BRB indicated that diphenhydramine, nicotine, oxycodone, naloxone, tramadol, 3,4-methylenedioxyamphetamine (MDMA, ecstasy), heroin, methadone and verapamil are common substrates. Conclusions and Implications A proton-antiporter is physiologically involved in the transport of clonidine and diphenhydramine and is quantitatively more important than their passive diffusion flux at the mouse BRB. The features of this molecularly unidentified transporter highlight its importance in regulating drug delivery at the retina and suggest that it has the capacity to handle several drugs. PMID:26177775

Mirincamycin, an old candidate for malaria combination treatment and prophylaxis in the 21st century: in vitro interaction profiles with potential partner drugs in continuous culture and field isolates.

PubMed

Starzengruber, Peter; Fuehrer, Hans-Peter; Swoboda, Paul; Ganesh, Deepa; Haque, Rashidul; Khan, Wasif A; Graninger, Wolfgang; Noedl, Harald

2014-06-10

Spreading resistance of Plasmodium falciparum to existing drugs calls for the search for novel anti-malarial drugs and combinations for the treatment of falciparum malaria. In vitro and ex vivo investigations were conducted with fresh P. falciparum field isolates and culture-adapted P. falciparum clones to evaluate the anti-malarial potential of mirincamycin, a lincosamide, alone and in combination with tafenoquine (TQ), dihydroartemisinin (DHA), and chloroquine (CQ). All samples were tested in a histidine-rich protein 2 (HRP2) drug susceptibility assay. Interaction analysis showed additive to synergistic interaction profiles with these potential partner drugs, with an overall geometric mean fractional inhibitory concentration at 50% inhibition (FIC₅₀) of 0.78, 0.80 and 0.80 for mirincamycin with TQ, DHA, and CQ, respectively. Antagonism was not found in any of the tested field isolates or clones. The strongest tendency toward synergy (i.e. the lowest FIC) was seen with a combination ratio of 1:0.27 to 1:7.2 (mean 1:2.7) for the combination with tafenoquine. The optimal combination ratios for DHA and CQ were 1:444.4 to 1:36,000 (mean 1:10,755.5) and 1:2.7 to 1:216 (mean 1:64.5), respectively. No evidence of an activity correlation (i.e. potential cross-resistance) with DHA, mefloquine, quinine or chloroquine was seen whereas a significant correlation with the activity of clindamycin and azithromycin was detected. Mirincamycin combinations may be promising candidates for further clinical investigations in the therapy and prophylaxis of multidrug-resistant falciparum malaria or in combination with 4 or 8-aminoquinolines for the treatment and relapse prevention of vivax malaria.

Mirincamycin, an old candidate for malaria combination treatment and prophylaxis in the 21st century: in vitro interaction profiles with potential partner drugs in continuous culture and field isolates

PubMed Central

2014-01-01

Background Spreading resistance of Plasmodium falciparum to existing drugs calls for the search for novel anti-malarial drugs and combinations for the treatment of falciparum malaria. Methods In vitro and ex vivo investigations were conducted with fresh P. falciparum field isolates and culture-adapted P. falciparum clones to evaluate the anti-malarial potential of mirincamycin, a lincosamide, alone and in combination with tafenoquine (TQ), dihydroartemisinin (DHA), and chloroquine (CQ). All samples were tested in a histidine-rich protein 2 (HRP2) drug susceptibility assay. Results Interaction analysis showed additive to synergistic interaction profiles with these potential partner drugs, with an overall geometric mean fractional inhibitory concentration at 50% inhibition (FIC50) of 0.78, 0.80 and 0.80 for mirincamycin with TQ, DHA, and CQ, respectively. Antagonism was not found in any of the tested field isolates or clones. The strongest tendency toward synergy (i.e. the lowest FIC) was seen with a combination ratio of 1:0.27 to 1:7.2 (mean 1:2.7) for the combination with tafenoquine. The optimal combination ratios for DHA and CQ were 1:444.4 to 1:36,000 (mean 1:10,755.5) and 1:2.7 to 1:216 (mean 1:64.5), respectively. No evidence of an activity correlation (i.e. potential cross-resistance) with DHA, mefloquine, quinine or chloroquine was seen whereas a significant correlation with the activity of clindamycin and azithromycin was detected. Conclusions Mirincamycin combinations may be promising candidates for further clinical investigations in the therapy and prophylaxis of multidrug-resistant falciparum malaria or in combination with 4 or 8-aminoquinolines for the treatment and relapse prevention of vivax malaria. PMID:24916383

Identification of Bitterness-Masking Compounds from Cheese

PubMed Central

2012-01-01

Bitterness-masking compounds were identified in a natural white mold cheese. The oily fraction of the cheese was extracted and further fractionated by using silica gel column chromatography. The four fractions obtained were characterized by thin-layer chromatography and nuclear magnetic resonance spectroscopy. The fatty acid-containing fraction was found to have the highest bitterness-masking activity against quinine hydrochloride. Bitterness-masking activity was quantitated using a method based on subjective equivalents. At 0.5 mM, the fatty acid mixture, which had a composition similar to that of cheese, suppressed the bitterness of 0.008% quinine hydrochloride to be equivalent to that of 0.0049–0.0060% and 0.5 mM oleic acid to that of 0.0032–0.0038% solution. The binding potential between oleic acid and the bitter compounds was estimated by isothermal titration calorimetry. These results suggest that oleic acid masked bitterness by forming a complex with the bitter compounds. PMID:22502602

Curare: the South American arrow poison.

PubMed

Lee, M R

2005-02-01

The history of curare is both curious and convoluted. A product of South American culture it emerged in the sixteenth century from the mists of antiquity at the same time as quinine, coca, and chocolate. Like quinine, at first came the extract but no plant, and later the plant but no chemical compound. It took more than 300 years and the efforts of many explorers and scientists to resolve the problem. These included Condamine, Humboldt, Brodie, Waterton, Bernard, Dale, Walker, and King. Finally, the pure compound d-tubocurarine was isolated from the liana Chondrodendron and synthesised. Its specific physiological action was blockade of the effect of acetylcholine at the neuro-muscular junction. Such a paralytic poison could be used to kill oneself or others. The bizarre plot to kill the Prime Minister, Lloyd George, during the First World War is described. Fortunately this nefarious plan was thwarted by the Secret Service!

Peripheral nervous control of cold-induced reduction in the respiratory quotient of the rat

NASA Astrophysics Data System (ADS)

Refinetti, Roberto

1990-03-01

Cold-exposed rats show a reduction in the respiratory quotient which is indicative of a relative shift from carbohydrates to lipids as substrates for oxidative metabolism. In the present study, the effects of food deprivation and cold exposure on the respiratory quotient were observed. In addition, the involvement of the three main branches of the peripheral nervous system (sympathetic, parasympathetic, and somatic) was investigated by means of synaptic blockade with propranolol, atropine, and quinine, respectively. Both propranolol and quinine blocked the cold-induced decrease in respiratory quotient and increase in heat production, whereas atropine had only minor and very brief effects. It is concluded that both the sympathetic and somatic branches are involved in the metabolic changes associated with cold-induced thermogenesis and that the increase in metabolic heat production involves a shift from carbohydrate to lipid utilization irrespective of which of the two branches is activated.

21 CFR 886.1670 - Ophthalmic isotope uptake probe.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Ophthalmic isotope uptake probe. 886.1670 Section... (CONTINUED) MEDICAL DEVICES OPHTHALMIC DEVICES Diagnostic Devices § 886.1670 Ophthalmic isotope uptake probe. (a) Identification. An ophthalmic isotope uptake probe is an AC-powered device intended to measure...

21 CFR 886.1670 - Ophthalmic isotope uptake probe.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Ophthalmic isotope uptake probe. 886.1670 Section... (CONTINUED) MEDICAL DEVICES OPHTHALMIC DEVICES Diagnostic Devices § 886.1670 Ophthalmic isotope uptake probe. (a) Identification. An ophthalmic isotope uptake probe is an AC-powered device intended to measure...

21 CFR 886.1670 - Ophthalmic isotope uptake probe.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Ophthalmic isotope uptake probe. 886.1670 Section... (CONTINUED) MEDICAL DEVICES OPHTHALMIC DEVICES Diagnostic Devices § 886.1670 Ophthalmic isotope uptake probe. (a) Identification. An ophthalmic isotope uptake probe is an AC-powered device intended to measure...

21 CFR 892.1320 - Nuclear uptake probe.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Nuclear uptake probe. 892.1320 Section 892.1320...) MEDICAL DEVICES RADIOLOGY DEVICES Diagnostic Devices § 892.1320 Nuclear uptake probe. (a) Identification. A nuclear uptake probe is a device intended to measure the amount of radionuclide taken up by a...

21 CFR 892.1320 - Nuclear uptake probe.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Nuclear uptake probe. 892.1320 Section 892.1320...) MEDICAL DEVICES RADIOLOGY DEVICES Diagnostic Devices § 892.1320 Nuclear uptake probe. (a) Identification. A nuclear uptake probe is a device intended to measure the amount of radionuclide taken up by a...

[Fluorescence spectra and quantum yield of TiO2 nanocrystals synthesized by alcohothermal method].

PubMed

Song, Cui-Hong; Li, Yan-Ting; Li, Jing; Wei, Yong-Ju; Hu, Yu-Zhu; Wei, Yu

2008-01-01

Fluorescence spectra and fluorescence quantum yield of TiO2 nanocrystals were studied. Using tetra n-butyl titanate as a starting material, a facile alcohothermal technique was used to synthesize TiO2 nanocrystals. As can be seen from the transmittance electron microscopy (TEM) image, TiO2 nanocrystals with a relatively uniform particle size distribution of < 10 nm are present in the transparent sol. The transparent sol presents a strong stable fluorescence emission with a maximum at 450 nm, which is greatly dependent on the size quantization effects, defect energy level and the surface state of TiO2 nanocrystals. The quantum yield (gamma) of TiO2 was determined by the relative comparison procedure, using freshly prepared analytical purity quinine sulfate in 0.05 mol x L(-1) H2SO4 as a relative quantum yield standard. The emission quantum yield of TiO2 nanocrystals prepared in alcoholic media was calculated to be about 0.20 at wavelengths ranging from 330 to 370 nm, which was much higher than the values reported in previous works. So, it is supposed that nano-TiO2 will be applied as a potential quantum dots fluorescence probe in biological analysis.

Taste responses in patients with Parkinson's disease

PubMed Central

Sienkiewicz-Jaros..., H; Scinska, A; Kuran, W; Ryglewicz, D; Rogowski, A; Wrobel, E; Korkosz, A; Kukwa, A; Kostowski, W; Bienkowski, P

2005-01-01

Objective: Preclinical studies indicate that dopaminergic transmission in the basal ganglia may be involved in processing of both pleasant and unpleasant stimuli. Given this, the aim of the present study was to assess taste responses to sweet, bitter, sour, and salty substances in patients with Parkinson's disease (PD). Methods: Rated intensity and pleasantness of filter paper discs soaked in sucrose (10–60%), quinine (0.025–0.5%), citric acid (0.25–4.0%), or sodium chloride (1.25–20%) solutions was evaluated in 30 patients with PD and in 33 healthy controls. Paper discs soaked in deionised water served as control stimuli. In addition, reactivity to 100 ml samples of chocolate and vanilla milk was assessed in both groups. Taste detection thresholds were assessed by means of electrogustometry. Sociodemographic and neuropsychiatric data, including cigarette smoking, alcohol consumption, tea and coffee drinking, depressive symptoms, and cognitive functioning were collected. Results: In general, perceived intensity, pleasantness, and identification of the sucrose, quinine, citric acid, or sodium chloride samples did not differ between the PD patients and controls. Intensity ratings of the filter papers soaked in 0.025% quinine were significantly higher in the PD patients compared with the control group. No inter-group differences were found in taste responses to chocolate and vanilla milk. Electrogustometric thresholds were significantly (p = 0.001) more sensitive in the PD patients. Conclusions: PD is not associated with any major alterations in responses to pleasant or unpleasant taste stimuli. Patients with PD may present enhanced taste acuity in terms of electrogustometric threshold. PMID:15607993

Adherence to national guidelines for the diagnosis and management of severe malaria: a nationwide, cross-sectional survey in Malawi, 2012.

PubMed

Shah, Monica P; Briggs-Hagen, Melissa; Chinkhumba, Jobiba; Bauleni, Andy; Chalira, Alfred; Moyo, Dubulao; Dodoli, Wilfred; Luhanga, Misheck; Sande, John; Ali, Doreen; Gutman, Julie; Mathanga, Don P; Lindblade, Kim A

2016-07-19

Severe malaria has a case fatality rate of 10-20 %; however, few studies have addressed the quality of severe malaria case management. This study evaluated the diagnostic and treatment practices of malaria patients admitted to inpatient health facilities (HF) in Malawi. In July-August 2012, a nationwide, cross-sectional survey of severe malaria management was conducted in 36 HFs selected with equal probability from all eligible public sector HFs in Malawi. Patient records from all admissions during October 2011 and April 2012 (low and high season, respectively) were screened for an admission diagnosis of malaria or prescription of any anti-malarial. Eligible records were stratified by age (< 5 or ≥ 5 years). A maximum of eight records was randomly selected within each age and month stratum. Severe malaria was defined by admission diagnosis or documentation of at least one sign or symptom of severe malaria. Treatment with intravenous (IV) quinine or artesunate was considered correct. Patients without documentation of severe malaria were analysed as uncomplicated malaria patients; treatment with an artemisinin-based combination therapy (ACT) or oral quinine based on malaria test results was considered correct. All analyses accounted for HF level clustering and sampling weights. The analysis included 906 records from 35 HFs. Among these, 42 % (95 % confidence interval [CI] 35-49) had a severe malaria admission diagnosis and 50 % (95 % CI 44-57) had at least one severe malaria sign or symptom documented. Severe malaria patients defined by admission diagnosis (93, 95 % CI 86-99) were more likely to be treated correctly compared to patients defined by a severe sign (82, 95 % CI 75-89) (p < 0.0001). Among uncomplicated malaria patients, 26 % (95 % CI 18-35) were correctly treated and 53 % (95 % CI 42-64) were adequately treated with IV quinine alone or in combination with an ACT or oral quinine. A majority of patients diagnosed with severe malaria received the recommended IV therapy in accordance with national treatment guidelines. However, the inconsistencies between diagnosis of severe malaria and documentation of severe signs and symptoms highlight the need to improve healthcare worker recognition and documentation of severe signs and symptoms.

Safety of artemisinins in first trimester of prospectively followed pregnancies: an observational study

PubMed Central

Moore, Kerryn A; Simpson, Julie A; Paw, Moo Kho; Pimanpanarak, MuPawJay; Wiladphaingern, Jacher; Rijken, Marcus J; Jittamala, Podjanee; White, Nicholas J; Fowkes, Freya J I; Nosten, François; McGready, Rose

2016-01-01

Summary Background Artemisinins, the most effective antimalarials available, are not recommended for falciparum malaria during the first trimester of pregnancy because of safety concerns. Therefore, quinine is used despite its poor effectiveness. Assessing artemisinin safety requires weighing the risks of malaria and its treatment. We aimed to assess the effect of first-trimester malaria and artemisinin treatment on miscarriage and major congenital malformations. Methods In this observational study, we assessed data from antenatal clinics on the Thai–Myanmar border between Jan 1, 1994, and Dec 31, 2013. We included women who presented to antenatal clinics during their first trimester with a viable fetus. Women were screened for malaria, and data on malaria, antimalarial treatment, and birth outcomes were collected. The relationship between artemisinin treatments (artesunate, dihydroartemisinin, or artemether) and miscarriage or malformation was assessed using Cox regression with left-truncation and time-varying exposures. Findings Of 55 636 pregnancies registered between 1994 and 2013, 25 485 pregnancies were analysed for first-trimester malaria and miscarriage, in which 2558 (10%) had first-trimester malaria. The hazard of miscarriage increased 1·61-fold after an initial first-trimester falciparum episode (95% CI 1·32–1·97; p<0·0001), 3·24-fold following falciparum recurrence (2·24–4·68; p<0·0001), and 2·44-fold (1·01–5·88; p=0·0473) following recurrent symptomatic vivax malaria. No difference was noted in miscarriage in first-line falciparum treatments with artemisinin (n=183) versus quinine (n=842; HR 0·78 [95% CI 0·45–1·34]; p=0·3645) or in risk of major congenital malformations (two [2%] of 109 [95% CI 0·22–6·47] versus eight (1%) of 641 [0·54–2·44], respectively). Interpretation First-trimester falciparum and vivax malaria both increase the risk of miscarriage. We noted no evidence of an increased risk of miscarriage or of major congenital malformations associated with first-line treatment with an artemisinin derivative compared with quinine. In view of the low efficacy of quinine and wide availability of highly effective artemisinin-based combination therapies, it is time to reconsider first-trimester antimalarial treatment recommendations. Funding The Wellcome Trust and The Bill & Melinda Gates Foundation. PMID:26869377

[Interaction between CYP450 enzymes and metabolism of traditional Chinese medicine as well as enzyme activity assay].

PubMed

Lu, Tu-lin; Su, Lian-lin; Ji, De; Gu, Wei; Mao, Chun-qin

2015-09-01

Drugs are exogenous compounds for human bodies, and will be metabolized by many enzymes after administration. CYP450 enzyme, as a major metabolic enzyme, is an important phase I drug metabolizing enzyme. In human bodies, about 75% of drug metabolism is conducted by CYP450 enzymes, and CYP450 enzymes is the key factor for drug interactions between traditional Chinese medicine( TCM) -TCM, TCM-medicine and other drug combination. In order to make clear the interaction between metabolic enzymes and TCM metabolism, we generally chose the enzymatic activity as an evaluation index. That is to say, the enhancement or reduction of CYP450 enzyme activity was used to infer the inducing or inhibitory effect of active ingredients and extracts of traditional Chinese medicine on enzymes. At present, the common method for measuring metabolic enzyme activity is Cocktail probe drugs, and it is the key to select the suitable probe substrates. This is of great significance for study drug's absorption, distribution, metabolism and excretion (ADME) process in organisms. The study focuses on the interaction between TCMs, active ingredients, herbal extracts, cocktail probe substrates as well as CYP450 enzymes, in order to guide future studies.

Substandard anti-malarial drugs in Burkina Faso

PubMed Central

Tipke, Maike; Diallo, Salou; Coulibaly, Boubacar; Störzinger, Dominic; Hoppe-Tichy, Torsten; Sie, Ali; Müller, Olaf

2008-01-01

Background There is concern about an increasing infiltration of markets by substandard and fake medications against life-threatening diseases in developing countries. This is particularly worrying with regard to the increasing resistance development of Plasmodium falciparum against affordable anti-malarial medications, which has led to a change to more expensive drugs in most endemic countries. Methods A representative sample of modern anti-malarial medications from licensed (public and private pharmacies, community health workers) and illicit (market and street vendors, shops) sources has been collected in the Nouna Health District in north-western Burkina Faso in 2006. All drugs were tested for their quality with the standard procedures of the German Pharma Health Fund-Minilab. Detected low standard drugs were re-tested with European Pharmacopoeia 2.9.1 standards for disintegration and ultraviolet-visible spectroscopy at the laboratory of the Heidelberg University for confirmation. Results Overall, 86 anti-malarial drug samples were collected, of which 77 samples have been included in the final analysis. The sample consisted of 39/77 (50%) chloroquine, 10/77 (13%) pyrimethamine-sulphadoxine, 9/77 (12%) quinine, 6/77 (8%) amodiaquine, 9/77 (12%) artesunate, and 4/77 (5%) artemether-lumefantrine. 32/77 (42%) drug samples were found to be of poor quality, of which 28 samples failed the visual inspection, nine samples had substandard concentrations of the active ingredient, four samples showed poor disintegration, and one sample contained non of the stated active ingredient. The licensed and the illicit market contributed 5/47 (10.6%) and 27/30 (90.0%) samples of substandard drugs respectively. Conclusion These findings provide further evidence for the wide-spread existence of substandard anti-malarial medications in Africa and call for strengthening of the regulatory and quality control capacity of affected countries, particularly in view of the now wider available and substantially more costly artemisinin-based combination therapies. PMID:18505584

Repeated Artemisinin-Based Combination Therapies in a Malaria Hyperendemic Area of Mali: Efficacy, Safety, and Public Health Impact

PubMed Central

Sagara, Issaka; Fofana, Bakary; Gaudart, Jean; Sidibe, Bakary; Togo, Amadou; Toure, Sekou; Sanogo, Kassim; Dembele, Demba; Dicko, Alassane; Giorgi, Roch; Doumbo, Ogobara K.; Djimde, Abdoulaye A.

2012-01-01

Artemisinin-based combination therapies (ACTs) are the first-line treatment of uncomplicated malaria. The public health benefit and safety of repeated administration of a given ACT are poorly studied. We conducted a randomized trial comparing artemether-lumefantrine, artesunate plus amodiaquine (AS+AQ) and artesunate plus sulfadoxine-pyrimethamine (AS+SP) in patients 6 months of age and older with uncomplicated malaria in Mali from July 2005 to July 2007. The patient received the same initial treatment of each subsequent uncomplicated malaria episode except for treatment failures where quinine was used. Overall, 780 patients were included. Patients in the AS+AQ and AS+SP arms had significantly less risk of having malaria episodes; risk ratio (RR) = 0.84 (P = 0.002) and RR = 0.80 (P = 0.001), respectively. The treatment efficacy was similar and above 95% in all arms. Although all drugs were highly efficacious and well tolerated, AS+AQ and AS+SP were associated with less episodes of malaria. PMID:22764291

Insights into the Role of Heme in the Mechanism of Action of Antimalarials

PubMed Central

Combrinck, Jill M.; Mabotha, Tebogo E.; Ncokazi, Kanyile K.; Ambele, Melvin A.; Taylor, Dale; Smith, Peter J.; Hoppe, Heinrich C.; Egan, Timothy J.

2012-01-01

Using cell fractionation and measurement of Fe(III)heme-pyridine, the antimalarial chloroquine (CQ) has been shown to cause a dose-dependent decrease in hemozoin and concomitant increase in toxic “free” heme in cultured Plasmodium falciparum that is directly correlated with parasite survival. Transmission electron microscopy techniques have further shown that heme is redistributed from the parasite digestive vacuole to the cytoplasm and that CQ disrupts hemozoin crystal growth, resulting in mosaic boundaries in the crystals formed in the parasite. Extension of the cell fractionation study to other drugs has shown that artesunate, amodiaquine, lumefantrine, mefloquine and quinine, all clinically important antimalarials, also inhibit hemozoin formation in the parasite cell, while the antifolate pyrimethamine and its combination with sulfadoxine do not. This study finally provides direct evidence in support of the hemozoin inhibition hypothesis for the mechanism of action of CQ and shows that other quinoline and related antimalarials inhibit cellular hemozoin formation. PMID:23043646

The end of a dogma: the safety of doxycycline use in young children for malaria treatment.

PubMed

Gaillard, Tiphaine; Briolant, Sébastien; Madamet, Marylin; Pradines, Bruno

2017-04-13

Anti-malarial drug resistance to chloroquine and sulfadoxine-pyrimethamine has spread from Southeast Asia to Africa. Furthermore, the recent emergence of resistance to artemisinin-based combination therapy (ACT) in Southeast Asia highlights the need to identify new anti-malarial drugs. Doxycycline is recommended for malaria chemoprophylaxis for travel in endemic areas, or in combination with the use of quinine for malaria treatment when ACT is unavailable or when the treatment of severe malaria with artesunate fails. However, doxycycline is not used in young children under 8 years of age due to its contraindication due to the risk of yellow tooth discolouration and dental enamel hypoplasia. Doxycycline was developed after tetracycline and was labelled with the same side-effects as the earlier tetracyclines. However, recent studies report little or no effects of doxycycline on tooth staining or dental enamel hypoplasia in children under 8 years of age. In the United States, the Centers for Disease Control and Prevention have recommended the use of doxycycline for the treatment of acute and chronic Q fever and tick-borne rickettsial diseases in young children. It is time to rehabilitate doxycycline and to recommend it for malaria treatment in children under 8 years of age.

Radical cure of experimental babesiosis in immunodeficient mice using a combination of an endochin-like quinolone and atovaquone

PubMed Central

Lawres, Lauren A.; Garg, Aprajita; Kumar, Vidya; Bruzual, Igor; Forquer, Isaac P.; Renard, Isaline; Virji, Azan Z.; Boulard, Pierre; Rodriguez, Eduardo X.; Allen, Alexander J.; Pou, Sovitj; Wegmann, Keith W.; Winter, Rolf W.; Nilsen, Aaron; Mao, Jialing; Preston, Douglas A.; Belperron, Alexia A.; Bockenstedt, Linda K.; Hinrichs, David J.; Riscoe, Michael K.; Doggett, J. Stone

2016-01-01

Human babesiosis is a tick-borne multisystem disease caused by Babesia species of the apicomplexan phylum. Most clinical cases and fatalities of babesiosis are caused by Babesia microti. Current treatment for human babesiosis consists of two drug combinations, atovaquone + azithromycin or quinine + clindamycin. These treatments are associated with adverse side effects and a significant rate of drug failure. Here, we provide evidence for radical cure of experimental babesiosis in immunodeficient mice using a combination of an endochin-like quinolone (ELQ) prodrug and atovaquone. In vivo efficacy studies in mice using ELQ-271, ELQ-316, and the ELQ-316 prodrug, ELQ-334, demonstrated excellent growth inhibitory activity against the parasite, with potency equal to that of orally administered atovaquone at 10 mg/kg. Analysis of recrudescent parasites after ELQ or atovaquone monotherapy identified genetic substitutions in the Qi or Qo sites, respectively, of the cytochrome bc1 complex. Impressively, a combination of ELQ-334 and atovaquone, at doses as low as 5.0 mg/kg each, resulted in complete clearance of the parasite with no recrudescence up to 122 d after discontinuation of therapy. These results will set the stage for future clinical evaluation of ELQ and atovaquone combination therapy for treatment of human babesiosis. PMID:27270894

Probable chloroquine-resistant Plasmodium falciparum malaria from Mozambique A case report.

PubMed

Pillay, N; Bhoola, R L

1975-08-16

A female patient with Plasmodium falciparum malaria apparently resistant to chloroquine is descirbed. She had recently returned from Mozambique, which may prove to be a new endemic are with resistant strains. The infection was successfully treated with quinine.

Biology-driven library design for probe discovery.

PubMed

Inglese, James; Hasson, Samuel A

2011-10-28

Libraries of diverse small molecules are important to probe and drug discovery. The current trend toward building massive screening collections to support drug development, a special application of chemical biology, can limit their broader potential. Biology-driven construction methods (Wallace et al., 2011) are rapidly emerging to bring chemical libraries back on a viable path. Copyright © 2011 Elsevier Ltd. All rights reserved.

Portable sensors for drug and explosive detection

NASA Astrophysics Data System (ADS)

Leginus, Joseph M.

1994-03-01

Westinghouse Electric is developing portable, hand-held sensors capable of detecting numerous drugs of abuse (cocaine, heroin, amphetamines) and explosives (trinitrotoluene, pentaerythritol tetranitrate, nitroglycerin). The easy-to-use system consists of a reusable electronics module and disposable probes. The sensor illuminates and detects light transmitted through optical cells of the probe during an antibody-based latex agglutination reaction. Each probe contains all the necessary reagents to carry out a test in a single step. The probe has the ability to lift minute quantities of samples from a variety of surfaces and deliver the sample to a reaction region within the device. The sensor yields a qualitative answer in 30 to 45 seconds and is able to detect illicit substances at nanogram levels.

Use of near-infrared spectroscopy and multipoint measurements for quality control of pharmaceutical drug products.

PubMed

Boiret, Mathieu; Chauchard, Fabien

2017-01-01

Near-infrared (NIR) spectroscopy is a non-destructive analytical technique that enables better-understanding and optimization of pharmaceutical processes and final drug products. The use in line is often limited by acquisition speed and sampling area. This work focuses on performing a multipoint measurement at high acquisition speed at the end of the manufacturing process on a conveyor belt system to control both the distribution and the content of active pharmaceutical ingredient within final drug products, i.e., tablets. A specially designed probe with several collection fibers was developed for this study. By measuring spectral and spatial information, it provides physical and chemical knowledge on the final drug product. The NIR probe was installed on a conveyor belt system that enables the analysis of a lot of tablets. The use of these NIR multipoint measurement probes on a conveyor belt system provided an innovative method that has the potential to be used as a new paradigm to ensure the drug product quality at the end of the manufacturing process and as a new analytical method for the real-time release control strategy. Graphical abstract Use of near-infrared spectroscopy and multipoint measurements for quality control of pharmaceutical drug products.

Autoregulation of apical membrane Na+ permeability of tight epithelia. Noise analysis with amiloride and CGS 4270

PubMed Central

1985-01-01

Noise analysis of the Na+ channels of the apical membranes of frog skin bathed symmetrically in a Cl-HCO3 Ringer solution was done with amiloride and CGS 4270. Tissues were studied in their control states and after inhibition of transepithelial Na+ transport (Isc) by addition of quinine or quinidine to the apical solution. A critical examination of the amiloride-induced noise indicated that the single channel Na+ currents (iNa) were decreased by quinine and quinidine, probably because of depolarization of apical membrane voltage. Despite considerable statistical uncertainty in the methods of estimation of the Na+ channel density with amiloride-induced noise (NA, see text), the striking observation was a large increase of NA with amiloride inhibition of the rate of Na+ entry into the cells. NA was increased to 406% of control, whereas Isc was inhibited to 8.6% of control by 6 microM amiloride. Studies were done also with the Na+ channel blocker CGS 4270. Noise analysis with this compound was advantageous, permitting iCGSNa and NCGS to be measured in individual tissues with a relatively small inhibition of Isc. As with amiloride, inhibition of Isc with CGS 4270 caused large increases of the Na+ channel density (approximately 200% at approximately 35% inhibition of the Isc). Quinine and quinidine caused an approximately 50% increase of Na+ channel density while inhibiting iNa by approximately 60-70%. As inhibition of Na+ entry leads to an increase of Na+ channel density, a mechanism of autoregulation appears to be a major factor in adjusting the apical membrane Na+ permeability of the cells. PMID:2409219

The basel cocktail for simultaneous phenotyping of human cytochrome P450 isoforms in plasma, saliva and dried blood spots.

PubMed

Donzelli, Massimiliano; Derungs, Adrian; Serratore, Maria-Giovanna; Noppen, Christoph; Nezic, Lana; Krähenbühl, Stephan; Haschke, Manuel

2014-03-01

Phenotyping cocktails use a combination of cytochrome P450 (CYP)-specific probe drugs to simultaneously assess the activity of different CYP isoforms. To improve the clinical applicability of CYP phenotyping, the main objectives of this study were to develop a new cocktail based on probe drugs that are widely used in clinical practice and to test whether alternative sampling methods such as collection of dried blood spots (DBS) or saliva could be used to simplify the sampling process. In a randomized crossover study, a new combination of commercially available probe drugs (the Basel cocktail) was tested for simultaneous phenotyping of CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6 and CYP3A4. Sixteen subjects received low doses of caffeine, efavirenz, losartan, omeprazole, metoprolol and midazolam in different combinations. All subjects were genotyped, and full pharmacokinetic profiles of the probe drugs and their main metabolites were determined in plasma, dried blood spots and saliva samples. The Basel cocktail was well tolerated, and bioequivalence tests showed no evidence of mutual interactions between the probe drugs. In plasma, single timepoint metabolic ratios at 2 h (for CYP2C19 and CYP3A4) or at 8 h (for the other isoforms) after dosing showed high correlations with corresponding area under the concentration-time curve (AUC) ratios (AUC0-24h parent/AUC0-24h metabolite) and are proposed as simple phenotyping metrics. Metabolic ratios in dried blood spots (for CYP1A2 and CYP2C19) or in saliva samples (for CYP1A2) were comparable to plasma ratios and offer the option of minimally invasive or non-invasive phenotyping of these isoforms. This new combination of phenotyping probe drugs can be used without mutual interactions. The proposed sampling timepoints have the potential to facilitate clinical application of phenotyping but require further validation in conditions of altered CYP activity. The use of DBS or saliva samples seems feasible for phenotyping of the selected CYP isoforms.

Monitoring efficacy of commonly used antimalarials by a 14-day in-vivo test in a new settler's camp in endemic zone at Cox's Bazar.

PubMed

Rahman, M R; Hassan, M R; Faiz, M A; Samad, R; Paul, B; Jalil, M A

1998-12-01

The study was done in a new settler's camp "Barachara" under Sadar thana of Cox's Bazar district. It has a total population of 784 of all age groups, registered in the middle of the study period. A prospective evaluation of all cases of fever were done over 12 months, to see the pattern of febrile illness among the population and to compare the therapeutic efficacy of two alternative drug regimens for uncomplicated falciparum malaria (UM). Blood for malarial parasite (MP) was done in all cases of fever and was treated in line with the new clinical case definitions and treatment guidelines for malaria in Bangladesh. Slide positive UM cases were subjected to a "14-day in-vivo test" for therapeutic efficacy testing of antimalarial agents. The two drug regimens were randomised by lottery--a) 3 days oral chloroquine plus single dose sulphadoxin/pyrimethamine (CQ + SP) and, b) 3 days oral quinine plus single dose sulphadoxin/pyrimethamine (Q3 + SP). Drug administration was supervised by the field assistant and was followed up on days 3, 7 and 14 for blood slide examinations and clinical assessment. Sensitive response was observed in 79% of the cases in the CQ + SP group and 84% in the Q3 + SP group. Early treatment failure (persistently febrile and parasitaemic on days 3 or 7) was observed in 16% in the CQ + SP group and 9% in the Q3 + SP group. Both the evaluated drug regimens had less than 20% failures and can be used as alternative first line agents and Q3 + SP regimens can also be used as the second line agents for treatment failure (to chloroquine and/or SP) UM cases in the study area.

Severe Plasmodium knowlesi Malaria in a Tertiary Care Hospital, Sabah, Malaysia

PubMed Central

William, Timothy; Menon, Jayaram; Rajahram, Giri; Chan, Leslie; Ma, Gordon; Donaldson, Samantha; Khoo, Serena; Fredrick, Charlie; Jelip, Jenarun; Anstey, Nicholas M.

2011-01-01

The simian parasite Plasmodium knowlesi causes severe human malaria; the optimal treatment remains unknown. We describe the clinical features, disease spectrum, and response to antimalarial chemotherapy, including artemether-lumefantrine and artesunate, in patients with P. knowlesi malaria diagnosed by PCR during December 2007–November 2009 at a tertiary care hospital in Sabah, Malaysia. Fifty-six patients had PCR-confirmed P. knowlesi monoinfection and clinical records available for review. Twenty-two (39%) had severe malaria; of these, 6 (27%) died. Thirteen (59%) had respiratory distress; 12 (55%), acute renal failure; and 12, shock. None experienced coma. Patients with uncomplicated disease received chloroquine, quinine, or artemether-lumefantrine, and those with severe disease received intravenous quinine or artesunate. Parasite clearance times were 1–2 days shorter with either artemether-lumefantrine or artesunate treatment. P. knowlesi is a major cause of severe and fatal malaria in Sabah. Artemisinin derivatives rapidly clear parasitemia and are efficacious in treating uncomplicated and severe knowlesi malaria. PMID:21762579

Covariation in individuals' sensitivities to bitter compounds: evidence supporting multiple receptor/transduction mechanisms.

PubMed

Delwiche, J F; Buletic, Z; Breslin, P A

2001-07-01

People vary widely in their sensitivities to bitter compounds, but the intercorrelation of these sensitivities is unknown. Our goal was to investigate correlations as a function of individual sensitivities to several bitter compounds representative of different chemical classes and, from these correlations, infer the number and variety of potential bitterness transduction systems for these compounds. Twenty-six subjects rated and ranked quinine HCl, caffeine, (-)-epicatechin, tetralone, L-phenylalanine, L-tryptophan, magnesium sulfate, urea, sucrose octaacetate (SOA), denatonium benzoate, and n-propylthiouracil (PROP) for bitterness. By examining individual differences, ratings and rankings could be grouped into two general clusters--urea/phenylalanine/tryptophan/epicatechin, and quinine/caffeine/SOA/denatonium benzoate/tetralone/magnesium sulfate-none of which contained PROP. When subjects were grouped into the extremes of sensitivity to PROP, a significant difference was found in the bitterness ratings, but not in the rankings. Therefore, there are also subjects who possess diminished absolute sensitivity to bitter stimuli but do not differ from other subjects in their relative sensitivities to these compounds.

Determination of thiram in natural waters using flow-injection with cerium(IV)-quinine chemiluminescence system.

PubMed

Waseem, Amir; Yaqoob, Mohammad; Nabi, Abdul

2010-01-01

A simple and rapid flow-injection chemiluminescence method has been developed for the determination of dithiocarbamate fungicide thiram based on the chemiluminescence reaction of thiram with ceric sulfate and quinine in aqueous sulfuric acid. The present method allowed the determination of thiram in the concentration range of 7.5-2500 ng/mL and the detection limit (signal-to-noise ratio = 3) was 7.5 ng/mL with sample throughput of 120/h. The relative standard deviation was 2.5% for 10 replicate analyses of 500 ng/mL thiram. The effects of foreign species including various anions and cations present in water at environmentally relevant concentrations and some pesticides were also investigated. The proposed method was applied to determine thiram in spiked natural waters using octadecyl bonded phase silica (C(18)) cartridges for solid-phase extraction. The recoveries were in the range 99 +/- 1 to 104 +/- 1%. Copyright (c) 2009 John Wiley & Sons, Ltd.

Combinatorial approaches with selected phytochemicals to increase antibiotic efficacy against Staphylococcus aureus biofilms.

PubMed

Abreu, Ana Cristina; Saavedra, Maria José; Simões, Lúcia C; Simões, Manuel

2016-10-01

Combinations of selected phytochemicals (reserpine, pyrrolidine, quinine, morin and quercetin) with antibiotics (ciprofloxacin, tetracycline and erythromycin) were tested on the prevention and control of Staphylococcus aureus biofilms. The phytochemicals were also studied for their ability to avoid antibiotic adaptation and to inhibit antibiotic efflux pumps. Morin, pyrrolidine and quercetin at subinhibitory concentrations had significant effects in biofilm prevention and/or control when applied alone and combined with antibiotics. Synergism between antibiotics and phytochemicals was found especially against biofilms of NorA overexpressing strain S. aureus SA1199B. This strain when growing with subinhibitory concentrations of ciprofloxacin developed increased tolerance to this antibiotic. However, this was successfully reversed by quinine and morin. In addition, reserpine and quercetin showed significant efflux pump inhibition. The overall results demonstrate the role of phytochemicals in co-therapies to promote more efficient treatments and decrease antimicrobial resistance to antibiotics, with substantial effects against S. aureus in both planktonic and biofilm states.

Mechanism-Based Tumor-Targeting Drug Delivery System. Validation of Efficient Vitamin Receptor-Mediated Endocytosis and Drug Release

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

Chen, S.; Wong, S.; Zhao, X.

An efficient mechanism-based tumor-targeting drug delivery system, based on tumor-specific vitamin-receptor mediated endocytosis, has been developed. The tumor-targeting drug delivery system is a conjugate of a tumor-targeting molecule (biotin: vitamin H or vitamin B-7), a mechanism-based self-immolative linker and a second-generation taxoid (SB-T-1214) as the cytotoxic agent. This conjugate (1) is designed to be (i) specific to the vitamin receptors overexpressed on tumor cell surface and (ii) internalized efficiently through receptor-mediated endocytosis, followed by smooth drug release via glutathione-triggered self-immolation of the linker. In order to monitor and validate the sequence of events hypothesized, i.e., receptor-mediated endocytosis of the conjugate,more » drug release, and drug-binding to the target protein (microtubules), three fluorescent/fluorogenic molecular probes (2, 3, and 4) were designed and synthesized. The actual occurrence of these processes was unambiguously confirmed by means of confocal fluorescence microscopy (CFM) and flow cytometry using L1210FR leukemia cells, overexpressing biotin receptors. The molecular probe 4, bearing the taxoid linked to fluorescein, was also used to examine the cell specificity (i.e., efficacy of receptor-based cell targeting) for three cell lines, L1210FR (biotin receptors overexpressed), L1210 (biotin receptors not overexpressed), and WI38 (normal human lung fibroblast, biotin receptor negative). As anticipated, the molecular probe 4 exhibited high specificity only to L1210FR. To confirm the direct correlation between the cell-specific drug delivery and anticancer activity of the probe 4, its cytotoxicity against these three cell lines was also examined. The results clearly showed a good correlation between the two methods. In the same manner, excellent cell-specific cytotoxicity of the conjugate 1 (without fluorescein attachment to the taxoid) against the same three cell lines was confirmed. This mechanism-based tumor-targeting drug delivery system will find a range of applications.« less

Health worker and policy-maker perspectives on use of intramuscular artesunate for pre-referral and definitive treatment of severe malaria at health posts in Ethiopia.

PubMed

Kefyalew, Takele; Kebede, Zelalem; Getachew, Dawit; Mukanga, David; Awano, Tessema; Tekalegne, Agonafer; Batisso, Esey; Edossa, Wasihun; Mekonnen, Emebet; Tibenderana, James; Baba, Ebenezer Sheshi; Shumba, Constance; Nankabirwa, Joaniter I; Hamade, Prudence

2016-10-18

The World Health Organization (WHO) recommends injectable artesunate given either intravenously or by the intramuscular route for definitive treatment for severe malaria and recommends a single intramuscular dose of intramuscular artesunate or intramuscular artemether or intramuscular quinine, in that order of preference as pre-referral treatment when definitive treatment is not possible. Where intramuscular injections are not available, children under 6 years may be administered a single dose of rectal artesunate. Although the current malaria treatment guidelines in Ethiopia recommend intra-rectal artesunate or alternatively intramuscular artemether or intramuscular quinine as pre-referral treatment for severe malaria at the health posts, there are currently no WHO prequalified suppliers of intra-rectal artesunate and when available, its use is limited to children under 6 years of age leaving a gap for the older age groups. Intramuscular artesunate is not part of the drugs recommended for pre-referral treatment in Ethiopia. This study assessed the perspectives of health workers, and policy-makers on the use of intramuscular artesunate as a pre-referral and definitive treatment for severe malaria at the health post level. In-depth interviews were held with 101 individuals including health workers, malaria focal persons, and Regional Health Bureaus from Oromia and southern nations, nationalities, and peoples' region, as well as participants from the Federal Ministry of Health and development partners. An interview guide was used in the data collection and thematic content analysis was employed for analysis. Key findings from this study are: (1) provision of intramuscular artesunate as pre-referral and definitive treatment for severe malaria at health posts could be lifesaving; (2) with adequate training, and provision of facilities including beds, health posts can provide definitive treatment for severe malaria using intramuscular artesunate where referral is delayed or not possible; (3) health workers at health centres and hospitals frequently use the intravenous route because it allows for co-administration of other drugs, but they find the intramuscular route easier to use at the health post level; (4) the reasons commonly cited against the management of severe malaria using intramuscular artesunate at health post level were: lack of capacity to manage complications and fear of irrational drug use; (5) use of intramuscular artesunate at health post level will require evidence on safety and feasibility before policy shift. From the perspective of health workers, use of intramuscular artesunate as pre-referral treatment of severe malaria cases at the health post is possible but dependent on training and availability of skilled workers. Use of intramuscular artesunate as definitive treatment at health posts was not supported, however, operational research to establish its feasibility, safety and efficacy was recommended to guide any implementation of such an intervention.

Measurement of caspase-2 activation during different anti-tumor drugs induced apoptosis by FRET technique

NASA Astrophysics Data System (ADS)

Lin, Juqiang; Zeng, Shaoqun; Luo, Qingming; Rong, Chen; Zhang, Zhihong

2007-11-01

Caspase-2 is important for the engagement of the mitochondrial apoptotic pathway, in the presence of DNA-damaging agents, such as cisplatin; however, the mechanism by which caspase-2 executes apoptosis remains obscure. In this study, we carried out the measurements of the dynamics of caspase-2 activation in a single living cell by a FRET (fluorescence resonance energy transfer) probe. A FRET probe was constructed that encoded a CRS (caspase-2 recognition site) fused with a cyan fluorescent protein (CFP) and a red fluorescent protein (DsRed) (CFP-CRS-DsRed). Using this probe, we found that during TRAIL-induced apoptosis, caspase-2 was not activated, and caspase-2 activation occurred in etoposide and cisplatin treated cells. However, during cisplatin-induced apoptosis caspase-2 activation was initiated much earlier than that of etoposide. Cisplatin and etoposide is one of the most broadly used drugs in the Clinical applications of cancer chemotherapy, and TRAIL, which belongs to the TNF family proteins, can selectively induce apoptosis in many transformed cells but not in normal cells. Most of anticancer drugs can induce apoptosis mediated by the activation of caspase pathway. Thus, the perfect synergistic effect group of multi-drug can be selected by using our FRET probe.

STUDIES ON THE CHEMOTHERAPY OF CHLOROQUINERESISTANT FALCIPARUM MALARIA, VIVAX MALARIA, AND PRIMAQUINE HEMOLYSIS.

DTIC Science & Technology

to chloroquine, hydroxychloroquine , amodiaquin, and 377C54, and is sensitive to pyri methamine and quinine. The three strains from Southeast Asia...are resistant to chloroquine, hydroxychloroquine , amodiaquin, atabrine, chlorguanide, and 377C54; these three strains vary in their response to

A lactate dehydrogenase ELISA-based assay for the in vitro determination of Plasmodium berghei sensitivity to anti-malarial drugs.

PubMed

Orjuela-Sánchez, Pamela; Duggan, Erika; Nolan, John; Frangos, John A; Carvalho, Leonardo Jm

2012-11-05

Plasmodium berghei rodent malaria is a well-known model for the investigation of anti-malarial drug efficacy in vivo. However, the availability of drug in vitro assays in P. berghei is reduced when compared with the spectrum of techniques existing for Plasmodium falciparum. New alternatives to the current manual or automated methods described for P. berghei are attractive. The present study reports a new ELISA drug in vitro assay for P. berghei using two monoclonal antibodies against the parasite lactate dehydrogenase (pLDH). This procedure includes a short-in vitro culture, the purification of schizonts and the further generation of synchronized mice infections. Early stages of the parasite are then incubated against different concentrations of anti-malarial drugs using micro-plates. The novelty of this procedure in P. berghei relies on the quantification of the drug activity derived from the amount of pLDH estimated by an ELISA assay using two monoclonal antibodies: 14C1 and 19G7. The IC₅₀s obtained through the ELISA assay were compared with those from the micro-test. The initial parameters of the synchronized samples used in the in vitro assays were a parasitaemia of 0.5% and haematocrit of 1%, with an incubation period of 22 hours at 36.5°C. pLDH detection using a 14C1 coating at 10 μg/ml and 19G7 at 2.5 × 10⁻³ μg/ml provided good readouts of optical densities with low background in negative controls and specific detection levels for all parasite stages. IC₅₀s values derived from the ELISA assay for artesunate, chloroquine, amodiaquine and quinine were: 15, 7, 2, and 144 nM, respectively. When artesunate and chloroquine IC₅₀s were evaluated using the micro-test similar values were obtained. This ELISA-based in vitro drug assay is easy to implement, fast, and avoids the use radioisotopes or expensive equipment. The utility of this simple assay for screening anti-malarial drug activity against P. berghei in vitro is demonstrated.

Safety of artemisinins in first trimester of prospectively followed pregnancies: an observational study.

PubMed

Moore, Kerryn A; Simpson, Julie A; Paw, Moo Kho; Pimanpanarak, MuPawJay; Wiladphaingern, Jacher; Rijken, Marcus J; Jittamala, Podjanee; White, Nicholas J; Fowkes, Freya J I; Nosten, François; McGready, Rose

2016-05-01

Artemisinins, the most effective antimalarials available, are not recommended for falciparum malaria during the first trimester of pregnancy because of safety concerns. Therefore, quinine is used despite its poor effectiveness. Assessing artemisinin safety requires weighing the risks of malaria and its treatment. We aimed to assess the effect of first-trimester malaria and artemisinin treatment on miscarriage and major congenital malformations. In this observational study, we assessed data from antenatal clinics on the Thai-Myanmar border between Jan 1, 1994, and Dec 31, 2013. We included women who presented to antenatal clinics during their first trimester with a viable fetus. Women were screened for malaria, and data on malaria, antimalarial treatment, and birth outcomes were collected. The relationship between artemisinin treatments (artesunate, dihydroartemisinin, or artemether) and miscarriage or malformation was assessed using Cox regression with left-truncation and time-varying exposures. Of 55 636 pregnancies registered between 1994 and 2013, 25 485 pregnancies were analysed for first-trimester malaria and miscarriage, in which 2558 (10%) had first-trimester malaria. The hazard of miscarriage increased 1·61-fold after an initial first-trimester falciparum episode (95% CI 1·32-1·97; p<0·0001), 3·24-fold following falciparum recurrence (2·24-4·68; p<0·0001), and 2·44-fold (1·01-5·88; p=0·0473) following recurrent symptomatic vivax malaria. No difference was noted in miscarriage in first-line falciparum treatments with artemisinin (n=183) versus quinine (n=842; HR 0·78 [95% CI 0·45-1·34]; p=0·3645) or in risk of major congenital malformations (two [2%] of 109 [95% CI 0·22-6·47] versus eight (1%) of 641 [0·54-2·44], respectively). First-trimester falciparum and vivax malaria both increase the risk of miscarriage. We noted no evidence of an increased risk of miscarriage or of major congenital malformations associated with first-line treatment with an artemisinin derivative compared with quinine. In view of the low efficacy of quinine and wide availability of highly effective artemisinin-based combination therapies, it is time to reconsider first-trimester antimalarial treatment recommendations. The Wellcome Trust and The Bill & Melinda Gates Foundation. Copyright © 2016 Moore et al. Open Access article distributed under the terms of CC BY. Published by Elsevier Ltd.. All rights reserved.

Dendritic polymer imaging systems for the evaluation of conjugate uptake and cleavage

NASA Astrophysics Data System (ADS)

Krüger, Harald R.; Nagel, Gregor; Wedepohl, Stefanie; Calderón, Marcelo

2015-02-01

Fluorescent turn-on probes combined with polymers have a broad range of applications, e.g. for intracellular sensing of ions, small molecules, or DNA. In the field of polymer therapeutics, these probes can be applied to extend the in vitro characterization of novel conjugates beyond cytotoxicity and cellular uptake studies. This is particularly true in cases in which polymer conjugates contain drugs attached by cleavable linkers. Better information on the intracellular linker cleavage and drug release would allow a faster evaluation and optimization of novel polymer therapeutic concepts. We therefore developed a fluorescent turn-on probe that enables direct monitoring of pH-mediated cleavage processes over time. This is achieved by exploiting the fluorescence resonance energy transfer (FRET) between two dyes that have been coupled to a dendritic polymer. We demonstrate the use of this probe to evaluate polymer uptake and intracellular release of cargo in a cell based microplate assay that is suitable for high throughput screening.Fluorescent turn-on probes combined with polymers have a broad range of applications, e.g. for intracellular sensing of ions, small molecules, or DNA. In the field of polymer therapeutics, these probes can be applied to extend the in vitro characterization of novel conjugates beyond cytotoxicity and cellular uptake studies. This is particularly true in cases in which polymer conjugates contain drugs attached by cleavable linkers. Better information on the intracellular linker cleavage and drug release would allow a faster evaluation and optimization of novel polymer therapeutic concepts. We therefore developed a fluorescent turn-on probe that enables direct monitoring of pH-mediated cleavage processes over time. This is achieved by exploiting the fluorescence resonance energy transfer (FRET) between two dyes that have been coupled to a dendritic polymer. We demonstrate the use of this probe to evaluate polymer uptake and intracellular release of cargo in a cell based microplate assay that is suitable for high throughput screening. Electronic supplementary information (ESI) available: Including detailed synthetic procedures of the dye and conjugate synthesis, as well as cellular uptake and inhibitor studies. See DOI: 10.1039/c4nr04467c

Early Probe and Drug Discovery in Academia: A Minireview.

PubMed

Roy, Anuradha

2018-02-09

Drug discovery encompasses processes ranging from target selection and validation to the selection of a development candidate. While comprehensive drug discovery work flows are implemented predominantly in the big pharma domain, early discovery focus in academia serves to identify probe molecules that can serve as tools to study targets or pathways. Despite differences in the ultimate goals of the private and academic sectors, the same basic principles define the best practices in early discovery research. A successful early discovery program is built on strong target definition and validation using a diverse set of biochemical and cell-based assays with functional relevance to the biological system being studied. The chemicals identified as hits undergo extensive scaffold optimization and are characterized for their target specificity and off-target effects in in vitro and in animal models. While the active compounds from screening campaigns pass through highly stringent chemical and Absorption, Distribution, Metabolism, and Excretion (ADME) filters for lead identification, the probe discovery involves limited medicinal chemistry optimization. The goal of probe discovery is identification of a compound with sub-µM activity and reasonable selectivity in the context of the target being studied. The compounds identified from probe discovery can also serve as starting scaffolds for lead optimization studies.

2D IR spectroscopy reveals the role of water in the binding of channel-blocking drugs to the influenza M2 channel.

PubMed

Ghosh, Ayanjeet; Wang, Jun; Moroz, Yurii S; Korendovych, Ivan V; Zanni, Martin; DeGrado, William F; Gai, Feng; Hochstrasser, Robin M

2014-06-21

Water is an integral part of the homotetrameric M2 proton channel of the influenza A virus, which not only assists proton conduction but could also play an important role in stabilizing channel-blocking drugs. Herein, we employ two dimensional infrared (2D IR) spectroscopy and site-specific IR probes, i.e., the amide I bands arising from isotopically labeled Ala30 and Gly34 residues, to probe how binding of either rimantadine or 7,7-spiran amine affects the water dynamics inside the M2 channel. Our results show, at neutral pH where the channel is non-conducting, that drug binding leads to a significant increase in the mobility of the channel water. A similar trend is also observed at pH 5.0 although the difference becomes smaller. Taken together, these results indicate that the channel water facilitates drug binding by increasing its entropy. Furthermore, the 2D IR spectral signatures obtained for both probes under different conditions collectively support a binding mechanism whereby amantadine-like drugs dock in the channel with their ammonium moiety pointing toward the histidine residues and interacting with a nearby water cluster, as predicted by molecular dynamics simulations. We believe these findings have important implications for designing new anti-influenza drugs.

Influences of Realgar-Indigo naturalis, A Traditional Chinese Medicine Formula, on the Main CYP450 Activities in Rats Using a Cocktail Method

PubMed Central

Xu, Huan-Hua; Hao, Fei-Ran; Wang, Mei-Xi; Ren, Si-Jia; Li, Ming; Tan, Hong-Ling; Wang, Yu-Guang; Tang, Xiang-Lin; Xiao, Cheng-Rong; Liang, Qian-De

2017-01-01

The purpose of this work was to study the influences of Realgar-Indigo naturalis (RIF) and its principal element realgar on 4 main cytochrome P450 enzymes activities in rats. A simple and efficient cocktail method was developed to detect the four probe drugs simultaneously. In this study, Wistar rats were administered intragastric RIF and realgar for 14 days; mixed probe drugs were injected into rats by caudal vein. Through analyzing the pharmacokinetic parameter of mixed probe drugs in rats, we can calculate the CYPs activities. The results showed that RIF could inhibit CYP1A2 enzyme activity and induce CYP2C11 enzyme activity significantly. Interestingly, in realgar high dosage group, CYP3A1/2 enzyme activity was inhibited significantly, and different dosage of realgar manifested a good dose-dependent manner. The RIF results indicated that drug coadministrated with RIF may need to be paid attention in relation to drug-drug interactions (DDIs). Realgar, a toxic traditional Chinese medicine (TCM), does have curative effect on acute promyelocytic leukemia (APL). Its toxicity studies should be focused on. We found that, in realgar high dosage group, CYP3A1/2 enzymes activity was inhibited. This phenomenon may explain its potential toxicity mechanism. PMID:28421119

Influences of Realgar-Indigo naturalis, A Traditional Chinese Medicine Formula, on the Main CYP450 Activities in Rats Using a Cocktail Method.

PubMed

Xu, Huan-Hua; Hao, Fei-Ran; Wang, Mei-Xi; Ren, Si-Jia; Li, Ming; Tan, Hong-Ling; Wang, Yu-Guang; Tang, Xiang-Lin; Xiao, Cheng-Rong; Liang, Qian-De; Gao, Yue; Ma, Zeng-Chun

2017-01-01

The purpose of this work was to study the influences of Realgar- Indigo naturalis (RIF) and its principal element realgar on 4 main cytochrome P450 enzymes activities in rats. A simple and efficient cocktail method was developed to detect the four probe drugs simultaneously. In this study, Wistar rats were administered intragastric RIF and realgar for 14 days; mixed probe drugs were injected into rats by caudal vein. Through analyzing the pharmacokinetic parameter of mixed probe drugs in rats, we can calculate the CYPs activities. The results showed that RIF could inhibit CYP1A2 enzyme activity and induce CYP2C11 enzyme activity significantly. Interestingly, in realgar high dosage group, CYP3A1/2 enzyme activity was inhibited significantly, and different dosage of realgar manifested a good dose-dependent manner. The RIF results indicated that drug coadministrated with RIF may need to be paid attention in relation to drug-drug interactions (DDIs). Realgar, a toxic traditional Chinese medicine (TCM), does have curative effect on acute promyelocytic leukemia (APL). Its toxicity studies should be focused on. We found that, in realgar high dosage group, CYP3A1/2 enzymes activity was inhibited. This phenomenon may explain its potential toxicity mechanism.

In vivo Phenotyping Methods: Cytochrome P450 Probes with Emphasis on the Cocktail Approach.

PubMed

Keller, Guillermo Alberto; Gago, María Laura Ferreirós; Diez, Roberto Alejandro; Di Girolamo, Guillermo

2017-01-01

Differences in drug response among patients are common. Most major drugs are effective in only 25 to 60 percent of the patients, in part due to the CYP enzymes, whose activity vary up to 50-fold between individuals for some index metabolic reactions. Several factors affect CYP activity, among which genetic polymorphisms have been studied as the major cause for long time. Age, gender, disease states, and environmental influences such as smoking, concomitant drug treatment or exposure to environmental chemicals are also important. This article reviews the available literature on multiple phenotypes assessment as an important tool to predict possible therapeutic failures or toxic reactions to conventional drug doses during patient evaluation. Probe drugs can be used in various combinations allowing for the in vivo assessment of multiple pathways of drug metabolism in a single experiment, configuring a new tool known as phenotyping "cocktails". There are several drug cocktails with different advantages and disadvantages. Most of them have sufficient clinical evidence and data validation to support their use in clinical setting as a surrogate for the risk of adverse reaction in the course of therapy, leading to a better balance between efficacy and safety. Probes characteristics and metabolic ratio measurements are important in the evaluation of phenotyping cocktails as near-future applications. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

A Pharmacogenetic Screening Experiment Demonstrating Principles of Genetic Constitution on Drug Metabolism.

ERIC Educational Resources Information Center

Robbins, Doris K.; Wedlund, Peter J.

1990-01-01

A laboratory experiment designed to provide rapid, inexpensive student exposure to pharmacogenetics in drug elimination and patient therapy is described. The test, performed on students, determines expression of a drug metabolism enzyme following ingestion of a probe drug. (Author/MSE)

Intracellular water - an overlooked drug target? Cisplatin impact in cancer cells probed by neutrons.

PubMed

Marques, M P M; Batista de Carvalho, A L M; Sakai, V Garcia; Hatter, L; Batista de Carvalho, L A E

2017-01-25

The first neutron scattering study on human nucleated cells is reported, addressing the subject of solvent-slaving to a drug by probing intracellular water upon drug exposure. Inelastic and quasi-elastic neutron scattering spectroscopy with isotope labelling was applied for monitoring interfacial water response to the anticancer drug cisplatin, in the low prognosis human metastatic breast cancer cells MDA-MB-231. Optical vibrational data were also obtained for lyophilised cells. Concentration-dependent dynamical changes evidencing a progressive mobility reduction were unveiled between untreated and cisplatin-exposed samples, concurrent with variations in the native organisation of water molecules within the intracellular medium as a consequence of drug action. The results thus obtained yielded a clear picture of the intracellular water response to cisplatin and constitute the first reported experimental proof of a drug impact on the cytomatrix by neutron techniques. This is an innovative way of tackling a drug's pharmacodynamics, searching for alternative targets of drug action.

Treatment of fevers prior to introducing rapid diagnostic tests for malaria in registered drug shops in Uganda.

PubMed

Mbonye, Anthony K; Lal, Sham; Cundill, Bonnie; Hansen, Kristian Schultz; Clarke, Siân; Magnussen, Pascal

2013-04-16

Since drug shops play an important role in treatment of fever, introducing rapid diagnostic tests (RDTs) for malaria at drug shops may have the potential of targeting anti-malarial drugs to those with malaria parasites and improve rational drug use. As part of a cluster randomized trial to examine impact on appropriate treatment of malaria in drug shops in Uganda and adherence to current malaria treatment policy guidelines, a survey was conducted to estimate baseline prevalence of, and factors associated with, appropriate treatment of malaria to enable effective design and implementation of the cluster randomized trial. A survey was conducted within 20 geographical clusters of drug shops from May to September 2010 in Mukono district, central Uganda. A cluster was defined as a parish representing a cluster of drug shops. Data was collected using two structured questionnaires: a provider questionnaire to capture data on drug shops (n=65) including provider characteristics, knowledge on treatment of malaria, previous training received, type of drugs stocked, reported drug sales, and record keeping practices; and a patient questionnaire to capture data from febrile patients (n=540) exiting drug shops on presenting symptoms, the consultation process, treatment received, and malaria diagnoses. Malaria diagnosis made by drug shop vendors were confirmed by the study team through microscopy examination of a blood slide to ascertain whether appropriate treatment was received. Among febrile patients seen at drug shops, 35% had a positive RDT result and 27% had a positive blood slide. Many patients (55%) had previously sought care from another drug shop prior to this consultation. Three quarters (73%) of all febrile patients seen at drug shops received an anti-malarial, of whom 39% received an ACT and 33% received quinine. The rest received another non-artemisinin monotherapy. Only one third (32%) of patients with a positive blood slide had received treatment with Coartem® while 34% of those with a negative blood slide had not received an anti-malarial. Overall appropriate treatment was 34 (95% CI: 28 - 40) with substantial between-cluster variation, ranging from 1% to 55%. In this setting, the proportion of malaria patients receiving appropriate ACT treatment at drug shops was low. This was due to the practice of presumptive treatment, inadequate training on malaria management and lack of knowledge that Coartem® was the recommended first-line treatment for malaria. There is urgent need for interventions to improve treatment of malaria at these outlets.

Treatment of fevers prior to introducing rapid diagnostic tests for malaria in registered drug shops in Uganda

PubMed Central

2013-01-01

Background Since drug shops play an important role in treatment of fever, introducing rapid diagnostic tests (RDTs) for malaria at drug shops may have the potential of targeting anti-malarial drugs to those with malaria parasites and improve rational drug use. As part of a cluster randomized trial to examine impact on appropriate treatment of malaria in drug shops in Uganda and adherence to current malaria treatment policy guidelines, a survey was conducted to estimate baseline prevalence of, and factors associated with, appropriate treatment of malaria to enable effective design and implementation of the cluster randomized trial. Methods A survey was conducted within 20 geographical clusters of drug shops from May to September 2010 in Mukono district, central Uganda. A cluster was defined as a parish representing a cluster of drug shops. Data was collected using two structured questionnaires: a provider questionnaire to capture data on drug shops (n=65) including provider characteristics, knowledge on treatment of malaria, previous training received, type of drugs stocked, reported drug sales, and record keeping practices; and a patient questionnaire to capture data from febrile patients (n=540) exiting drug shops on presenting symptoms, the consultation process, treatment received, and malaria diagnoses. Malaria diagnosis made by drug shop vendors were confirmed by the study team through microscopy examination of a blood slide to ascertain whether appropriate treatment was received. Results Among febrile patients seen at drug shops, 35% had a positive RDT result and 27% had a positive blood slide. Many patients (55%) had previously sought care from another drug shop prior to this consultation. Three quarters (73%) of all febrile patients seen at drug shops received an anti-malarial, of whom 39% received an ACT and 33% received quinine. The rest received another non-artemisinin monotherapy. Only one third (32%) of patients with a positive blood slide had received treatment with Coartem® while 34% of those with a negative blood slide had not received an anti-malarial. Overall appropriate treatment was 34 (95% CI: 28 – 40) with substantial between-cluster variation, ranging from 1% to 55%. Conclusion In this setting, the proportion of malaria patients receiving appropriate ACT treatment at drug shops was low. This was due to the practice of presumptive treatment, inadequate training on malaria management and lack of knowledge that Coartem® was the recommended first-line treatment for malaria. There is urgent need for interventions to improve treatment of malaria at these outlets. PMID:23587179

A SYBR Green 1-based in vitro test of susceptibility of Ghanaian Plasmodium falciparum clinical isolates to a panel of anti-malarial drugs.

PubMed

Quashie, Neils B; Duah, Nancy O; Abuaku, Benjamin; Quaye, Lydia; Ayanful-Torgby, Ruth; Akwoviah, George A; Kweku, Margaret; Johnson, Jacob D; Lucchi, Naomi W; Udhayakumar, Venkatachalam; Duplessis, Christopher; Kronmann, Karl C; Koram, Kwadwo A

2013-12-17

Based on report of declining efficacy of chloroquine, Ghana shifted to the use of artemisinin-based combination therapy (ACT) in 2005 as the first-line anti-malarial drug. Since then, there has not been any major evaluation of the efficacy of anti-malarial drugs in Ghana in vitro. The sensitivity of Ghanaian Plasmodium falciparum isolates to anti-malarial drugs was, therefore, assessed and the data compared with that obtained prior to the change in the malaria treatment policy. A SYBR Green 1 fluorescent-based in vitro drug sensitivity assay was used to assess the susceptibility of clinical isolates of P. falciparum to a panel of 12 anti-malarial drugs in three distinct eco-epidemiological zones in Ghana. The isolates were obtained from children visiting health facilities in sentinel sites located in Hohoe, Navrongo and Cape Coast municipalities. The concentration of anti-malarial drug inhibiting parasite growth by 50% (IC50) for each drug was estimated using the online program, ICEstimator. Pooled results from all the sentinel sites indicated geometric mean IC50 values of 1.60, 3.80, 4.00, 4.56, 5.20, 6.11, 10.12, 28.32, 31.56, 93.60, 107.20, and 8952.50 nM for atovaquone, artesunate, dihydroartemisin, artemether, lumefantrine, amodiaquine, mefloquine, piperaquine, chloroquine, tafenoquine, quinine, and doxycycline, respectively. With reference to the literature threshold value indicative of resistance, the parasites showed resistance to all the test drugs except the artemisinin derivatives, atovaquone and to a lesser extent, lumefantrine. There was nearly a two-fold decrease in the IC50 value determined for chloroquine in this study compared to that determined in 2004 (57.56 nM). This observation is important, since it suggests a significant improvement in the efficacy of chloroquine, probably as a direct consequence of reduced drug pressure after cessation of its use. Compared to that measured prior to the change in treatment policy, significant elevation of artesunate IC50 value was observed. The results also suggest the existence of possible cross-resistance among some of the test drugs. Ghanaian P. falciparum isolates, to some extent, have become susceptible to chloroquine in vitro, however the increasing trend in artesunate IC50 value observed should be of concern. Continuous monitoring of ACT in Ghana is recommended.

Inhibitors of Fatty Acid Synthase for Prostate Cancer. Revision

DTIC Science & Technology

2013-05-01

the fact that is recognized saturated fat as a substrate. This report summarizes the the immense amount of structure-activity-relationships for new...indazole ring of structure 3a; and coupling of various aldehydes and ,- unsaturated ethers to the 5 position of the quinine under acidic

Polymeric nanotheranostics for real-time non-invasive optical imaging of breast cancer progression and drug release.

PubMed

Ferber, Shiran; Baabur-Cohen, Hemda; Blau, Rachel; Epshtein, Yana; Kisin-Finfer, Einat; Redy, Orit; Shabat, Doron; Satchi-Fainaro, Ronit

2014-09-28

Polymeric nanocarriers conjugated with low molecular weight drugs are designed in order to improve their efficacy and toxicity profile. This approach is particularly beneficial for anticancer drugs, where the polymer-drug conjugates selectively accumulate at the tumor site, due to the enhanced permeability and retention (EPR) effect. The conjugated drug is typically inactive, and upon its pH- or enzymatically-triggered release from the carrier, it regains its therapeutic activity. These settings lack information regarding drug-release time, kinetics and location. Thereby, real-time non-invasive intravital monitoring of drug release is required for theranostics (therapy and diagnostics). We present here the design, synthesis and characterization of a theranostic nanomedicine, based on N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer, owing its fluorescence-based monitoring of site-specific drug release to a self-quenched near-infrared fluorescence (NIRF) probe. We designed two HPMA copolymer-based systems that complement to a theranostic nanomedicine. The diagnostic system consists of self-quenched Cy5 (SQ-Cy5) as a reporter probe and the therapeutic system is based on the anticancer agent paclitaxel (PTX). HPMA copolymer-PTX/SQ-Cy5 systems enable site-specific release upon enzymatic degradation in cathepsin B-overexpressing breast cancer cells. The release of the drug occurs concomitantly with the activation of the fluorophore to its Turn-ON state. HPMA copolymer-SQ-Cy5 exhibits preferable body distribution and drug release compared with the free drug and probe when administered to cathepsin B-overexpressing 4T1 murine mammary adenocarcinoma-bearing mice. This approach of co-delivery of two complementary systems serves as a proof-of-concept for real-time deep tissue intravital orthotopic monitoring and may have the potential use in clinical utility as a theranostic nanomedicine. Copyright © 2014. Published by Elsevier Ireland Ltd.

Molecular imaging probe development: a chemistry perspective

PubMed Central

Nolting, Donald D; Nickels, Michael L; Guo, Ning; Pham, Wellington

2012-01-01

Molecular imaging is an attractive modality that has been widely employed in many aspects of biomedical research; especially those aimed at the early detection of diseases such as cancer, inflammation and neurodegenerative disorders. The field emerged in response to a new research paradigm in healthcare that seeks to integrate detection capabilities for the prediction and prevention of diseases. This approach made a distinct impact in biomedical research as it enabled researchers to leverage the capabilities of molecular imaging probes to visualize a targeted molecular event non-invasively, repeatedly and continuously in a living system. In addition, since such probes are inherently compact, robust, and amenable to high-throughput production, these probes could potentially facilitate screening of preclinical drug discovery, therapeutic assessment and validation of disease biomarkers. They could also be useful in drug discovery and safety evaluations. In this review, major trends in the chemical synthesis and development of positron emission tomography (PET), optical and magnetic resonance imaging (MRI) probes are discussed. PMID:22943038

Factors associated with contracting malaria in Ward 29 of Shamva District, Zimbabwe, 2014.

PubMed

Muchena, Gladwin; Gombe, Notion; Takundwa, Lucia; Tshimanga, Mufuta; Bangure, Donewell; Masuka, Nyasha; Juru, Tsitsi

2017-04-25

Malaria cases at Wadzanayi Clinic in Shamva District, Zimbabwe, increased drastically, surpassing the epidemic threshold, in week four of December 2013. This rise was sustained, which necessitated an investigation of the outbreak. To identify risk factors and system weaknesses to improve epidemic preparedness and response. An unmatched 1:1 case-control study was conducted in Ward 29 of Shamva District in Zimbabwe. Epidemic preparedness and response were assessed using the Zimbabwean epidemic preparedness and response guidelines. The sociodemographic characteristics of all participants were similar, except for gender. The risk factors for contracting malaria were performing early morning chores (odds ratio (OR) 2.75; 95% confidence interval (CI) 1.20 - 6.32), having a body of water near the home (OR 3.41; 95% CI 1.62 - 7.20) and having long grass near the home (OR 2.61; 95% CI 1.10 - 6.37). Protective factors were staying indoors at night (OR 0.13; 95% CI 0.06 - 0.28) and staying in a sprayed home (OR 0.36; 95% CI 0.21 - 0.92). All cases were diagnosed with a malaria rapid diagnostic test. All complicated cases were treated with quinine. Four out of 58 uncomplicated cases were treated with quinine. The rest were treated with co-artemether. There was no documentation of the outbreak response by the district health executive. Respraying (indoor residual spraying) was carried out, with a coverage of 78% of rooms sprayed. One nurse out of seven at Wadzanayi Clinic was trained in integrated disease surveillance and response, and malaria case management. District malaria thresholds were outdated. Malaria commodities such as drugs and sprays did not have reorder limits. This study re-emphasises the importance of environmental- and personal-level factors as determinants of malaria. Poor out-break preparedness and response may have propagated the malaria outbreak in this setting. Health education and the use of mosquito repellants should be emphasised. Larvicide may reduce the malaria burden. Epidemic preparedness and response need to be strengthened. Outbreak investigation remains important. This study emphasises the need for malaria interventions to be tailored to locally prevailing determinants to avert outbreaks.

CYP3A4 substrate selection and substitution in the prediction of potential drug-drug interactions.

PubMed

Galetin, Aleksandra; Ito, Kiyomi; Hallifax, David; Houston, J Brian

2005-07-01

The complexity of in vitro kinetic phenomena observed for CYP3A4 substrates (homo- or heterotropic cooperativity) confounds the prediction of drug-drug interactions, and an evaluation of alternative and/or pragmatic approaches and substrates is needed. The current study focused on the utility of the three most commonly used CYP3A4 in vitro probes for the prediction of 26 reported in vivo interactions with azole inhibitors (increase in area under the curve ranged from 1.2 to 24, 50% in the range of potent inhibition). In addition to midazolam, testosterone, and nifedipine, quinidine was explored as a more "pragmatic" substrate due to its kinetic properties and specificity toward CYP3A4 in comparison with CYP3A5. Ki estimates obtained in human liver microsomes under standardized in vitro conditions for each of the four probes were used to determine the validity of substrate substitution in CYP3A4 drug-drug interaction prediction. Detailed inhibitor-related (microsomal binding, depletion over incubation time) and substrate-related factors (cooperativity, contribution of other metabolic pathways, or renal excretion) were incorporated in the assessment of the interaction potential. All four CYP3A4 probes predicted 69 to 81% of the interactions with azoles within 2-fold of the mean in vivo value. Comparison of simple and multisite mechanistic models and interaction prediction accuracy for each of the in vitro probes indicated that midazolam and quinidine in vitro data provided the best assessment of a potential interaction, with the lowest bias and the highest precision of the prediction. Further investigations with a wider range of inhibitors are required to substantiate these findings.

[Pharmacologists in the camps in the Third Reich--part second].

PubMed

Labuzek, Krzysztof; Prusek, Katarzyna; Gonciarz, Maciej; Okopień, Boguslaw

2013-10-01

SS Hygiene Institute provided adequate funding for research on the treatment of mycobacterial infections, and two scientists who became famous in the subject were Dr. Waldemar Hoven (KL Buchenwald) and Dr. Kurt Heissmeyer (KL Neuengamme). They conducted researches not only on adult prisoners, but also on the Jewish children. Studies of tuberculosis were also conducted under the auspices of the German Medical Association by Dr. Rudolf Brachtel. In turn, Dr. Klaus Schilling dealt with the treatment and immunoprophylaxis of malaria. He tested such substances, as pyramidon, aspirin, quinine and atebrin on more than 1200 prisoners. These sulfonamide-derived drugs, were also studied by prof. Karl Gebhardt and Dr. Fritz Fischer. They assessed the efficacy of these drugs in the treatment of "dirty" wounds incurred by German soldiers. Dr. Heinrich Schutz, Karl Babor and Waldemar Wolter they were enthusiasts in so-called biochemical therapy, based on the use of substances of natural origin, such as salt. After termination of War, during the Nuremberg Trials, many of them evaded responsibility, they were running medical practices, some were publishing. However, despite those facts, trials of Nazi war criminals were not result less, they opened world's eyes for the necessity of clarifying rudiments of human subject research, they gave foundations to define records like The Convention for the Protection of Human Rights and Dignity of the Human Being with regard to the Application of Biology and Medicine or Good Clinical Practice.

Lack of relation between drug-seeking behavior in an addiction model and the expression of behavioral sensitization in response to ethanol challenge in mice.

PubMed

Ribeiro, A F; Pigatto, G; Goeldner, F O; Lopes, J F; de Lacerda, R B

2008-01-01

Drug-induced sensitization has been associated with enhanced self-administration and may contribute to addiction. The possible association between sensitization and voluntary ethanol consumption using an addiction model was investigated. Mice (n = 60) were individually housed with ad libitum access to food and had free choice between ethanol (5% and 10%) and water in a four-phase paradigm: free choice (12 weeks), withdrawal (2 weeks), re-exposure (2 weeks), and quinine-adulteration (2 weeks). Control mice (n = 10) had access to water. Mice were characterized as addicted (n = 10, ethanol preference without reducing intake with adulterated ethanol), heavy (n = 22, ethanol preference but reduced intake with adulterated ethanol), and light (n = 21, water preference). Oral ethanol then was withdrawn, and 24 h later mice received a 2 g/kg ethanol (i.p.) challenge dose or saline, and ambulation was evaluated 10 min later. Half of the classified mice received daily 2 g/kg ethanol injections for 14 days, and ambulation was assessed 10 min after the last dose. Acute ethanol increased ambulation in all groups compared to the control group, and chronic ethanol induced sensitization, showing no difference among ethanol-treated mice. The data suggest that independent neural mechanisms are responsible for the development of addiction and sensitization.

A Variant PfCRT Isoform Can Contribute to Plasmodium falciparum Resistance to the First-Line Partner Drug Piperaquine

PubMed Central

Dhingra, Satish K.; Redhi, Devasha; Combrinck, Jill M.; Yeo, Tomas; Okombo, John; Henrich, Philipp P.; Cowell, Annie N.; Gupta, Purva; Stegman, Matthew L.; Hoke, Jonathan M.; Cooper, Roland A.; Winzeler, Elizabeth; Mok, Sachel; Egan, Timothy J.

2017-01-01

ABSTRACT Current efforts to reduce the global burden of malaria are threatened by the rapid spread throughout Asia of Plasmodium falciparum resistance to artemisinin-based combination therapies, which includes increasing rates of clinical failure with dihydroartemisinin plus piperaquine (PPQ) in Cambodia. Using zinc finger nuclease-based gene editing, we report that addition of the C101F mutation to the chloroquine (CQ) resistance-conferring PfCRT Dd2 isoform common to Asia can confer PPQ resistance to cultured parasites. Resistance was demonstrated as significantly higher PPQ concentrations causing 90% inhibition of parasite growth (IC90) or 50% parasite killing (50% lethal dose [LD50]). This mutation also reversed Dd2-mediated CQ resistance, sensitized parasites to amodiaquine, quinine, and artemisinin, and conferred amantadine and blasticidin resistance. Using heme fractionation assays, we demonstrate that PPQ causes a buildup of reactive free heme and inhibits the formation of chemically inert hemozoin crystals. Our data evoke inhibition of heme detoxification in the parasite’s acidic digestive vacuole as the primary mode of both the bis-aminoquinoline PPQ and the related 4-aminoquinoline CQ. Both drugs also inhibit hemoglobin proteolysis at elevated concentrations, suggesting an additional mode of action. Isogenic lines differing in their pfmdr1 copy number showed equivalent PPQ susceptibilities. We propose that mutations in PfCRT could contribute to a multifactorial basis of PPQ resistance in field isolates. PMID:28487425

Analytical detection and biological assay of antileukemic drug 5-fluorouracil using gold nanoparticles as probe.

PubMed

Selvaraj, Vaithilingam; Alagar, Muthukaruppan

2007-06-07

Gold nanoparticles are reported and evaluated as probes for the detection of anticancer drug 5-fluorouracil (5FU). The nature of binding between 5FU and gold nanoparticles via complexation is investigated using ultraviolet visible spectrophotometry, cyclic voltammetry, transmission electron microscopy, fluorescence and Fourier transform infrared (FTIR) spectroscopy. The bound antileukemic drug is fluorescent and the quenching property of gold nanoparticles could be exploited for biological investigations. The 5FU-colloidal gold complex (Au@5FU) is observed to have appreciable antibacterial and antifungal activity against Micrococcus luteus, Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli, Aspergillus fumigatus, and Aspergillus niger. The experimental studies suggest that gold nanoparticles have the potential to be used as effective carriers for anticancer drugs.

Quality of antimalarial drugs and antibiotics in Papua New Guinea: a survey of the health facility supply chain.

PubMed

Hetzel, Manuel W; Page-Sharp, Madhu; Bala, Nancy; Pulford, Justin; Betuela, Inoni; Davis, Timothy M E; Lavu, Evelyn K

2014-01-01

Poor-quality life-saving medicines are a major public health threat, particularly in settings with a weak regulatory environment. Insufficient amounts of active pharmaceutical ingredients (API) endanger patient safety and may contribute to the development of drug resistance. In the case of malaria, concerns relate to implications for the efficacy of artemisinin-based combination therapies (ACT). In Papua New Guinea (PNG), Plasmodium falciparum and P. vivax are both endemic and health facilities are the main source of treatment. ACT has been introduced as first-line treatment but other drugs, such as primaquine for the treatment of P. vivax hypnozoites, are widely available. This study investigated the quality of antimalarial drugs and selected antibiotics at all levels of the health facility supply chain in PNG. Medicines were obtained from randomly sampled health facilities and selected warehouses and hospitals across PNG and analysed for API content using validated high performance liquid chromatography (HPLC). Of 360 tablet/capsule samples from 60 providers, 9.7% (95% CI 6.9, 13.3) contained less, and 0.6% more, API than pharmacopoeial reference ranges, including 29/37 (78.4%) primaquine, 3/70 (4.3%) amodiaquine, and one sample each of quinine, artemether, sulphadoxine-pyrimethamine and amoxicillin. According to the package label, 86.5% of poor-quality samples originated from India. Poor-quality medicines were found in 48.3% of providers at all levels of the supply chain. Drug quality was unrelated to storage conditions. This study documents the presence of poor-quality medicines, particularly primaquine, throughout PNG. Primaquine is the only available transmission-blocking antimalarial, likely to become important to prevent the spread of artemisinin-resistant P. falciparum and eliminating P. vivax hypnozoites. The availability of poor-quality medicines reflects the lack of adequate quality control and regulatory mechanisms. Measures to stop the availability of poor-quality medicines should include limiting procurement to WHO prequalified products and implementing routine quality testing.

Quality of Antimalarial Drugs and Antibiotics in Papua New Guinea: A Survey of the Health Facility Supply Chain

PubMed Central

Hetzel, Manuel W.; Page-Sharp, Madhu; Bala, Nancy; Pulford, Justin; Betuela, Inoni; Davis, Timothy M. E.; Lavu, Evelyn K.

2014-01-01

Background Poor-quality life-saving medicines are a major public health threat, particularly in settings with a weak regulatory environment. Insufficient amounts of active pharmaceutical ingredients (API) endanger patient safety and may contribute to the development of drug resistance. In the case of malaria, concerns relate to implications for the efficacy of artemisinin-based combination therapies (ACT). In Papua New Guinea (PNG), Plasmodium falciparum and P. vivax are both endemic and health facilities are the main source of treatment. ACT has been introduced as first-line treatment but other drugs, such as primaquine for the treatment of P. vivax hypnozoites, are widely available. This study investigated the quality of antimalarial drugs and selected antibiotics at all levels of the health facility supply chain in PNG. Methods and Findings Medicines were obtained from randomly sampled health facilities and selected warehouses and hospitals across PNG and analysed for API content using validated high performance liquid chromatography (HPLC). Of 360 tablet/capsule samples from 60 providers, 9.7% (95% CI 6.9, 13.3) contained less, and 0.6% more, API than pharmacopoeial reference ranges, including 29/37 (78.4%) primaquine, 3/70 (4.3%) amodiaquine, and one sample each of quinine, artemether, sulphadoxine-pyrimethamine and amoxicillin. According to the package label, 86.5% of poor-quality samples originated from India. Poor-quality medicines were found in 48.3% of providers at all levels of the supply chain. Drug quality was unrelated to storage conditions. Conclusions This study documents the presence of poor-quality medicines, particularly primaquine, throughout PNG. Primaquine is the only available transmission-blocking antimalarial, likely to become important to prevent the spread of artemisinin-resistant P. falciparum and eliminating P. vivax hypnozoites. The availability of poor-quality medicines reflects the lack of adequate quality control and regulatory mechanisms. Measures to stop the availability of poor-quality medicines should include limiting procurement to WHO prequalified products and implementing routine quality testing. PMID:24828338

New chemical probe technologies: applications to imaging and drug discovery (Conference Presentation)

NASA Astrophysics Data System (ADS)

Bogyo, Matthew

2017-02-01

Proteases are enzymes that play pathogenic roles in many common human diseases such as cancer, asthma, arthritis, atherosclerosis and infection by pathogens. Tools to dynamically monitor their activity can be used as diagnostic agents, as imaging contrast agents for intra-operative image guidance and for the identification of novel classes of protease-targeted drugs. I will describe our efforts to design and synthesize small molecule probes that produce a fluorescent signal upon binding to a protease target. We have identified probes that show tumor-specific retention, fast activation kinetics, and rapid systemic distribution making them useful for real-time fluorescence guided tumor resection and other diagnostic imaging applications.

Liquid Microjunction Surface Sampling Probe Electrospray Mass Spectrometry for Detection of Drugs and Metabolites in Thin Tissue Sections

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

Van Berkel, Gary J; Kertesz, Vilmos; Koeplinger, Kenneth A.

2008-01-01

A self-aspirating, liquid micro-junction surface sampling probe/electrospray emitter mass spectrometry system was demonstrated for use in the direct analysis of spotted and dosed drugs and their metabolites in thin tissue sections. Proof-of-principle sampling and analysis directly from tissue without the need for sample preparation was demonstrated first by raster scanning a region on a section of rat liver onto which reserpine was spotted. The mass spectral signal from selected reaction monitoring was used to develop a chemical image of the spotted drug on the tissue. The probe was also used to selectively spot sample areas of sagittal whole mouse bodymore » tissue sections that had been dosed orally (90 mg/kg) with R,S-sulforaphane 3 hrs prior to sacrifice. Sulforaphane and its glutathione and N-acetyl cysteine conjugates were monitored with selected reaction monitoring and detected in the stomach and various other tissues from the dosed mouse. No signal for these species was observed in the tissue from a control mouse. The same dosed tissue section was used to illustrate the possibility of obtaining a line scan across the whole body section. In total these results illustrate the potential for rapid screening of the distribution of drugs and metabolites in tissue sections with the micro-liquid junction surface sampling probe/electrospray mass spectrometry approach.« less

Comparison of Xpert MTB/RIF Assay and GenoType MTBDRplus DNA Probes for Detection of Mutations Associated with Rifampicin Resistance in Mycobacterium tuberculosis.

PubMed

Rahman, Arfatur; Sahrin, Mahfuza; Afrin, Sadia; Earley, Keith; Ahmed, Shahriar; Rahman, S M Mazidur; Banu, Sayera

2016-01-01

GeneXpert MTB/RIF (Xpert) and Genotype MTBDRplus (DRplus) are two World Health Organization (WHO) endorsed probe based molecular drug susceptibility testing (DST) methods for rapid diagnosis of drug resistant tuberculosis. Both methods target the same 81 bp Rifampicin Resistance Determining Region (RRDR) of bacterial RNA polymerase β subunit (rpoB) for detection of Rifampicin (RIF) resistance associated mutations using DNA probes. So there is a correspondence of the probes of each other and expected similarity of probe binding. We analyzed 92 sputum specimens by Xpert, DRplus and LJ proportion method (LJ-DST). We compared molecular DSTs with gold standard LJ-DST. We wanted to see the agreement level of two molecular methods for detection of RIF resistance associated mutations. The 81bp RRDR region of rpoB gene of discrepant cases between the two molecular methods was sequenced by Sanger sequencing. The agreement of Xpert and DRplus with LJ-DST for detection of RIF susceptibility was found to be 93.5% and 92.4%, respectively. We also found 92.4% overall agreement of two molecular methods for the detection of RIF susceptibility. A total of 84 out of 92 samples (91.3%) had agreement on the molecular locus of RRDR mutation by DRplus and Xpert. Sanger sequencing of 81bp RRDR revealed that Xpert probes detected seven of eight discrepant cases correctly and DRplus was erroneous in all the eight cases. Although the overall concordance with LJ-DST was similar for both Xpert and DRplus assay, Xpert demonstrated more accuracy in the detection of RIF susceptibility for discrepant isolates compared with DRplus. This observation would be helpful for the improvement of probe based detection of drug resistance associated mutations especially rpoB mutation in M. tuberculosis.

[The American Malaria Program (1941-1946) and its sequelae for biomedical research after World War II].

PubMed

Bickel, M H

1999-01-01

After Pearl Harbor 1941 and the Japanese conquest of the Netherlands East Indies the U.S. were confronted with both a war in the malaria-ridden South Pacific and the loss of the sources of quinine. This situation gave birth to a Cooperative Wartime Program with the participation of national scientific and medical organizations, universities, hospitals, industries, and the Armed Forces. It worked as a flexible system of coordinated and cooperative units subsidized by the U.S. Government. In the course of WWII malaria casualties dropped beyond expectation due to an improved usage of quinacrine (Atebrine) which was based on new knowledge in pharmacokinetics. Furthermore, basic knowledge in malariology was improved, and a mass-screening resulted in new antimalarial drugs, such as chloroquine. The experiences of the Malaria Program were used by one of its chief architects, James A. Shannon, to transform the National Institutes of Health (NIH) into the model medical research institution whose budget for extramural programs also allowed for the nationwide post-war boom of medical research.

Monitoring ion-channel function in real time through quantum decoherence

PubMed Central

Hall, Liam T.; Hill, Charles D.; Cole, Jared H.; Städler, Brigitte; Caruso, Frank; Mulvaney, Paul; Wrachtrup, Jörg; Hollenberg, Lloyd C. L.

2010-01-01

In drug discovery, there is a clear and urgent need for detection of cell-membrane ion-channel operation with wide-field capability. Existing techniques are generally invasive or require specialized nanostructures. We show that quantum nanotechnology could provide a solution. The nitrogen-vacancy (NV) center in nanodiamond is of great interest as a single-atom quantum probe for nanoscale processes. However, until now nothing was known about the quantum behavior of a NV probe in a complex biological environment. We explore the quantum dynamics of a NV probe in proximity to the ion channel, lipid bilayer, and surrounding aqueous environment. Our theoretical results indicate that real-time detection of ion-channel operation at millisecond resolution is possible by directly monitoring the quantum decoherence of the NV probe. With the potential to scan and scale up to an array-based system, this conclusion may have wide-ranging implications for nanoscale biology and drug discovery. PMID:20937908

Monitoring ion-channel function in real time through quantum decoherence.

PubMed

Hall, Liam T; Hill, Charles D; Cole, Jared H; Städler, Brigitte; Caruso, Frank; Mulvaney, Paul; Wrachtrup, Jörg; Hollenberg, Lloyd C L

2010-11-02

In drug discovery, there is a clear and urgent need for detection of cell-membrane ion-channel operation with wide-field capability. Existing techniques are generally invasive or require specialized nanostructures. We show that quantum nanotechnology could provide a solution. The nitrogen-vacancy (NV) center in nanodiamond is of great interest as a single-atom quantum probe for nanoscale processes. However, until now nothing was known about the quantum behavior of a NV probe in a complex biological environment. We explore the quantum dynamics of a NV probe in proximity to the ion channel, lipid bilayer, and surrounding aqueous environment. Our theoretical results indicate that real-time detection of ion-channel operation at millisecond resolution is possible by directly monitoring the quantum decoherence of the NV probe. With the potential to scan and scale up to an array-based system, this conclusion may have wide-ranging implications for nanoscale biology and drug discovery.

2D IR spectroscopy reveals the role of water in the binding of channel-blocking drugs to the influenza M2 channel

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

Ghosh, Ayanjeet, E-mail: ayanjeet@sas.upenn.edu, E-mail: gai@sas.upenn.edu; Gai, Feng, E-mail: ayanjeet@sas.upenn.edu, E-mail: gai@sas.upenn.edu; Hochstrasser, Robin M.

Water is an integral part of the homotetrameric M2 proton channel of the influenza A virus, which not only assists proton conduction but could also play an important role in stabilizing channel-blocking drugs. Herein, we employ two dimensional infrared (2D IR) spectroscopy and site-specific IR probes, i.e., the amide I bands arising from isotopically labeled Ala30 and Gly34 residues, to probe how binding of either rimantadine or 7,7-spiran amine affects the water dynamics inside the M2 channel. Our results show, at neutral pH where the channel is non-conducting, that drug binding leads to a significant increase in the mobility ofmore » the channel water. A similar trend is also observed at pH 5.0 although the difference becomes smaller. Taken together, these results indicate that the channel water facilitates drug binding by increasing its entropy. Furthermore, the 2D IR spectral signatures obtained for both probes under different conditions collectively support a binding mechanism whereby amantadine-like drugs dock in the channel with their ammonium moiety pointing toward the histidine residues and interacting with a nearby water cluster, as predicted by molecular dynamics simulations. We believe these findings have important implications for designing new anti-influenza drugs.« less

[Optimization and assessment of a reverse hybridization system for the detection of HBV drug-resistant mutations].

PubMed

Liu, Yan-chen; Huang, Ai-long; Hu, Yuan; Hu, Jie-li; Lai, Guo-qi; Zhang, Wen-lu

2011-12-01

To establish a detection method for HBV drug-resistant mutations related to lamivudine, adefovir and entecavir by optimization and assessment of reverse hybridization system. 26 degenerated probes covering 10 drug-resistant hotspots of 3 drugs were synthesized and immobilized on the same positively charged nylon membrane. PCR products labeled with digoxigenin were hybridized with corresponding probes. To improve the sensitivity and specificity, 4 reaction steps of reverse hybridization were optimized including the number of labeled digoxigenin, the energy intensity of UV cross-linking, hybridization and stringency wash conditions. To prove the feasibility, the specificity, sensitivity and accuracy of this system were assessed respectively. Sensitive and specific results are obtained by the optimization of the following 4 reaction steps: the primers labeled with 3 digoxigenin, energy intensity of UV cross-linking for 1500 x 0.1 mJ/cm², hybridization at 42 degrees C and stringency wash with 0.5 x SSC and 0.1% SDS solution at 44 degrees C for 30 min. In the assessment of system, the majority of probes have high specificity. The quantity of PCR product with a concentration of 10 ng/μl or above can be detected by this method. The concordant rate between reverse hybridization and direct sequencing is 93.9% in the clinical sample test. Though the specificity of several probes needs to be improved further, it is a simple, rapid and sensitive method which can detect HBV resistant mutations related to lamivudine, adefovir and entecavir simultaneously. Due to the short distance between 180 and 181, likewise 202 and 204, the sequence of the same probe covers two codon positions, and hybridization will be interfered by each other. To avoid such interference, the possible solution is that probes are designed by arranging and combining various forms of two near codons.

Probe Heating Method for the Analysis of Solid Samples Using a Portable Mass Spectrometer

PubMed Central

Kumano, Shun; Sugiyama, Masuyuki; Yamada, Masuyoshi; Nishimura, Kazushige; Hasegawa, Hideki; Morokuma, Hidetoshi; Inoue, Hiroyuki; Hashimoto, Yuichiro

2015-01-01

We previously reported on the development of a portable mass spectrometer for the onsite screening of illicit drugs, but our previous sampling system could only be used for liquid samples. In this study, we report on an attempt to develop a probe heating method that also permits solid samples to be analyzed using a portable mass spectrometer. An aluminum rod is used as the sampling probe. The powdered sample is affixed to the sampling probe or a droplet of sample solution is placed on the tip of the probe and dried. The probe is then placed on a heater to vaporize the sample. The vapor is then introduced into the portable mass spectrometer and analyzed. With the heater temperature set to 130°C, the developed system detected 1 ng of methamphetamine, 1 ng of amphetamine, 3 ng of 3,4-methylenedioxymethamphetamine, 1 ng of 3,4-methylenedioxyamphetamine, and 0.3 ng of cocaine. Even from mixtures consisting of clove powder and methamphetamine powder, methamphetamine ions were detected by tandem mass spectrometry. The developed probe heating method provides a simple method for the analysis of solid samples. A portable mass spectrometer incorporating this method would thus be useful for the onsite screening of illicit drugs. PMID:26819909

Gustatory receptor neuron responds to DEET and other insect repellents in the yellow fever mosquito, aedes aegypti

USDA-ARS?s Scientific Manuscript database

Three gustatory receptor neurons were characterized for contact chemoreceptive sensilla on the labella of female yellow fever mosquitoes, Aedes aegypti. The neuron with the smallest amplitude spike responded to the feeding deterrent, quinine, as well as DEET and other insect repellents. Two other ...

Electrophysiological responses of gustatory receptor neurons on the labella of the common malaria mosquito Anopheles quadrimaculatus Say (Diptera: Culicidae)

USDA-ARS?s Scientific Manuscript database

We recorded electrical responses from sensory cells associated with gustatory sensilla on the labella of female Anopheles quadrimaculatus to salt, sucrose, quinine (a feeding deterrent) and the insect repellent, N,N-diethyl-3-methylbenzamide (DEET). A salt-sensitive cell responded to increasing con...

Responses of primate taste cortex neurons to the astringent tastant tannic acid.

PubMed

Critchley, H D; Rolls, E T

1996-04-01

In order to advance knowledge of the neural control of feeding, we investigated the cortical representation of the taste of tannic acid, which produces the taste of astringency. It is a dietary component of biological importance particularly to arboreal primates. Recordings were made from 74 taste responsive neurons in the orbitofrontal cortex. Single neurons were found that were tuned to respond to 0.001 M tannic acid, and represented a subpopulation of neurons that was distinct from neurons responsive to the tastes of glucose (sweet), NaCl (salty), HCl (sour), quinine (bitter) and monosodium glutamate (umami). In addition, across the population of 74 neurons, tannic acid was as well represented as the tastes of NaCl, HCl quinine or monosodium glutamate. Multidimensional scaling analysis of the neuronal responses to the tastants indicates that tannic acid lies outside the boundaries of the four conventional taste qualities (sweet, sour, bitter and salty). Taken together these data indicate that the astringent taste of tannic acid should be considered as a taste quality, which receives a separate representation from sweet, salt, bitter and sour in the primate cortical taste areas.

Interaction of a potential chloride channel blocker with a model transport protein: a spectroscopic and molecular docking investigation.

PubMed

Ganguly, Aniruddha; Paul, Bijan Kumar; Ghosh, Soumen; Dalapati, Sasanka; Guchhait, Nikhil

2014-05-14

The present work demonstrates a detailed characterization of the interaction of a potential chloride channel blocker, 9-methyl anthroate (9-MA), with a model transport protein, Bovine Serum Albumin (BSA). The modulated photophysical properties of the emissive drug molecule within the microheterogeneous bio-environment of the protein have been exploited spectroscopically to monitor the probe-protein binding interaction. Apart from evaluating the binding constant, the probable location of the neutral molecule within the protein cavity (subdomain IB) is explored by an AutoDock-based blind docking simulation. The absence of the Red-Edge Effect has been corroborated by the enhanced lifetime of the probe, being substantially greater than the solvent reorientation time. A dip-and-rise characteristic of the rotational relaxation profile of the drug within the protein has been argued to originate from a significant difference in the lifetime as well as amplitude of the free and protein-bound drug molecule. Unfolding of the protein in the presence of the drug molecule has been probed by the decrease of the α-helical content, obtained via circular dichroism (CD) spectroscopy, which is also supported by the gradual loss of the esterase activity of the protein in the presence of the drug molecule.

Compound annotation with real time cellular activity profiles to improve drug discovery.

PubMed

Fang, Ye

2016-01-01

In the past decade, a range of innovative strategies have been developed to improve the productivity of pharmaceutical research and development. In particular, compound annotation, combined with informatics, has provided unprecedented opportunities for drug discovery. In this review, a literature search from 2000 to 2015 was conducted to provide an overview of the compound annotation approaches currently used in drug discovery. Based on this, a framework related to a compound annotation approach using real-time cellular activity profiles for probe, drug, and biology discovery is proposed. Compound annotation with chemical structure, drug-like properties, bioactivities, genome-wide effects, clinical phenotypes, and textural abstracts has received significant attention in early drug discovery. However, these annotations are mostly associated with endpoint results. Advances in assay techniques have made it possible to obtain real-time cellular activity profiles of drug molecules under different phenotypes, so it is possible to generate compound annotation with real-time cellular activity profiles. Combining compound annotation with informatics, such as similarity analysis, presents a good opportunity to improve the rate of discovery of novel drugs and probes, and enhance our understanding of the underlying biology.

Synthesis and evaluation of sensitizer drug photorelease chemistry: Micro-optic method applied to singlet oxygen generation and drug delivery

NASA Astrophysics Data System (ADS)

Ghosh, Goutam

This thesis summarizes a new micro-optic method for singlet oxygen generation and sensitizer drug delivery, which include i) synthesis and evaluation of a first generation device for drug delivery from native and fluorinated silica probe tips, ii) synthesis of PEG conjugated sensitizers to study phototoxicity in ovarian cancer cells, and iii) synthesis and evaluation of tris-PEGylated chlorin conjugated fluorinated silica for its future integration into the device to use as a 2nd generation device. A first generation micro-optic device was developed that works by sparging O2 gas and light generating cytotoxic singlet oxygen that cleaves the covalently attached drug (sensitizer) from the probe tip at the distal end of the fiber. The aim is to develop a 1st and 2nd generation device for site specific delivery of photosensitizer and singlet oxygen to overcome the challenges involved in systemic administration of the sensitizer. Synthesis and evaluation of drug (pheophorbide-a) delivery applying micro-optic method from native and fluorinated silica probe tip was achieved. The amount of sensitizer photocleavage depends on the loading level of sensitizer onto the probe tips. We also found that photorelease efficiency depends on the nature of the solvents where sensitizer is photocleaved. For example, no photorelease was observed in an aqueous solvent where sensitizer remained adsorbed to the native silica probe-tip. But, 90% photocleavage was obtained in octanol. A significant amount of photosensitizer (formate ester of pyropheophorbide- a) diffused into the liposome when photocleavage study was carried out in liposome. Substantial increase of photorelease was observed in organic solvent when pyropheophorbide-a (PPa) sensitizer was attached to the partially fluorinated porous Vycor glass. We also explored sensitizer photorelease from the fluorinated silica surface at various temperatures and we found that autocatalytic photorelease happened at room temperature and above. No photorelease was observed at low temperature. Chlorin e6 and its one, two and three short chain methoxy triethylene glycol (PEG) conjugated derivatives were synthesized. A comparative study of photocytotoxicity and cellular uptake between each showed that 17 3,152,131- chlorin e6 methoxy triethylene glycol triester has the highest photocytotoxic activity and uptake by ovarian OVCAR-5 cancer cells. Therefore, we decided to load three short chain PEG conjugated chlorin e6 onto the silica surface through spacer alkene for delivery via a fiber-optic probe tip. In order to load chlorin e6-triPEG ester conjugate, in chapter 4, we explored different synthetic strategies. We have been successful in synthesizing spacer alkene succinate linker conjugated chlorin e6 -tri PEG ester, which was attached to the fiber-optic probe tip. Reactions were carried out in mild conditions to avoid detachment of the PEG ester from the carboxylic acid sites of chlorin. Photocleavage of the triPEG modified fluorinated probe tip system was studied in n-butanol.

A Model of Alcohol Drinking under an Intermittent Access Schedule Using Group-Housed Mice

PubMed Central

Smutek, Magdalena; Turbasa, Mateusz; Sikora, Magdalena; Piechota, Marcin; Zajdel, Joanna; Przewlocki, Ryszard; Parkitna, Jan Rodriguez

2014-01-01

Here, we describe a new model of voluntary alcohol drinking by group-housed mice. The model employs sensor-equipped cages that track the behaviors of the individual animals via implanted radio chips. After the animals were allowed intermittent access to alcohol (three 24 h intervals every week) for 4 weeks, the proportions of licks directed toward bottles containing alcohol were 50.9% and 39.6% for the male and female mice, respectively. We used three approaches (i.e., quinine adulteration, a progressive ratio schedule and a schedule involving a risk of punishment) to test for symptoms of compulsive alcohol drinking. The addition of 0.01% quinine to the alcohol solution did not significantly affect intake, but 0.03% quinine induced a greater than 5-fold reduction in the number of licks on the alcohol bottles. When the animals were required to perform increasing numbers of instrumental responses to obtain access to the bottle with alcohol (i.e., a progressive ratio schedule), they frequently reached a maximum of 21 responses irrespective of the available reward. Although the mice rarely achieved higher response criteria, the number of attempts was ∼10 times greater in case of alcohol than water. We have developed an approach for mapping social interactions among animals that is based on analysis of the sequences of entries into the cage corners. This approach allowed us to identify the mice that followed other animals in non-random fashions. Approximately half of the mice displayed at least one interaction of this type. We have not yet found a clear correlation between imitative behavior and relative alcohol preference. In conclusion, the model we describe avoids the limitations associated with testing isolated animals and reliably leads to stable alcohol drinking. Therefore, this model may be well suited to screening for the effects of genetic mutations or pharmacological treatments on alcohol-induced behaviors. PMID:24804807

Changes in taste receptor cell [Ca2+]i modulate chorda tympani responses to bitter, sweet, and umami taste stimuli

PubMed Central

DeSimone, John A.; Phan, Tam-Hao T.; Ren, ZuoJun; Mummalaneni, Shobha

2012-01-01

The relationship between taste receptor cell (TRC) intracellular Ca2+ ([Ca2+]i) and rat chorda tympani (CT) nerve responses to bitter (quinine and denatonium), sweet (sucrose, glycine, and erythritol), and umami [monosodium glutamate (MSG) and MSG + inosine 5′-monophosphate (IMP)] taste stimuli was investigated before and after lingual application of ionomycin (Ca2+ ionophore) + Ca2+, 1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid acetoxymethyl ester (BAPTA-AM; Ca2+ chelator), U73122 (phospholipase C blocker), thapsigargin (Ca2+-ATPase blocker), and diC8-PIP2 (synthetic phosphatidylinositol 4,5-bisphosphate). The phasic CT response to quinine was indifferent to changes in [Ca2+]i. However, a decrease in [Ca2+]i inhibited the tonic part of the CT response to quinine. The CT responses to sweet and umami stimuli were indifferent to changes in TRC [Ca2+]i. However, a decrease in [Ca2+]i attenuated the synergistic effects of ethanol on the CT response to sweet stimuli and of IMP on the glutamate CT response. U73122 and thapsigargin inhibited the phasic and tonic CT responses to bitter, sweet, and umami stimuli. Although diC8-PIP2 increased the CT response to bitter and sweet stimuli, it did not alter the CT response to glutamate but did inhibit the synergistic effect of IMP on the glutamate response. The results suggest that bitter, sweet, and umami taste qualities are transduced by [Ca2+]i-dependent and [Ca2+]i-independent mechanisms. Changes in TRC [Ca2+]i in the BAPTA-sensitive cytosolic compartment regulate quality-specific taste receptors and ion channels that are involved in the neural adaptation and mixture interactions. Changes in TRC [Ca2+]i in a separate subcompartment, sensitive to inositol trisphosphate and thapsigargin but inaccessible to BAPTA and ionomycin + Ca2+, are associated with neurotransmitter release. PMID:22993258

Learning context modulates aversive taste strength in honey bees.

PubMed

de Brito Sanchez, Maria Gabriela; Serre, Marion; Avarguès-Weber, Aurore; Dyer, Adrian G; Giurfa, Martin

2015-03-01

The capacity of honey bees (Apis mellifera) to detect bitter substances is controversial because they ingest without reluctance different kinds of bitter solutions in the laboratory, whereas free-flying bees avoid them in visual discrimination tasks. Here, we asked whether the gustatory perception of bees changes with the behavioral context so that tastes that are less effective as negative reinforcements in a given context become more effective in a different context. We trained bees to discriminate an odorant paired with 1 mol l(-1) sucrose solution from another odorant paired with either distilled water, 3 mol l(-1) NaCl or 60 mmol l(-1) quinine. Training was either Pavlovian [olfactory conditioning of the proboscis extension reflex (PER) in harnessed bees], or mainly operant (olfactory conditioning of free-walking bees in a Y-maze). PER-trained and maze-trained bees were subsequently tested both in their original context and in the alternative context. Whereas PER-trained bees transferred their choice to the Y-maze situation, Y-maze-trained bees did not respond with a PER to odors when subsequently harnessed. In both conditioning protocols, NaCl and distilled water were the strongest and the weakest aversive reinforcement, respectively. A significant variation was found for quinine, which had an intermediate aversive effect in PER conditioning but a more powerful effect in the Y-maze, similar to that of NaCl. These results thus show that the aversive strength of quinine varies with the learning context, and reveal the plasticity of the bee's gustatory system. We discuss the experimental constraints of both learning contexts and focus on stress as a key modulator of taste in the honey bee. Further explorations of bee taste are proposed to understand the physiology of taste modulation in bees. © 2015. Published by The Company of Biologists Ltd.

Long Term Effects of Aversive Reinforcement on Colour Discrimination Learning in Free-Flying Bumblebees

PubMed Central

Rodríguez-Gironés, Miguel A.; Trillo, Alejandro; Corcobado, Guadalupe

2013-01-01

The results of behavioural experiments provide important information about the structure and information-processing abilities of the visual system. Nevertheless, if we want to infer from behavioural data how the visual system operates, it is important to know how different learning protocols affect performance and to devise protocols that minimise noise in the response of experimental subjects. The purpose of this work was to investigate how reinforcement schedule and individual variability affect the learning process in a colour discrimination task. Free-flying bumblebees were trained to discriminate between two perceptually similar colours. The target colour was associated with sucrose solution, and the distractor could be associated with water or quinine solution throughout the experiment, or with one substance during the first half of the experiment and the other during the second half. Both acquisition and final performance of the discrimination task (measured as proportion of correct choices) were determined by the choice of reinforcer during the first half of the experiment: regardless of whether bees were trained with water or quinine during the second half of the experiment, bees trained with quinine during the first half learned the task faster and performed better during the whole experiment. Our results confirm that the choice of stimuli used during training affects the rate at which colour discrimination tasks are acquired and show that early contact with a strongly aversive stimulus can be sufficient to maintain high levels of attention during several hours. On the other hand, bees which took more time to decide on which flower to alight were more likely to make correct choices than bees which made fast decisions. This result supports the existence of a trade-off between foraging speed and accuracy, and highlights the importance of measuring choice latencies during behavioural experiments focusing on cognitive abilities. PMID:23951186

Drug use in the management of uncomplicated malaria in public health facilities in the Democratic Republic of the Congo.

PubMed

Ntamabyaliro, Nsengi Y; Burri, Christian; Nzolo, Didier B; Engo, Aline B; Lula, Yves N; Mampunza, Samuel M; Nsibu, Célestin N; Mesia, Gauthier K; Kayembe, Jean-Marie N; Likwela, Joris L; Kintaudi, Leon M; Tona, Gaston L

2018-05-03

Malaria the first causes of death from parasitic infection worldwide. Interventions to reduce the burden of malaria have produced a tremendous drop in malaria morbidity and mortality. However, progress is slower in DRC, which shares with Nigeria 39% of deaths related to malaria globally. Inappropriate use of drugs may be one of the factors of this below-average performance. The aim of this study was to describe the use of drugs in the management of uncomplicated malaria in public health facilities in DRC. A drug use study was carried out in DRC from January to March 2014. In each of the former 11 provinces of DRC, one Rural Health Centre, one Urban Health Centre and one General Hospital were selected. In each of them, 100 patient's files containing prescription of anti-malarials from January to December 2013 were randomly selected. Among them, all of the files with diagnosis of uncomplicated malaria were included in this study. Prescribed anti-malarials, co-prescribed drugs and their indications were collected. Descriptive analyses were performed. A total of 2300 files out of 3300 (69.7%) concerned uncomplicated malaria and were included in analysis. Malaria treatment was initiated after a positive RDT or microscopy in 51.5% of cases, upon suspicion without requesting biological confirmation in 37% and despite negative results in 11%. Twenty-nine (29) different treatment regimens were used. The drugs recommended by the National Malaria Control Programme were used in 54.3% of cases (artesunate-amodiaquine 37.4% or artemether-lumefantrine 16.9%). The second most used anti-malarial was quinine (32.4%). Apart from anti-malarials, an average of 3.1 drugs per patient were prescribed, among which antibiotics (67.9%), analgesics and non-steroidal anti-inflammatory (NSAIDs) (all abbreviations to be explicated on first use) (70.6%), vitamins (29.1%), anaemia drugs, including blood transfusion (9.1%) and corticosteroids (5.7%), In 51.4% of cases there was no indication for the concomitant medication. Management of uncomplicated malaria in DRC is characterized by a low adherence to treatment policy, numerous treatment regimens, and abundant concomitant medication potentially harmful to the patient. This may contribute to the low performance of DRC in malaria control. Determinant of this irrational use of drugs need to be assessed in order to formulate and implement efficient corrective measures.

ADVANCES IN DISCOVERING SMALL MOLECULES TO PROBE PROTEIN FUNCTION IN A SYSTEMS CONTEXT

PubMed Central

Doyle, Shelby K; Pop, Marius S; Evans, Helen L; Koehler, Angela N

2015-01-01

High throughput screening has historically been used for drug discovery almost exclusively by the pharmaceutical industry. Due to a significant decrease in costs associated with establishing a high throughput facility and an exponential interest in discovering probes of development and disease associated biomolecules, HTS core facilities have become an integral part of most academic and non-profit research institutions over the past decade. This major shift has led to the development of new HTS methodologies extending beyond the capabilities and target classes used in classical drug discovery approaches such as traditional enzymatic activity-based screens. In this brief review we describe some of the most interesting developments in HTS technologies and methods for chemical probe discovery. PMID:26615565

Non-invasive optical modulation of local vascular permeability

NASA Astrophysics Data System (ADS)

Choi, Myunghwan; Choi, Chulhee

2011-03-01

For a systemically administered drug to act, it first needs to cross the vascular wall. This step represents a bottleneck for drug development, especially in the brain or retina, where tight junctions between endothelial cells form physiological barriers. Here, we demonstrate that femtosecond pulsed laser irradiation focused on the blood vessel wall induces transient permeabilization of plasma. Nonlinear absorption of the pulsed laser enabled the noninvasive modulation of vascular permeability with high spatial selectivity in three dimensions. By combining this method with systemic injection, we could locally deliver molecular probes in various tissues, such as brain cortex, meninges, ear, striated muscle, and bone. We suggest this method as a novel delivery tool for molecular probes or drugs.

Radiopharmaceuticals in PET, Progress and Promise

DOE R&D Accomplishments Database

Wolf, A. P.; Fowler, J. S.

1988-11-01

It is the intention of this presentation to focus on the current state of radiopharmaceuticals for PET and where this is leading us. PET radiopharmaceuticals can be broken down into perhaps seven categories at present with each being applicable to a different aspect of human biochemistry. These are: metabolic probes, neurochemical probes, enzyme probes, ion channel blockers, blood flow agents, ethical drugs and other positron emitters.

Real-time monitoring of drug-induced changes in the stomach acidity of living rats using improved pH-sensitive nitroxides and low-field EPR techniques

NASA Astrophysics Data System (ADS)

Potapenko, Dmitrii I.; Foster, Margaret A.; Lurie, David J.; Kirilyuk, Igor A.; Hutchison, James M. S.; Grigor'ev, Igor A.; Bagryanskaya, Elena G.; Khramtsov, Valery V.

2006-09-01

New improved pH-sensitive nitroxides were applied for in vivo studies. An increased stability of the probes towards reduction was achieved by the introduction of the bulky ethyl groups in the vicinity of the paramagnetic N sbnd O fragment. In addition, the range of pH sensitivity of the approach was extended by the synthesis of probes with two ionizable groups, and, therefore, with two p Ka values. Stability towards reduction and spectral characteristics of the three new probes were determined in vitro using 290 MHz radiofrequency (RF)- and X-band electron paramagnetic resonance (EPR), longitudinally detected EPR (LODEPR), and field-cycled dynamic nuclear polarization (FC-DNP) techniques. The newly synthesized probe, 4-[bis(2-hydroxyethyl)amino]-2-pyridine-4-yl-2,5,5-triethyl-2,5-dihydro-1 H-imidazol-oxyl, was found to be the most appropriate for the application in the stomach due to both higher stability and convenient pH sensitivity range from pH 1.8 to 6. LODEPR, FC-DNP and proton-electron double resonance imaging (PEDRI) techniques were used to detect the nitroxide localization and acidity in the rat stomach. Improved probe characteristics allowed us to follow in vivo the drug-induced perturbation in the stomach acidity and its normalization afterwards during 1 h or longer period of time. The results show the applicability of the techniques for monitoring drug pharmacology and disease in the living animals.

Open Access High Throughput Drug Discovery in the Public Domain: A Mount Everest in the Making

PubMed Central

Roy, Anuradha; McDonald, Peter R.; Sittampalam, Sitta; Chaguturu, Rathnam

2013-01-01

High throughput screening (HTS) facilitates screening large numbers of compounds against a biochemical target of interest using validated biological or biophysical assays. In recent years, a significant number of drugs in clinical trails originated from HTS campaigns, validating HTS as a bona fide mechanism for hit finding. In the current drug discovery landscape, the pharmaceutical industry is embracing open innovation strategies with academia to maximize their research capabilities and to feed their drug discovery pipeline. The goals of academic research have therefore expanded from target identification and validation to probe discovery, chemical genomics, and compound library screening. This trend is reflected in the emergence of HTS centers in the public domain over the past decade, ranging in size from modestly equipped academic screening centers to well endowed Molecular Libraries Probe Centers Network (MLPCN) centers funded by the NIH Roadmap initiative. These centers facilitate a comprehensive approach to probe discovery in academia and utilize both classical and cutting-edge assay technologies for executing primary and secondary screening campaigns. The various facets of academic HTS centers as well as their implications on technology transfer and drug discovery are discussed, and a roadmap for successful drug discovery in the public domain is presented. New lead discovery against therapeutic targets, especially those involving the rare and neglected diseases, is indeed a Mount Everestonian size task, and requires diligent implementation of pharmaceutical industry’s best practices for a successful outcome. PMID:20809896

Chemotherapy of Rodent Malaria. Part 1

DTIC Science & Technology

1987-10-01

to produce exaggerated resistance factors (I 90 values). For example, the ED of chloroquine against the artemisinin 90 resistant ART strain...primaquine, quinine, cinchonine, quinidine, mefloquine, halofantrine, artemisinin , pyronaridine, mepacrine and Mannich bases (such as WR 228258). It is...RC. It is markedly resistant to primaquine and possesses slight cross-resistance to quinidine, mefloquine, artemisinin . There is also a marked cross

Simultaneous Assessment of Transporter-Mediated Drug-Drug Interactions Using a Probe Drug Cocktail in Cynomolgus Monkey.

PubMed

Kosa, Rachel E; Lazzaro, Sarah; Bi, Yi-An; Tierney, Brendan; Gates, Dana; Modi, Sweta; Costales, Chester; Rodrigues, A David; Tremaine, Larry M; Varma, Manthena V

2018-06-07

We aim to establish an in vivo preclinical model to enable simultaneous assessment of inhibition potential of an investigational drug on clinically relevant drug transporters, organic anion transporting polypeptide (OATP)1B, breast cancer resistance protein (BCRP), P-glycoprotein (P-gp) and organic anion transporter (OAT)3. Pharmacokinetics of substrate cocktail consisting of pitavastatin (OATP1B substrate), rosuvastatin (OATP1B/BCRP/OAT3), sulfasalazine (BCRP) and talinolol (P-gp) were obtained in cynomolgus monkey - alone or in combination with transporter inhibitors. Single dose rifampicin (30 mg/kg) significantly (p<0.01) increased the plasma exposure of all four drugs, with a marked effect on pitavastatin and rosuvastatin (AUC ratio ~21-39). Elacridar, BCRP/P-gp inhibitor, increased the AUC of sulfasalazine, talinolol, as well as rosuvastatin and pitavastatin. An OAT1/3 inhibitor (probenecid) significantly (p<0.05) impacted the renal clearance of rosuvastatin (~8-fold). In vitro, rifampicin (10μM) inhibited uptake of pitavastatin, rosuvastatin and sulfasalazine by monkey and human primary hepatocytes. Transport studies using membrane vesicles suggested that all probe substrates, except talinolol, are transported by cynoBCRP; while talinolol is a cynoP-gp substrate. Elacridar and rifampicin inhibited both cynoBCRP and cynoP-gp in vitro, indicating potential for in vivo intestinal efflux inhibition. In conclusion, a probe substrate cocktail was validated to simultaneously evaluate perpetrator impact on multiple clinically relevant transporters using the cynomolgus monkey. The results support the use of the cynomolgus monkey as a model that could enable drug-drug interaction risk assessment, before advancing a new molecular entity into clinical development, as well as providing mechanistic insights on transporter-mediated interactions. The American Society for Pharmacology and Experimental Therapeutics.

Memantine transport across the mouse blood-brain barrier is mediated by a cationic influx H+ antiporter.

PubMed

Mehta, Dharmini C; Short, Jennifer L; Nicolazzo, Joseph A

2013-12-02

Memantine (MEM) is prescribed in mono and combination therapies for treating the symptoms of moderate to severe Alzheimer's disease (AD). Despite MEM being widely prescribed with other AD and non-AD medicines, very little is known about its mechanism of transport across the blood-brain barrier (BBB), and whether the nature of this transport lends MEM to a potential for drug-drug interactions at the BBB. Therefore, the purpose of this study was to characterize the mechanisms facilitating MEM brain uptake in Swiss Outbred mice using an in situ transcardiac perfusion technique, and identify the putative transporter involved in MEM disposition into the brain. Following transcardiac perfusion of MEM with increasing concentrations, the brain uptake of MEM was observed to be saturable. Furthermore, MEM brain uptake was reduced (up to 55%) by various cationic transporter inhibitors (amantadine, quinine, tetraethylammonium, choline and carnitine) and was dependent on extracellular pH, while being independent of membrane depolarization and the presence of Na(+) in the perfusate. In addition, MEM brain uptake was observed to be sensitive to changes in intracellular pH, hence, likely to be driven by H(+)/MEM antiport mechanisms. Taken together, these findings implicate the involvement of an organic cation transporter regulated by proton antiport mechanisms in the transport of MEM across the mouse BBB, possibly the organic cation/carnitine transporter, OCTN1. These studies also clearly demonstrate the brain uptake of MEM is significantly reduced by other cationic compounds, highlighting the need to consider the possibility of drug interactions with MEM at the BBB, potentially leading to reduced brain uptake and, therefore, altered efficacy of MEM when used in patients on multidrug regimens.

Expression of HIV gp120 protein increases sensitivity to the rewarding properties of methamphetamine in mice

PubMed Central

Kesby, James P.; Hubbard, David T.; Markou, Athina; Semenova, Svetlana

2012-01-01

Methamphetamine abuse and human immunodeficiency virus (HIV) infection induce neuropathological changes in corticolimbic brain areas involved in reward and cognitive function. Little is known about the combined effects of methamphetamine and HIV infection on cognitive and reward processes. The HIV/gp120 protein induces neurodegeneration in mice, similar to HIV-induced pathology in humans. We investigated the effects of gp120 expression on associative learning, preference for methamphetamine and non-drug reinforcers, and sensitivity to the conditioned rewarding properties of methamphetamine in transgenic (tg) mice expressing HIV/gp120 protein (gp120-tg). gp120-tg mice learned the operant response for food at the same rate as non-tg mice. In the two-bottle choice procedure with restricted access to drugs, gp120-tg mice exhibited greater preference for methamphetamine and saccharin than non-tg mice, whereas preference for quinine was similar between genotypes. Under conditions of unrestricted access to methamphetamine, the mice exhibited a decreased preference for increasing methamphetamine concentrations. However, male gp120-tg mice showed a decreased preference for methamphetamine at lower concentrations than non-tg male mice. gp120-tg mice developed methamphetamine-induced conditioned place preference at lower methamphetamine doses compared with non-tg mice. No differences in methamphetamine pharmacokinetics were found between genotypes. These results indicate that gp120-tg mice exhibit no deficits in associative learning or reward/motivational function for a natural reinforcer. Interestingly, gp120 expression resulted in increased preference for methamphetamine and a highly palatable non-drug reinforcer (saccharin) and increased sensitivity to methamphetamine-induced conditioned reward. These data suggest that HIV-positive individuals may have increased sensitivity to methamphetamine, leading to high methamphetamine abuse potential in this population. PMID:23252824

Ex Vivo Susceptibility of Plasmodium falciparum to Antimalarial Drugs in Western, Northern, and Eastern Cambodia, 2011-2012: Association with Molecular Markers

PubMed Central

Lim, Pharath; Dek, Dalin; Try, Vorleak; Eastman, Richard T.; Chy, Sophy; Sreng, Sokunthea; Suon, Seila; Mao, Sivanna; Sopha, Chantha; Sam, Baramey; Ashley, Elizabeth A.; Miotto, Olivo; Dondorp, Arjen M.; White, Nicholas J.; Su, Xin-zhuan; Char, Meng Chuor; Anderson, Jennifer M.; Amaratunga, Chanaki; Menard, Didier

2013-01-01

In 2008, dihydroartemisinin (DHA)-piperaquine (PPQ) became the first-line treatment for uncomplicated Plasmodium falciparum malaria in western Cambodia. Recent reports of increased treatment failure rates after DHA-PPQ therapy in this region suggest that parasite resistance to DHA, PPQ, or both is now adversely affecting treatment. While artemisinin (ART) resistance is established in western Cambodia, there is no evidence of PPQ resistance. To monitor for resistance to PPQ and other antimalarials, we measured drug susceptibilities for parasites collected in 2011 and 2012 from Pursat, Preah Vihear, and Ratanakiri, in western, northern, and eastern Cambodia, respectively. Using a SYBR green I fluorescence assay, we calculated the ex vivo 50% inhibitory concentrations (IC50s) of 310 parasites to six antimalarials: chloroquine (CQ), mefloquine (MQ), quinine (QN), PPQ, artesunate (ATS), and DHA. Geometric mean IC50s (GMIC50s) for all drugs (except PPQ) were significantly higher in Pursat and Preah Vihear than in Ratanakiri (P ≤ 0.001). An increased copy number of P. falciparum mdr1 (pfmdr1), an MQ resistance marker, was more prevalent in Pursat and Preah Vihear than in Ratanakiri and was associated with higher GMIC50s for MQ, QN, ATS, and DHA. An increased copy number of a chromosome 5 region (X5r), a candidate PPQ resistance marker, was detected in Pursat but was not associated with reduced susceptibility to PPQ. The ex vivo IC50 and pfmdr1 copy number are important tools in the surveillance of multidrug-resistant (MDR) parasites in Cambodia. While MDR P. falciparum is prevalent in western and northern Cambodia, there is no evidence for PPQ resistance, suggesting that DHA-PPQ treatment failures result mainly from ART resistance. PMID:23939897

Combating severe malaria in African children*

PubMed Central

Breman, J. G.; Campbell, C. C.

1988-01-01

An initiative to reduce childhood mortality due to malaria, diarrhoea and vaccine-preventable diseases, called the Africa Child Survival Initiative—Combatting Childhood Communicable Diseases (CCCD) project, was started in 1982 and is now operating in 13 African countries, 12 of which are endemic for malaria. The project's malaria control strategy relies on the use of drugs, mainly chloroquine, to prevent severe illness and death in children less than 5 years of age; chemoprophylaxis for pregnant women is also advised to prevent low birth weight in newborns. The strategy is based on WHO recommendations which focus on improved diagnosis and treatment of cases and chemoprophylaxis for pregnant women. In 9 out of the 13 CCCD countries the sensitivity of Plasmodium falciparum to chloroquine in children was investigated and a drug sensitivity surveillance network was established. In areas with chloroquine-resistant P. falciparum, treatment with chloroquine was found to decrease the temperature in febrile children and to greatly reduce the parasite density, thus preventing severe illness and possible death. Baseline surveys in 6 countries have shown a wide range of treatment practices, e.g., use of chloroquine in various doses without standard guidelines and the excessive use of quinine and chloroquine injections in some health units. As pregnant women are often not taking chemoprophylaxis, research has been started on alternative approaches to drug treatment to prevent the adverse effects of malaria on the fetus. Only 4 of the 12 malarious countries had malaria control units when their CCCD programme began and these were concerned mainly with vector control issues; 11 of 12 countries now have such units and a written CCCD malaria plan. These countries have now integrated malaria control activities into primary health care and have begun to implement standardized treatment and prevention practices that are described in their national CCCD malaria plans. PMID:3061675

Chloroquine transport in Plasmodium falciparum. 1. Influx and efflux kinetics for live trophozoite parasites using a novel fluorescent chloroquine probe.

PubMed

Cabrera, Mynthia; Natarajan, Jayakumar; Paguio, Michelle F; Wolf, Christian; Urbach, Jeffrey S; Roepe, Paul D

2009-10-13

Several models for how amino acid substitutions in the Plasmodium falciparum chloroquine resistance transporter (PfCRT) confer resistance to chloroquine (CQ) and other antimalarial drugs have been proposed. Distinguishing between these models requires detailed analysis of high-resolution CQ transport data that is unfortunately impossible to obtain with traditional radio-tracer methods. Thus, we have designed and synthesized fluorescent CQ analogues for drug transport studies. One probe places a NBD (6-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)hexanoic acid) group at the tertiary aliphatic N of CQ, via a flexible 6 C amide linker. This probe localizes to the malarial parasite digestive vacuole (DV) during initial perfusion under physiologic conditions and exhibits similar pharmacology relative to CQ, vs both CQ-sensitive (CQS) and CQ-resistant (CQR) parasites. Using live, synchronized intraerythrocytic parasites under continuous perfusion, we define NBD-CQ influx and efflux kinetics for CQS vs CQR parasites. Since this fluorescence approach provides data at much higher kinetic resolution relative to fast-filtration methods using (3)H-CQ, rate constants vs linear initial rates for CQ probe flux can be analyzed in detail. Importantly, we find that CQR parasites have a decreased rate constant for CQ influx into the DV and that this is due to mutation of PfCRT. Analysis of zero trans efflux for CQS and CQR parasites suggests that distinguishing between bound vs free pools of intra-DV drug probe is essential for proper kinetic analysis of efflux. The accompanying paper (DOI 10.1021/bi901035j ) further probes efflux kinetics for proteoliposomes containing purified, reconstituted PfCRT.

Using Environment-Sensitive Fluorescent Probes to Characterize Liquid-Liquid Phase Separation in Supersaturated Solutions of Poorly Water Soluble Compounds.

PubMed

Raina, Shweta A; Alonzo, David E; Zhang, Geoff G Z; Gao, Yi; Taylor, Lynne S

2015-11-01

Highly supersaturated aqueous solutions of poorly soluble compounds can undergo liquid-liquid phase separation (LLPS) when the concentration exceeds the "amorphous solubility". This phenomenon has been widely observed during high throughput screening of new molecular entities as well as during the dissolution of amorphous solid dispersions. In this study, we have evaluated the use of environment-sensitive fluorescence probes to investigate the formation and properties of the non-crystalline drug-rich aggregates formed in aqueous solutions as a result of LLPS. Six different environment-sensitive fluorophores were employed to study LLPS in highly supersaturated solutions of several model compounds, all dihydropyridine derivatives. Each fluoroprobe exhibited a large hypsochromic shift with decreasing environment polarity. Upon drug aggregate formation, the probes partitioned into the drug-rich phase and exhibited changes in emission wavelength and intensity consistent with sensing a lower polarity environment. The LLPS onset concentrations determined using the fluorescence measurements were in good agreement with light scattering measurements as well as theoretically estimated amorphous solubility values. Environment-sensitive fluorescence probes are useful to help understand the phase behavior of highly supersaturated aqueous solutions, which in turn is important in the context of developing enabling formulations for poorly soluble compounds.

Connecting Neuronal Cell Protective Pathways and Drug Combinations in a Huntington's Disease Model through the Application of Quantitative Systems Pharmacology.

PubMed

Pei, Fen; Li, Hongchun; Henderson, Mark J; Titus, Steven A; Jadhav, Ajit; Simeonov, Anton; Cobanoglu, Murat Can; Mousavi, Seyed H; Shun, Tongying; McDermott, Lee; Iyer, Prema; Fioravanti, Michael; Carlisle, Diane; Friedlander, Robert M; Bahar, Ivet; Taylor, D Lansing; Lezon, Timothy R; Stern, Andrew M; Schurdak, Mark E

2017-12-19

Quantitative Systems Pharmacology (QSP) is a drug discovery approach that integrates computational and experimental methods in an iterative way to gain a comprehensive, unbiased understanding of disease processes to inform effective therapeutic strategies. We report the implementation of QSP to Huntington's Disease, with the application of a chemogenomics platform to identify strategies to protect neuronal cells from mutant huntingtin induced death. Using the STHdh Q111 cell model, we investigated the protective effects of small molecule probes having diverse canonical modes-of-action to infer pathways of neuronal cell protection connected to drug mechanism. Several mechanistically diverse protective probes were identified, most of which showed less than 50% efficacy. Specific combinations of these probes were synergistic in enhancing efficacy. Computational analysis of these probes revealed a convergence of pathways indicating activation of PKA. Analysis of phospho-PKA levels showed lower cytoplasmic levels in STHdh Q111 cells compared to wild type STHdh Q7 cells, and these levels were increased by several of the protective compounds. Pharmacological inhibition of PKA activity reduced protection supporting the hypothesis that protection may be working, in part, through activation of the PKA network. The systems-level studies described here can be broadly applied to any discovery strategy involving small molecule modulation of disease phenotype.

Institute for Molecular Medicine Research Program

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

Phelps, Michael E

2012-12-14

The objectives of the project are the development of new Positron Emission Tomography (PET) imaging instrumentation, chemistry technology platforms and new molecular imaging probes to examine the transformations from normal cellular and biological processes to those of disease in pre-clinical animal models. These technology platforms and imaging probes provide the means to: 1. Study the biology of disease using pre-clinical mouse models and cells. 2. Develop molecular imaging probes for imaging assays of proteins in pre-clinical models. 3. Develop imaging assays in pre-clinical models to provide to other scientists the means to guide and improve the processes for discovering newmore » drugs. 4. Develop imaging assays in pre-clinical models for others to use in judging the impact of drugs on the biology of disease.« less

Automated clustering of probe molecules from solvent mapping of protein surfaces: new algorithms applied to hot-spot mapping and structure-based drug design

NASA Astrophysics Data System (ADS)

Lerner, Michael G.; Meagher, Kristin L.; Carlson, Heather A.

2008-10-01

Use of solvent mapping, based on multiple-copy minimization (MCM) techniques, is common in structure-based drug discovery. The minima of small-molecule probes define locations for complementary interactions within a binding pocket. Here, we present improved methods for MCM. In particular, a Jarvis-Patrick (JP) method is outlined for grouping the final locations of minimized probes into physical clusters. This algorithm has been tested through a study of protein-protein interfaces, showing the process to be robust, deterministic, and fast in the mapping of protein "hot spots." Improvements in the initial placement of probe molecules are also described. A final application to HIV-1 protease shows how our automated technique can be used to partition data too complicated to analyze by hand. These new automated methods may be easily and quickly extended to other protein systems, and our clustering methodology may be readily incorporated into other clustering packages.

IMMUNOREACTIONS INVOLVING PLATELETS

PubMed Central

Shulman, N. Raphael

1958-01-01

Quantitative aspects of platelet agglutination and inhibition of clot retraction by the antibody of quinidine purpura were described. The reactions appeared to depend on formation of types of antibody-quinidine-platelet complexes which could fix complement but complement was not necessary for these reactions. Complement fixation was at least 10 times more sensitive than platelet agglutination or inhibition of clot retraction for measurement and detection of antibody activity. Although it has been considered that antibodies of drug purpura act as platelet lysins in the presence of complement and that direct lysis of platelets accounts for development of thrombocytopenia in drug purpura, the present study suggests that attachment of antibody produces a change in platelets which is manifested in vitro only by increased susceptibility to non-specific factors which can alter the stability of platelets in the absence of antibody. The attachment of antibody to platelets in vivo may only indirectly affect platelet survival. In contrast to human platelets, dog, rabbit, and guinea pig platelets, and normal or trypsin-treated human red cells did not agglutinate, fix complement, or adsorb antibody; and intact human endothelial cells did not fix complement or adsorb antibody. Rhesus monkey platelets were not agglutinated by the antibody but did adsorb antibody and fix complement although their activity in these reactions differed quantitatively from that of human platelets. Cinchonine could be substituted for quinidine in agglutination and inhibition of clot retraction reactions but quinine and cinchonidine could not. Attempts to cause passive anaphylaxis in guinea pigs with the antibody of quinidine purpura were not successful. PMID:13525580

Functional Chemical Groups that May Likely Become a Source for the Synthesis of Novel Central Nervous System (CNS) Acting Drugs.

PubMed

Saganuwan, Saganuwan A

2017-01-01

Central Nervous System (CNS) disorders are on increase perhaps due to genetic, enviromental, social and dietetic factors. Unfortunately, a large number of CNS drugs have adverse effects such as addiction, tolerance, psychological and physical dependence. In view of this, literature search was carried out with a view to identify functional chemical groups that may serve as lead molecules for synthesis of compounds that may have CNS activity. The search revealed that heterocycles that have heteroatoms such as nitrogen (N), sulphur (S) and oxygen (O) form the largest class of organic compounds. They replace carbon in a benzene ring to form pyridine. Compounds with furan, thiophene, pyrrole, pyridine, azole, imidazole, indole, purine, pyrimidine, esters, carboxylic acid, aldehyde, pyrylium, pyrone, pyrodine, barbituric acid, barbiturate, quinoline, quinolone, isoquinolone, coumarin, alkylpyridine, picoline, piperidine, diazine, carboxamide, flavonoid glycoside, oxindole, aminophenol, benzimidazole, benzoxazole, benzothiazole, and chromone chemical groups among others may have CNS effects ranging from depression passing through euphoria to convulsion. Examples of the compounds with the functional groups include but not limited to coal tar, pyridostigmine, pralidoxime, quinine, mefloquine, pyrilamine, pyronaridine, ciprofloxacin and piroxicam. A number of them can undergo keto-enol tautomerism. Chiral amines may be used for derivation of chiral carboxylic acids which are components of tautomers. Some tautomers may cause parkinsonism and Stevens Johnson syndrome. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Systemic modulation of serotonergic synapses via reuptake blockade or 5HT1A receptor antagonism does not alter perithreshold taste sensitivity in rats.

PubMed

Mathes, Clare M; Spector, Alan C

2014-09-01

Systemic blockade of serotonin (5HT) reuptake with paroxetine has been shown to increase sensitivity to sucrose and quinine in humans. Here, using a 2-response operant taste detection task, we measured the effect of paroxetine and the 5HT1A receptor antagonist WAY100635 on the ability of rats to discriminate sucrose, NaCl, and citric acid from water. After establishing individual psychometric functions, 5 concentrations of each taste stimulus were chosen to represent the dynamic portion of the concentration-response curve, and the performance of the rats to these stimuli was assessed after vehicle, paroxetine (7mg/kg intraperitoneally), and WAY100635 (0.3mg/kg subcutaneously; 1mg/kg intravenously) administration. Although, at times, overall performance across concentrations dropped, at most, 5% from vehicle to drug conditions, no differences relative to vehicle were seen on the parameters of the psychometric function (asymptote, slope, or EC50) after drug administration. In contrast to findings in humans, our results suggest that modulation of 5HT activity has little impact on sucrose detectability at perithreshold concentrations in rats, at least at the doses used in this task. In the rat model, the purported paracrine/neurocrine action of serotonin in the taste bud may work in a manner that does not impact overt taste detection behavior. © The Author 2014. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Efficacy and safety of chloroquine for treatment in patients with uncomplicated Plasmodium vivax infections in endemic countries.

PubMed

Naing, Cho; Aung, Kyan; Win, Daw-Khin; Wah, Mak Joon

2010-11-01

Chloroquine (CQ) is a relatively inexpensive drug for treatment of malaria. If efficacy of CQ is still assumed, then it should be indicated in malaria treatment policies as the drug of choice for uncomplicated Plasmodium vivax malaria in endemic countries with resource constraints. The objective of this review is to summarize the existing evidence on the relative efficacy and safety of CQ in treating patients with uncomplicated P. vivax malaria in endemic countries. We searched online data bases (PUBMED, MEDLINE, EMBASE, The Cochrane Library) and the reference lists of the retrieved articles. Fifteen randomized controlled trials (n=6215) assessing the relative efficacy and safety of CQ for treatment of uncomplicated P. vivax malaria were included. CQ monotherapy was compared to CQ plus primaquine (PQ), artemisinin/artemether, artemisinin based combination therapy, quinine, CQ plus tafenoquine, chlorguanil plus dapsone, azithromycin, or placebo. Treatment efficacy was not significantly different between the CQ monotherapy group and that of the CQ with PQ 14 day group at 28 day follow-up (55/711, 7.7% vs 35/712, 4.9%; P=0.16). Evidence from the trials identified for this review draw a fairly clear conclusion about the relative efficacy and safety of CQ for treating uncomplicated P. vivax malaria infection. However, further research in this field with well powered, randomized, non-inferiority design, using the standardized protocol is needed. Copyright © 2010 Royal Society of Tropical Medicine and Hygiene. Published by Elsevier Ltd. All rights reserved.

Mice expressing a “hyper-sensitive” form of the CB1 cannabinoid receptor (CB1) show modestly enhanced alcohol preference and consumption

PubMed Central

Gonek, Maciej; Zee, Michael L.; Farnsworth, Jill C.; Amin, Randa A.; Andrews, Mary-Jeanette; Davis, Brian J.; Mackie, Ken; Morgan, Daniel J.

2017-01-01

We recently characterized S426A/S430A mutant mice expressing a desensitization-resistant form of the CB1 receptor. These mice display an enhanced response to endocannabinoids and ∆9-THC. In this study, S426A/S430A mutants were used as a novel model to test whether ethanol consumption, morphine dependence, and reward for these drugs are potentiated in mice with a “hyper-sensitive” form of CB1. Using an unlimited-access, two-bottle choice, voluntary drinking paradigm, S426A/S430A mutants exhibit modestly increased intake and preference for low (6%) but not higher concentrations of ethanol. S426A/S430A mutants and wild-type mice show similar taste preference for sucrose and quinine, exhibit normal sensitivity to the hypothermic and ataxic effects of ethanol, and have normal blood ethanol concentrations following administration of ethanol. S426A/S430A mutants develop robust conditioned place preference for ethanol (2 g/kg), morphine (10 mg/kg), and cocaine (10 mg/kg), demonstrating that drug reward is not changed in S426A/S430A mutants. Precipitated morphine withdrawal is also unchanged in opioid-dependent S426A/S430A mutant mice. Although ethanol consumption is modestly changed by enhanced CB1 signaling, reward, tolerance, and acute sensitivity to ethanol and morphine are normal in this model. PMID:28426670

Estimating antimalarial drugs consumption in Africa before the switch to artemisinin-based combination therapies (ACTs).

PubMed

Kindermans, Jean-Marie; Vandenbergh, Daniel; Vreeke, Ed; Olliaro, Piero; D'Altilia, Jean-Pierre

2007-07-10

Having reliable forecasts is critical now for producers, malaria-endemic countries and agencies in order to adapt production and procurement of the artemisinin-based combination treatments (ACTs), the new first-line treatments of malaria. There is no ideal method to quantify drug requirements for malaria. Morbidity data give uncertain estimations. This study uses drug consumption to provide elements to help estimate quantities and financial requirements of ACTs. The consumption of chloroquine, sulphadoxine/pyrimethamine and quinine both through the private and public sector was assessed in five sub-Saharan Africa countries with different epidemiological patterns (Senegal, Rwanda, Tanzania, Malawi, Zimbabwe). From these data the number of adult treatments per capita was calculated and the volumes and financial implications derived for the whole of Africa. Identifying and obtaining data from the private sector was difficult. The quality of information on drug supply and distribution in countries must be improved. The number of adult treatments per capita and per year in the five countries ranged from 0.18 to 0.50. Current adult treatment prices for ACTs range US$ 1-1.8. Taking the upper range for both volumes and costs, the highest number of adult treatments consumed for Africa was estimated at 314.5 million, corresponding to an overall maximum annual need for financing ACT procurement of US$ 566.1 million. In reality, both the number of cases treated and the cost of treatment are likely to be lower (projections for the lowest consumption estimate with the least expensive ACT would require US $ 113 million per annum). There were substantial variations in the market share between public and private sources among these countries (the public sector share ranging from 98% in Rwanda to 33% in Tanzania). Additional studies are required to build a more robust methodology, and to assess current consumptions more accurately in order to better quantify volumes and finances for production and procurement of ACTs.

High-Throughput Cytochrome P450 Cocktail Inhibition Assay for Assessing Drug-Drug and Drug-Botanical Interactions

PubMed Central

Li, Guannan; Huang, Ke; Nikolic, Dejan

2015-01-01

Detection of drug-drug interactions is essential during the early stages of drug discovery and development, and the understanding of drug-botanical interactions is important for the safe use of botanical dietary supplements. Among the different forms of drug interactions that are known, inhibition of cytochrome P450 (P450) enzymes is the most common cause of drug-drug or drug-botanical interactions. Therefore, a rapid and comprehensive mass spectrometry–based in vitro high-throughput P450 cocktail inhibition assay was developed that uses 10 substrates simultaneously against nine CYP isoforms. Including probe substrates for CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and two probes targeting different binding sites of CYP3A4/5, this cocktail simultaneously assesses at least as many P450 enzymes as previous assays while remaining among the fastest due to short incubation times and rapid analysis using ultrahigh pressure liquid chromatography–tandem mass spectrometry. The method was validated using known inhibitors of each P450 enzyme and then shown to be useful not only for single-compound testing but also for the evaluation of potential drug-botanical interactions using the botanical dietary supplement licorice (Glycyrrhiza glabra) as an example. PMID:26285764

Rifampicin resistance mutations in the 81 bp RRDR of rpoB gene in Mycobacterium tuberculosis clinical isolates using Xpert MTB/RIF in Khyber Pakhtunkhwa, Pakistan: a retrospective study.

PubMed

Ullah, Irfan; Shah, Aamer Ali; Basit, Anila; Ali, Mazhar; Khan, Afsar; Ullah, Ubaid; Ihtesham, Muhammad; Mehreen, Sumaira; Mughal, Anita; Javaid, Arshad

2016-08-12

Multi-drug resistant tuberculosis (MDR-TB) is a major public health problem especially in developing countries. World Health Organization (WHO) recommends use of Xpert MTB/RIF assay to simultaneously detecting Mycobacterium tuberculosis (MTB) and rifampicin (RIF) resistance. The primary objective of this study was to determine the frequency of MDR-TB in patients suspected to have drug resistance in Khyber Pakhtunkhwa. The frequency of probes for various rpoB gene mutations using Xpert MTB/RIF assay within 81 bp RRDR (Rifampicin Resistance Determining Region) was the secondary objective. A total of 2391 specimens, received at Programmatic Management of Drug Resistant TB (PMDT) Unit, Lady Reading Hospital (LRH) Peshawar, Pakistan, between October 2011 and December 2014, were analyzed by Xpert MTB/RIF test. MTB positive with rifampicin resistance were further analyzed to first line anti-mycobacterial drug susceptibility testing (DST) using middle brook 7H10 medium. The data was analyzed using statistical software; SPSS version 18. Out of 2391 specimens, 1408 (59 %) were found positive for MTB and among them, 408 (29 %) showed rifampicin-resistance with four different rpoB gene mutations within 81 bp RRDR. The frequency of various probes among RIF-resistant isolates was observed as: probe E, in 314 out of 408 isolates; B, 44 out of 408; A, 5 out of 408; D, 34 out of 408; and probe C was observed among 6 out of 408 RIF-resistant isolates. The probe A&B and E&D mutation combination was found in only 1 isolate in each case, while B&D mutation combination was detected among 3 out of 408 RIF-resistant isolates. Hence, it is concluded from our study on a selected population, 29 % of patients had MDR-TB. Probe E related mutations (also known as codon 531and 533) were the most common rpoB genetic mutation [314 (77 %)], acknowledged by Xpert MTB/RIF assay. Least mutation was detected within the sequence 511 (1.2 %).

Theranostic nanoemulsions: codelivery of hydrophobic drug and hydrophilic imaging probe for cancer therapy and imaging.

PubMed

Yang, Xinggang; Wang, Dun; Ma, Yan; Zhao, Qiang; Fallon, John K; Liu, Dan; Xu, Xian Emma; Wang, Yongjun; He, Zhonggui; Liu, Feng

2014-12-01

To develop a theranostic nanoemulsion (TNE) that can codeliver the conjugates of a hydrophobic drug paclitaxel (PTX) and a hydrophilic imaging probe sulforhodamine B (SRB). The TNE was established using core-matched technology, and can achieve high encapsulation efficiency and synchronized release of the loaded cargo. It has been examined for a correlation between the dynamic uptake of PTX and the intensity of SRB imaging signal in different organs. Our data demonstrate that the TNE, with improved circulation time, increases therapeutic efficacy and imaging efficiency in both drug-sensitive and drug-resistant cancer. The TNE could not satisfy the demand of visual diagnosis in the living animal because of interference. We therefore formulated a long-circulating theranostic nanoemulsion (LCTNE). Results showed that the LCTNE can meet imaging requirements in vivo. The LCTNE plays a good therapeutic and diagnostic role for subcutaneous tumors in the living animal.

Contested Cultural Spaces: Exploring Illicit Drug-Using through "Trainspotting"

ERIC Educational Resources Information Center

Hemingway, Judy

2006-01-01

Contending that culture is one of the most potentially divisive signifiers of human activity, this paper probes some of the complexities that attend the (un)popular culture of illicit drug-using with which many young people in contemporary Britain are identified. Irvine Welsh's multi-media drugs narrative "Trainspotting" is drawn on to…

A Portable, Low-Cost, LED Fluorimeter for Middle School, High School, and Undergraduate Chemistry Labs

ERIC Educational Resources Information Center

Wigton, Benjamin T.; Chohan, Balwant S.; McDonald, Cole; Johnson, Matt; Schunk, Doug; Kreuter, Rod; Sykes, Dan

2011-01-01

A low-cost portable fluorimeter was constructed using a 360 nm LED for excitation and a silicon photodiode for detection. The instrument is simple to operate and has been used to investigate fluorescent whitening agents extracted from various brands of paper, to determine the linear range and limit of detection of quinine in various commercial…

Beethoven's autopsy revisited: A pathologist sounds a final note.

PubMed

Oiseth, Stanley J

2017-08-01

This review of the original autopsy report of Beethoven's remains indicates Paget's disease within the skull, which was dense and twice normal thickness, with dilated vessels at the petrous bone. The facial nerves were enlarged and the eighth nerves atrophied despite their sharing a common meatus at the internal auditory canal. Nephrolithiasis and pyelonephritis with cortical and perinephric abscesses were also reported. The hypercalcaemia was probably caused by hyperparathyroidism, which may be associated with Paget's disease, and both may have played a role in his psychiatric symptoms as well as in his abdominal pain and gastrointestinal complaints. Since Paget's disease may also be associated with gout, some of the joint pains could be attributable to this as well. Hypovitaminosis A from chronic pancreatitis is suggested as a cause of painful eyes and either quinine abuse or severe hypercalcaemia as a cause of arrhythmias. Beethoven died of terminal cirrhosis with chronic pancreatitis, most likely related to chronic excessive intake of alcohol. Thus, Paget's disease, complicated by hyperparathyroidism, gout, and attempts to find relief of symptoms through the use of alcohol, quinine, and possibly salicylates can explain virtually all of Beethoven's medical problems, some of which appear to have influenced his musical compositions.

Updated CDC Recommendations for Using Artemether-Lumefantrine for the Treatment of Uncomplicated Malaria in Pregnant Women in the United States.

PubMed

Ballard, Sarah-Blythe; Salinger, Allison; Arguin, Paul M; Desai, Meghna; Tan, Kathrine R

2018-04-13

Malaria infection during pregnancy is associated with an increased risk for maternal and fetal complications. In the United States, treatment options for uncomplicated, chloroquine-resistant Plasmodium falciparum and P. vivax malaria in pregnant women are limited to mefloquine or quinine plus clindamycin (1). However, limited availability of quinine and increasing resistance to mefloquine restrict these options. Strong evidence now demonstrates that artemether-lumefantrine (AL) (Coartem) is effective and safe in the treatment of malaria in pregnancy. The World Health Organization (WHO) has endorsed artemisinin-based combination therapies (ACTs), such as AL, for treatment of uncomplicated malaria during the second and third trimesters of pregnancy and is currently considering whether to add ACTs, including AL, as an option for malaria treatment during the first trimester (2,3). This policy note reviews the evidence and updates CDC recommendations to include AL as a treatment option for uncomplicated malaria during the second and third trimesters of pregnancy and during the first trimester of pregnancy when other treatment options are unavailable. These updated recommendations reflect current evidence and are consistent with WHO treatment guidelines.

A possible role of a cerebral energy gene in alcoholism.

PubMed

Ribeiro, A F; Correia, D; Boerngen-Lacerda, R; Brunialti-Godard, A L

2012-02-17

We examined a possible relationship between genes responsible for energy metabolism of the brain and addictive behavior in an animal model. We used non-inbred, Swiss mice exposed to a three-bottle free-choice model [water, 5% (v/v) ethanol, and 10% (v/v) ethanol] over a 16-week period, consisting of four phases: acquisition, withdrawal, reexposure, and quinine-adulteration. The mice were then behaviorally classified into three groups: loss-of-control-drinker (preference for ethanol and high levels of consumption during all phases, N = 6), heavy-drinker (preference for ethanol and high levels of consumption during acquisition and reduction during quinine-adulteration, N = 7), and light-drinker (preference for water during all phases, N = 10). Another group only received tap water (ethanol-naive control mice, N = 9). Further analysis using quantitative real-time PCR showed that in mice behaviorally classified as loss-of-control-drinkers, there was a significant inverse correlation between transcript levels of the Hadh gene and those of other energy metabolism genes in the nucleus of the amygdala, suggesting that this pathway may contribute to ethanol consumption in these mice. We conclude that cerebral energy metabolism is involved with ethanol addiction, meriting further study.

[The struggle against malaria in the Ottoman Empire during World War I and the legal regulations made to this end].

PubMed

Koylu, Zafer; Doğan, Nihal

2010-01-01

One of the most important disadvantages of war environmental is infectious diseases. The Ottoman Empire combated infectious diseases in addition to the war because of Balkan wars and afterwards first world war. Because of increasing migrations to Anatolia after Balkan wars spread some epidemic diseases, such as cholera, typhoid fever, plaque, dysentery, syphilis. With the start of the First World War, malaria began to spread within civilian population as well as the military. The population fell from power because of illness and therefore could not process the land tax failed to pay taxes. Founded in 1914 with the fight against epidemic diseases was initiated by the Sıhhiye ministry. Quinine was formed as tablets which was imported from Germany by legal regulation and was distributed to the public by Ziraat Bank. However, malaria epidemic could not be prevented because of long war years, lack of population, insufficiency of the preventive methods and lack of quinine, and about three quarters of the population caught malaria and in four years 412.000 soldiers had malaria and 20.000 of them died despite of measures.

Associative visual learning by tethered bees in a controlled visual environment.

PubMed

Buatois, Alexis; Pichot, Cécile; Schultheiss, Patrick; Sandoz, Jean-Christophe; Lazzari, Claudio R; Chittka, Lars; Avarguès-Weber, Aurore; Giurfa, Martin

2017-10-10

Free-flying honeybees exhibit remarkable cognitive capacities but the neural underpinnings of these capacities cannot be studied in flying insects. Conversely, immobilized bees are accessible to neurobiological investigation but display poor visual learning. To overcome this limitation, we aimed at establishing a controlled visual environment in which tethered bees walking on a spherical treadmill learn to discriminate visual stimuli video projected in front of them. Freely flying bees trained to walk into a miniature Y-maze displaying these stimuli in a dark environment learned the visual discrimination efficiently when one of them (CS+) was paired with sucrose and the other with quinine solution (CS-). Adapting this discrimination to the treadmill paradigm with a tethered, walking bee was successful as bees exhibited robust discrimination and preferred the CS+ to the CS- after training. As learning was better in the maze, movement freedom, active vision and behavioral context might be important for visual learning. The nature of the punishment associated with the CS- also affects learning as quinine and distilled water enhanced the proportion of learners. Thus, visual learning is amenable to a controlled environment in which tethered bees learn visual stimuli, a result that is important for future neurobiological studies in virtual reality.

Cell Wall Remodeling by a Synthetic Analog Reveals Metabolic Adaptation in Vancomycin Resistant Enterococci.

PubMed

Pidgeon, Sean E; Pires, Marcos M

2017-07-21

Drug-resistant bacterial infections threaten to overburden our healthcare system and disrupt modern medicine. A large class of potent antibiotics, including vancomycin, operate by interfering with bacterial cell wall biosynthesis. Vancomycin-resistant enterococci (VRE) evade the blockage of cell wall biosynthesis by altering cell wall precursors, rendering them drug insensitive. Herein, we reveal the phenotypic plasticity and cell wall remodeling of VRE in response to vancomycin in live bacterial cells via a metabolic probe. A synthetic cell wall analog was designed and constructed to monitor cell wall structural alterations. Our results demonstrate that the biosynthetic pathway for vancomycin-resistant precursors can be hijacked by synthetic analogs to track the kinetics of phenotype induction. In addition, we leveraged this probe to interrogate the response of VRE cells to vancomycin analogs and a series of cell wall-targeted antibiotics. Finally, we describe a proof-of-principle strategy to visually inspect drug resistance induction. Based on our findings, we anticipate that our metabolic probe will play an important role in further elucidating the interplay among the enzymes involved in the VRE biosynthetic rewiring.

A Suite of "Minimalist" Photo-Crosslinkers for Live-Cell Imaging and Chemical Proteomics: Case Study with BRD4 Inhibitors.

PubMed

Pan, Sijun; Jang, Se-Young; Wang, Danyang; Liew, Si Si; Li, Zhengqiu; Lee, Jun-Seok; Yao, Shao Q

2017-09-18

Affinity-based probes (AfBPs) provide a powerful tool for large-scale chemoproteomic studies of drug-target interactions. The development of high-quality probes capable of recapitulating genuine drug-target engagement, however, could be challenging. "Minimalist" photo-crosslinkers, which contain an alkyl diazirine group and a chemically tractable tag, could alleviate such challenges, but few are currently available. Herein, we have developed new alkyl diazirine-containing photo-crosslinkers with different bioorthogonal tags. They were subsequently used to create a suite of AfBPs based on GW841819X (a small molecule inhibitor of BRD4). Through in vitro and in situ studies under conditions that emulated native drug-target interactions, we have obtained better insights into how a tag might affect the probe's performance. Finally, SILAC-based chemoproteomic studies have led to the discovery of a novel off-target, APEX1. Further studies showed GW841819X binds to APEX1 and caused up-regulation of endogenous DNMT1 expression under normoxia conditions. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Hot spot analysis for driving the development of hits into leads in fragment based drug discovery

PubMed Central

Hall, David R.; Ngan, Chi Ho; Zerbe, Brandon S.; Kozakov, Dima; Vajda, Sandor

2011-01-01

Fragment based drug design (FBDD) starts with finding fragment-sized compounds that are highly ligand efficient and can serve as a core moiety for developing high affinity leads. Although the core-bound structure of a protein facilitates the construction of leads, effective design is far from straightforward. We show that protein mapping, a computational method developed to find binding hot spots and implemented as the FTMap server, provides information that complements the fragment screening results and can drive the evolution of core fragments into larger leads with a minimal loss or, in some cases, even a gain in ligand efficiency. The method places small molecular probes, the size of organic solvents, on a dense grid around the protein, and identifies the hot spots as consensus clusters formed by clusters of several probes. The hot spots are ranked based on the number of probe clusters, which predicts the binding propensity of the subsites and hence their importance for drug design. Accordingly, with a single exception the main hot spot identified by FTMap binds the core compound found by fragment screening. The most useful information is provided by the neighboring secondary hot spots, indicating the regions where the core can be extended to increase its affinity. To quantify this information, we calculate the density of probes from mapping, which describes the binding propensity at each point, and show that the change in the correlation between a ligand position and the probe density upon extending or repositioning the core moiety predicts the expected change in ligand efficiency. PMID:22145575

A fluorescent probe for ecstasy.

PubMed

Masseroni, D; Biavardi, E; Genovese, D; Rampazzo, E; Prodi, L; Dalcanale, E

2015-08-18

A nanostructure formed by the insertion in silica nanoparticles of a pyrene-derivatized cavitand, which is able to specifically recognize ecstasy in water, is presented. The absence of effects from interferents and an efficient electron transfer process occurring after complexation of ecstasy, makes this system an efficient fluorescent probe for this popular drug.

Seven Novel Probe Systems for Real-Time PCR Provide Absolute Single-Base Discrimination, Higher Signaling, and Generic Components

PubMed Central

Murray, James L.; Hu, Peixu; Shafer, David A.

2015-01-01

We have developed novel probe systems for real-time PCR that provide higher specificity, greater sensitivity, and lower cost relative to dual-labeled probes. The seven DNA Detection Switch (DDS)-probe systems reported here employ two interacting polynucleotide components: a fluorescently labeled probe and a quencher antiprobe. High-fidelity detection is achieved with three DDS designs: two internal probes (internal DDS and Flip probes) and a primer probe (ZIPR probe), wherein each probe is combined with a carefully engineered, slightly mismatched, error-checking antiprobe. The antiprobe blocks off-target detection over a wide range of temperatures and facilitates multiplexing. Other designs (Universal probe, Half-Universal probe, and MacMan probe) use generic components that enable low-cost detection. Finally, single-molecule G-Force probes employ guanine-mediated fluorescent quenching by forming a hairpin between adjacent C-rich and G-rich sequences. Examples provided show how these probe technologies discriminate drug-resistant Mycobacterium tuberculosis mutants, Escherichia coli O157:H7, oncogenic EGFR deletion mutations, hepatitis B virus, influenza A/B strains, and single-nucleotide polymorphisms in the human VKORC1 gene. PMID:25307756

The Safety of Artemisinin Derivatives for the Treatment of Malaria in the 2nd or 3rd Trimester of Pregnancy: A Systematic Review and Meta-Analysis.

PubMed

Kovacs, Stephanie D; van Eijk, Anna Maria; Sevene, Esperanca; Dellicour, Stephanie; Weiss, Noel S; Emerson, Scott; Steketee, Richard; Ter Kuile, Feiko O; Stergachis, Andy

2016-01-01

Given the high morbidity for mother and fetus associated with malaria in pregnancy, safe and efficacious drugs are needed for treatment. Artemisinin derivatives are the most effective antimalarials, but are associated with teratogenic and embryotoxic effects in animal models when used in early pregnancy. However, several organ systems are still under development later in pregnancy. We conducted a systematic review and meta-analysis of the occurrence of adverse pregnancy outcomes among women treated with artemisinins monotherapy or as artemisinin-based combination therapy during the 2nd or 3rd trimesters relative to pregnant women who received non-artemisinin antimalarials or none at all. Pooled odds ratio (POR) were calculated using Mantel-Haenszel fixed effects model with a 0.5 continuity correction for zero events. Eligible studies were identified through Medline, Embase, and the Malaria in Pregnancy Consortium Library. Twenty studies (11 cohort studies and 9 randomized controlled trials) contributed to the analysis, with 3,707 women receiving an artemisinin, 1,951 a non-artemisinin antimalarial, and 13,714 no antimalarial. The PORs (95% confidence interval (CI)) for stillbirth, fetal loss, and congenital anomalies when comparing artemisinin versus quinine were 0.49 (95% CI 0.24-0.97, I2 = 0%, 3 studies); 0.58 (95% CI 0.31-1.16, I2 = 0%, 6 studies); and 1.00 (95% CI 0.27-3.75, I2 = 0%, 3 studies), respectively. The PORs comparing artemisinin users to pregnant women who received no antimalarial were 1.13 (95% CI 0.77-1.66, I2 = 86.7%, 3 studies); 1.10 (95% CI 0.79-1.54, I2 = 0%, 4 studies); and 0.79 (95% CI 0.37-1.67, I2 = 0%, 3 studies) for miscarriage, stillbirth and congenital anomalies respectively. Treatment with artemisinin in 2nd and 3rd trimester was not associated with increased risks of congenital malformations or miscarriage and may be was associated with a reduced risk of stillbirths compared to quinine. This study updates the reviews conducted by the WHO in 2002 and 2006 and supports the current WHO malaria treatment guidelines malaria in pregnancy.

The Safety of Artemisinin Derivatives for the Treatment of Malaria in the 2nd or 3rd Trimester of Pregnancy: A Systematic Review and Meta-Analysis

PubMed Central

van Eijk, Anna Maria; Sevene, Esperanca; Dellicour, Stephanie; Weiss, Noel S.; Emerson, Scott; Steketee, Richard; ter Kuile, Feiko O.; Stergachis, Andy

2016-01-01

Given the high morbidity for mother and fetus associated with malaria in pregnancy, safe and efficacious drugs are needed for treatment. Artemisinin derivatives are the most effective antimalarials, but are associated with teratogenic and embryotoxic effects in animal models when used in early pregnancy. However, several organ systems are still under development later in pregnancy. We conducted a systematic review and meta-analysis of the occurrence of adverse pregnancy outcomes among women treated with artemisinins monotherapy or as artemisinin-based combination therapy during the 2nd or 3rd trimesters relative to pregnant women who received non-artemisinin antimalarials or none at all. Pooled odds ratio (POR) were calculated using Mantel-Haenszel fixed effects model with a 0.5 continuity correction for zero events. Eligible studies were identified through Medline, Embase, and the Malaria in Pregnancy Consortium Library. Twenty studies (11 cohort studies and 9 randomized controlled trials) contributed to the analysis, with 3,707 women receiving an artemisinin, 1,951 a non-artemisinin antimalarial, and 13,714 no antimalarial. The PORs (95% confidence interval (CI)) for stillbirth, fetal loss, and congenital anomalies when comparing artemisinin versus quinine were 0.49 (95% CI 0.24–0.97, I2 = 0%, 3 studies); 0.58 (95% CI 0.31–1.16, I2 = 0%, 6 studies); and 1.00 (95% CI 0.27–3.75, I2 = 0%, 3 studies), respectively. The PORs comparing artemisinin users to pregnant women who received no antimalarial were 1.13 (95% CI 0.77–1.66, I2 = 86.7%, 3 studies); 1.10 (95% CI 0.79–1.54, I2 = 0%, 4 studies); and 0.79 (95% CI 0.37–1.67, I2 = 0%, 3 studies) for miscarriage, stillbirth and congenital anomalies respectively. Treatment with artemisinin in 2nd and 3rd trimester was not associated with increased risks of congenital malformations or miscarriage and may be was associated with a reduced risk of stillbirths compared to quinine. This study updates the reviews conducted by the WHO in 2002 and 2006 and supports the current WHO malaria treatment guidelines malaria in pregnancy. PMID:27824884

Analysis of polymorphisms in Plasmodium falciparum genes related to drug resistance: a survey over four decades under different treatment policies in Brazil.

PubMed

Inoue, Juliana; Lopes, Dinora; do Rosário, Virgílio; Machado, Marta; Hristov, Angélica D; Lima, Giselle Fmc; Costa-Nascimento, Maria J; Segurado, Aluísio C; Di Santi, Silvia M

2014-09-19

Anti-malarial resistance in Plasmodium falciparum remains an obstacle for malaria control. Resistance-associated genes were analysed in Brazilian samples over four decades to evaluate the impact of different treatment regimens on the parasite genetic profile. Samples were collected on filter paper from patients infected in the Amazon region from 1984 to 2011. DNA was extracted with Chelex® 100 and monoinfection confirmed by PCR. SNPs in the pfcrt, pfmdr1, pfdhfr and pfdhps genes were assessed by PCR-RFLP. The pfmdr1 copy number was estimated using real time quantitative PCR with SYBR® Green. Parasite response was assessed ex vivo with seven concentrations of each anti-malarial. Patients were treated according to Brazilian guidelines: quinine plus tetracycline or mefloquine in period 1 and ACT in period 2. All 96 samples presented the pfcrt 76T mutant throughout the assessed periods. In addition, all isolates showed ex vivo chloroquine resistance. The pfmdr1 86Y was detected in 1.5% of samples in period 1, and in 25% in period 2. All samples presented the pfmdr1 1246Y. The analysis of pfmdr1 copy number showed amplification in 37.3% in period 1 and in 42% in period 2. Mutations in pfdhfr were shown as follows: 51I in all samples in period 1 and in 81.2% in period 2; 59R in 6.4% in period 2. The pfdhfr 108N and the pfdhps 437G were seen in all samples along time; the pfdhps 540E in 93.7% in period 1 and in 75% in period 2. The 76T mutation associated to chloroquine resistance is still present in the parasite population, although this anti-malarial was withdrawn from the chemotherapy of P. falciparum in Brazil in the mid-1980s. All isolates assayed ex vivo for chloroquine showed resistant phenotype and 76T. No association was observed between pfmdr1 mutations and resistance to quinine, mefloquine and artemisinin derivatives. Additionally, the pfdhfr 108N mutation was detected in all samples throughout the evaluated periods, demonstrating fixation of the mutant allele in the parasite population. Changes in Brazilian national guidelines for the malaria chemotherapy in the last 27 years yielded a discreet genetic impact in the parasite population.

In vitro susceptibility to quinine and microsatellite variations of the Plasmodium falciparum Na+/H+ exchanger transporter (Pfnhe-1) gene in 393 isolates from Dakar, Senegal.

PubMed

Pascual, Aurélie; Fall, Bécaye; Wurtz, Nathalie; Fall, Mansour; Camara, Cheikhou; Nakoulima, Aminata; Baret, Eric; Diatta, Bakary; Fall, Khadidiatou Ba; Mbaye, Pape Saliou; Diémé, Yaya; Bercion, Raymond; Bogreau, Hervé; Briolant, Sébastien; Rogier, Christophe; Wade, Boubacar; Pradines, Bruno

2013-06-07

Although the World Health Organization recommends replacing quinine (QN) by artesunate due to its increased efficacy and the higher tolerance to the drug in both adults and children, QN remains a first-line treatment for severe malaria, especially in Africa. Investigations of microsatellite Pfnhe-1 ms4760 polymorphisms in culture-adapted isolates from around the world have revealed that an increase in the number of DNNND amino acid motifs was associated with decreased QN susceptibility, whereas an increase in the number of DDNHNDNHNND motifs was associated with increased QN susceptibility. In this context, to further analyse associations between Pfnhe-1 ms4760 polymorphisms and QN susceptibility, 393 isolates freshly collected between October 2009 and January 2010 and July 2010 and February 2011, respectively, at the Hôpital Principal de Dakar, Senegal were assessed ex vivo for QN susceptibility, and their genes were amplified and sequenced. Of the 393 Plasmodium falciparum clinical isolates collected, 145 were successfully cultured. The 145 QN IC50s ranged from 2.1 to 1291 nM, and 17 isolates (11.7%) exceed the QN reduced susceptibility threshold of 611 nM. Among the 393 P. falciparum clinical isolates, 47 different alleles were observed. The three most prevalent profiles were ms4760-1 (no = 72; 18.3%), ms4760-3 (no = 65; 16.5%) and ms4760-7 (no = 40; 10.2%). There were no significant associations observed between QN IC50 values and i) the number of repeats of DNNND in block II (p = 0.0955, Kruskal-Wallis test); ii) the number of repeats of DDNHNDNHNND in block V (p = 0.1455, Kruskal-Wallis test); or iii) ms4760 profiles (p = 0.1809, Kruskal-Wallis test). Pfnhe-1 ms4760 was highly diverse in parasite isolates from Dakar (47 different profiles). Three profiles (ms4760-1, ms4760-3 and ms4760-7) were predominant. The number of repeats for block II (DNNND) or block V (DDNHNDNHNND) was not significantly associated with QN susceptibility. New studies, and especially in vivo studies, are necessary to confirm the role of Pfnhe-1 ms4760 as a marker of QN resistance.

Image Guided Biodistribution and Pharmacokinetic Studies of Theranostics

PubMed Central

Ding, Hong; Wu, Fang

2012-01-01

Image guided technique is playing an increasingly important role in the investigation of the biodistribution and pharmacokinetics of drugs or drug delivery systems in various diseases, especially cancers. Besides anatomical imaging modalities such as computed tomography (CT), magnetic resonance imaging (MRI), molecular imaging strategy including optical imaging, positron emission tomography (PET) and single-photon emission computed tomography (SPECT) will facilitate the localization and quantization of radioisotope or optical probe labeled nanoparticle delivery systems in the category of theranostics. The quantitative measurement of the bio-distribution and pharmacokinetics of theranostics in the fields of new drug/probe development, diagnosis and treatment process monitoring as well as tracking the brain-blood-barrier (BBB) breaking through by high sensitive imaging method, and the applications of the representative imaging modalities are summarized in this review. PMID:23227121

Comparison of results for morphine urinalyses by radioimmunoassay and thin-layer chromatography in a narcotic clinic setting.

PubMed

Kokoski, R J; Jain, M

1975-03-01

Radioimmunoassay (RIA) and thin-layer chromatography (TLC) were compared for morphine detection in an actual narcotic clinic setting. A choice of urines from all those screened by TLC allowed a critical comparison as to actual use or non-use of narcotic drugs, rather than a sampling at random in which the question of possible false positives or negatives cannot be conclusively answered. Although RIA is more sensitive than TLC, its advantage is apparent only in those cases where urine specimens are difficult to obtain frequently regularly or where the use of morphine is suspected by the positive identification of quinine in urine that was morphine-negative by TLC. In a selected group of negative and positive specimens chosen without conscious bias, the two methods gave consistently similar results, indicating that the modified TLC method provided a few or no false positives or negatives if the negatives were from those cases that were not positive anytime up to 3-4 days before urine collection. We conclude that RIA can be of significant value as a supplement to a TLC screening program, without sacrificing the many advantages that TLC has to offer.

Antiplatelet activity of L-sulforaphane by regulation of platelet activation factors, glycoprotein IIb/IIIa and thromboxane A2.

PubMed

Oh, Chung-Hun; Shin, Jang-In; Mo, Sang Joon; Yun, Sung-Jo; Kim, Sung-Hoon; Rhee, Yun-Hee

2013-07-01

L-sulforaphane was identified as an anticarcinogen that could produce quinine reductase and a phase II detoxification enzyme. In recent decades, multi-effects of L-sulforaphane may have been investigated, but, to the authors' knowledge, the antiplatelet activation of L-sulforaphane has not been studied yet.In this study, 2 μg/ml of collagen, 50 μg/ml of ADP and 5 μg/ml of thrombin were used for platelet aggregations with or without L-sulforaphane. L-sulforaphane inhibited the platelet aggregation dose-dependently. Among these platelet activators, collagen was most inhibited by L-sulforaphane, which markedly decreased collagen-induced glycoprotein IIb/IIIa activation and thromboxane A2 (TxA2) formation in vitro. L-sulforaphane also reduced the collagen and epinephrine-induced pulmonary embolism, but did not affect prothrombin time (PT) in vivo. This finding demonstrated that L-sulforaphane inhibited the platelet activation through an intrinsic pathway.L-sulforaphane had a beneficial effect on various pathophysiological pathways of the collagen-induced platelet aggregation and thrombus formation as a selective inhibition of cyclooxygenase and glycoprotein IIb/IIIa antagonist. Thus, we recommend L-sulforaphane as a potential antithrombotic drug.

In Situ Probing Intracellular Drug Release from Redox-Responsive Micelles by United FRET and AIE.

PubMed

Wang, Xuelin; Li, Juanjuan; Yan, Qi; Chen, Yanrui; Fan, Aiping; Wang, Zheng; Zhao, Yanjun

2018-03-01

Redox-responsive micelles are versatile nanoplatforms for on-demand drug delivery, but the in situ evaluation of drug release is challenging. Fluorescence resonance energy transfer (FRET) technique shows potential for addressing this, while the aggregation-caused quenching effect limits the assay sensitivity. The aim of the current work is to combine aggregation-induced emission (AIE) probe with FRET to realize drug release assessment from micelles. Tetraphenylethene (TPE) is selected as AIE dye and curcumin (Cur) is chosen as the model drug as well as FRET receptor. The drug is covalently linked to a block copolymer via the disulfide bond linker and TPE is also chemically linked to the polymer via an amide bond; the obtained amphiphilic polymer conjugate self-assembles into micelles with a hydrodynamic size of ≈125 nm. Upon the supplement of glutathione or tris(2-carboxyethyl)phosphine) trigger (10 × 10 -3 m), the drug release induces the fluorescence increase of both TPE and Cur. Accompanied with the FRET decay, absorption enhancement and particle size increase are observed. The same phenomenon is observed in MCF-7 cells. The FRET-AIE approach can be a useful addition to the spectrum of available methods for monitoring drug release from stimuli-responsive nanomedicine. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Role of Cytochrome P450 3A4 and 1A2 Phenotyping in Patients with Advanced Non-small-Cell Lung Cancer Receiving Erlotinib Treatment.

PubMed

Parra-Guillen, Zinnia P; Berger, Peter B; Haschke, Manuel; Donzelli, Massimiliano; Winogradova, Daria; Pfister, Bogumila; Früh, Martin; Gillessen, Silke; Krähenbühl, Stephan; Kloft, Charlotte; Joerger, Markus

2017-10-01

Erlotinib is metabolized by cytochrome p450 (CYP) 3A and CYP1A. This study assessed CYP3A4 (midazolam) and CYP1A2 (caffeine) phenotyping in plasma and dried blood spots (DBS) for predicting the pharmacokinetics and toxicity of erlotinib in 36 patients with advanced NSCLC. On day 1, erlotinib 150 mg OD was initiated, and the two oral probe drugs midazolam (2 mg) and caffeine (100 mg) were added on day 1. Plasma and DBS were collected for erlotinib, OSI-420 and probe drugs for up to 6 hr on day 1 and 2-weekly up to week 10. Probe drugs, erlotinib and OSI-420 were analysed using LC-MS-MS, and PK data were processed using population modelling. A high correlation was found between plasma and DBS concentrations for erlotinib (R 2  = 0.960, p < 0.0001), OSI-420 (R 2  = 0.971, p < 0.0001), midazolam (R 2  = 0.995, p < 0.0001) and caffeine (R 2  = 0.968, p < 0.0001). Apparent oral caffeine clearance was significantly correlated with erlotinib clearance (R 2  = 0.33, p = 0.048), while midazolam clearance was not (R 2  = -0.09, p = 0.596). Erlotinib clearance was lower in patients experiencing grade 2 or 3 rash as compared to patients experiencing grade 0 or 1 rash (3.15 versus 3.93 L/hr, p = 0.086 for Student's t-test). The results suggest that probe drug phenotyping is unlikely to substitute therapeutic drug monitoring of erlotinib in patients with advanced NSCLC, but erlotinib PK sampling from DBS may replace more invasive venous sampling and facilitate TDM in patients with cancer. © 2017 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).

Development of novel small molecules for imaging and drug release

NASA Astrophysics Data System (ADS)

Cao, Yanting

Small organic molecules, including small molecule based fluorescent probes, small molecule based drugs or prodrugs, and smart multifunctional fluorescent drug delivery systems play important roles in biological research, drug discovery, and clinical practices. Despite the significant progress made in these fields, the development of novel and diverse small molecules is needed to meet various demands for research and clinical applications. My Ph.D study focuses on the development of novel functional molecules for recognition, imaging and drug release. In the first part, a turn-on fluorescent probe is developed for the detection of intracellular adenosine-5'-triphosphate (ATP) levels based on multiplexing recognitions. Considering the unique and complicated structure of ATP molecules, a fluorescent probe has been implemented with improved sensitivity and selectivity due to two synergistic binding recognitions by incorporating of 2, 2'-dipicolylamine (Dpa)-Zn(II) for targeting of phospho anions and phenylboronic acid group for cis-diol moiety. The novel probe is able to detect intracellular ATP levels in SH-SY5Y cells. Meanwhile, the advantages of multiplexing recognition design concept have been demonstrated using two control molecules. In the second part, a prodrug system is developed to deliver multiple drugs within one small molecule entity. The prodrug is designed by using 1-(2-nitrophenyl)ethyl (NPE) as phototrigger, and biphenol biquaternary ammonium as the prodrug. With controlled photo activation, both DNA cross-linking agents mechlorethamine and o-quinone methide are delivered and released at the preferred site, leading to efficient DNA cross-links formation and cell death. The prodrug shows negligible cytotoxicity towards normal skin cells (Hekn cells) with and without UV activation, but displays potent activity towards cancer cells (HeLa cells) upon UV activation. The multiple drug release system may hold a great potential for practical application. In the last part, a new photo-initiated fluorescent anticancer prodrug for DNA alkylating agent mechlorethamine releasing and monitoring has been developed. The theranostic prodrug consists a photolabile NPE group, an inactive form of mechlorethamine and a nonfluorescent coumarin in one small molecule. It is demonstrated that the prodrug shows negligible cytotoxicity towards normal skin cells (Hekn cells) with and without UV activation, while the original parent drug mechlorethamine can be photocontrol-released and induces effective DNA cross-linking activity. Importantly, the drug release progress can be conveniently monitored by the 'off-on' fluorescence enhancement in cells. Moreover, the selective prodrug is not only cell permeable but also nuclear permeable. Therefore, the prodrug serves as a promising drug delivery system for spatiotemporal control release and monitoring of an anticancer drug to obtain the optimal treatment efficacy.

Electron Microscopy of Intracellular Protozoa.

DTIC Science & Technology

1979-08-15

parxysm due to the increased metabolism during the fever or to hepatic cell damage. In P. knowlesi infection in monkeys, 23 I. I hypoglyceinia has...convoluted and collecting tubules (Winslow et al. , 1975). Blackwater fever is an acute hemolytic condition associated with fever , anemia, jaundice, and...history of irregular chemosuppression or inadequate chemotherapy, especially with quinine. The diagnosis of blackwatcr fever can be made only in patients

Bananas and Balsa, Quetzals and Quinine: A Rainforest Unit for Science and Language Arts.

ERIC Educational Resources Information Center

Pottle, Jean L.

The destruction of rain forests and the impact this has on the earth is an important environmental issue. This book was written to help students learn why it is important to protect those areas of the world. In this activity book, students are introduced to a number of inhabitants of the rain forest. They learn about the diversity of plants and…

Nature's Chiral Catalyst and Anti-Malarial Agent: Isolation and Structure Elucidation of Cinchonine and Quinine from "Cinchona calisaya"

ERIC Educational Resources Information Center

Carroll, Anne-Marie; Kavanagh, David J.; McGovern, Fiona P.; Reilly, Joe W.; Walsh, John J.

2012-01-01

Nature is a well-recognized source of compounds of interest, but access is often an issue. One pertinent example is the cinchona alkaloids from the bark of "Cinchona calisaya." In this experiment, students at the third-year undergraduate level undertake the selective isolation and characterization of two of the four main alkaloids present in the…

First-Generation H1 Antihistamines Found in Pilot Fatalities of Civil Aviation Accidents, 1990-2005

DTIC Science & Technology

2007-05-01

ephedrine, paroxetine, phenylpropanolamine, pseudoephedrine , quinine, and/or tetrahydrocannabinol carboxylic acid—were also present in the fatalities...antihistamine (Table II). Chlorpheniramine, ephedrine, phenylpropanolamine, and pseudoephedrine were also detected in one case and pheniramine and...detected in both cases and pseudoephedrine in 1. Blood was not available in either case. Pheniramine: This antihistamine was found in just 1 fatality

A Three-Dimensional DOSY HMQC Experiment for the High-Resolution Analysis of Complex Mixtures

NASA Astrophysics Data System (ADS)

Barjat, Hervé; Morris, Gareth A.; Swanson, Alistair G.

1998-03-01

A three-dimensional experiment is described in which NMR signals are separated according to their proton chemical shift,13C chemical shift, and diffusion coefficient. The sequence is built up from a stimulated echo sequence with bipolar field gradient pulses and a conventional decoupled HMQC sequence. Results are presented for a model mixture of quinine, camphene, and geraniol in deuteriomethanol.

Symmetry- and Solvent-Dependent Photophysics of Fluorenes Containing Donor and Acceptor Groups (Postprint)

DTIC Science & Technology

2014-07-01

available to the general public, including foreign nationals. Copies may be obtained from the Defense Technical Information Center (DTIC) (http...EXPERIMENTAL SECTION Instrumentation. NMR spectra were obtained using a Bruker Avance 400 MHz spectrometer, and chemical shifts were referenced to...yields were determined using the actinometry method previously described.37 Quinine sulfate was used as an actinometer with a known fluorescence quantum

Malaria's contribution to World War One - the unexpected adversary.

PubMed

Brabin, Bernard J

2014-12-16

Malaria in the First World War was an unexpected adversary. In 1914, the scientific community had access to new knowledge on transmission of malaria parasites and their control, but the military were unprepared, and underestimated the nature, magnitude and dispersion of this enemy. In summarizing available information for allied and axis military forces, this review contextualizes the challenge posed by malaria, because although data exist across historical, medical and military documents, descriptions are fragmented, often addressing context specific issues. Military malaria surveillance statistics have, therefore, been summarized for all theatres of the War, where available. These indicated that at least 1.5 million solders were infected, with case fatality ranging from 0.2 -5.0%. As more countries became engaged in the War, the problem grew in size, leading to major epidemics in Macedonia, Palestine, Mesopotamia and Italy. Trans-continental passages of parasites and human reservoirs of infection created ideal circumstances for parasite evolution. Details of these epidemics are reviewed, including major epidemics in England and Italy, which developed following home troop evacuations, and disruption of malaria control activities in Italy. Elsewhere, in sub-Saharan Africa many casualties resulted from high malaria exposure combined with minimal control efforts for soldiers considered semi-immune. Prevention activities eventually started but were initially poorly organized and dependent on local enthusiasm and initiative. Nets had to be designed for field use and were fundamental for personal protection. Multiple prevention approaches adopted in different settings and their relative utility are described. Clinical treatment primarily depended on quinine, although efficacy was poor as relapsing Plasmodium vivax and recrudescent Plasmodium falciparum infections were not distinguished and managed appropriately. Reasons for this are discussed and the clinical trial data summarized, as are controversies that arose from attempts at quinine prophylaxis (quininization). In essence, the First World War was a vast experiment in political, demographic, and medical practice which exposed large gaps in knowledge of tropical medicine and unfortunately, of malaria. Research efforts eventually commenced late in the War to address important clinical questions which established a platform for more effective strategies, but in 1918 this relentless foe had outwitted and weakened both allied and axis powers.

Nonpeptide-Based Small-Molecule Probe for Fluorogenic and Chromogenic Detection of Chymotrypsin.

PubMed

Wu, Lei; Yang, Shu-Hou; Xiong, Hao; Yang, Jia-Qian; Guo, Jun; Yang, Wen-Chao; Yang, Guang-Fu

2017-03-21

We report herein a nonpeptide-based small-molecule probe for fluorogenic and chromogenic detection of chymotrypsin, as well as the primary application for this probe. This probe was rationally designed by mimicking the peptide substrate and optimized by adjusting the recognition group. The refined probe 2 exhibits good specificity toward chymotrypsin, producing about 25-fold higher enhancement in both the fluorescence intensity and absorbance upon the catalysis by chymotrypsin. Compared with the most widely used peptide substrate (AMC-FPAA-Suc) of chymotrypsin, probe 2 shows about 5-fold higher binding affinity and comparable catalytical efficiency against chymotrypsin. Furthermore, it was successfully applied for the inhibitor characterization. To the best of our knowledge, probe 2 is the first nonpeptide-based small-molecule probe for chymotrypsin, with the advantages of simple structure and high sensitivity compared to the widely used peptide-based substrates. This small-molecule probe is expected to be a useful molecular tool for drug discovery and chymotrypsin-related disease diagnosis.

Impact of body weight, low energy diet and gastric bypass on drug bioavailability, cardiovascular risk factors and metabolic biomarkers: protocol for an open, non-randomised, three-armed single centre study (COCKTAIL)

PubMed Central

Andersson, Shalini; Sandbu, Rune; Robertsen, Ida; Johnson, Line Kristin; Angeles, Philip Carlo; Hertel, Jens Kristoffer; Skovlund, Eva; Heijer, Maria; Ek, Anna-Lena; Krogstad, Veronica; Karlsen, Tor-Ivar; Christensen, Hege; Andersson, Tommy B; Karlsson, Cecilia

2018-01-01

Introduction Roux-en-Y gastric bypass (GBP) is associated with changes in cardiometabolic risk factors and bioavailability of drugs, but whether these changes are induced by calorie restriction, the weight loss or surgery per se, remains uncertain. The COCKTAIL study was designed to disentangle the short-term (6 weeks) metabolic and pharmacokinetic effects of GBP and a very low energy diet (VLED) by inducing a similar weight loss in the two groups. Methods and analysis This open, non-randomised, three-armed, single-centre study is performed at a tertiary care centre in Norway. It aims to compare the short-term (6 weeks) and long-term (2 years) effects of GBP and VLED on, first, bioavailability and pharmacokinetics (24 hours) of probe drugs and biomarkers and, second, their effects on metabolism, cardiometabolic risk factors and biomarkers. The primary outcomes will be measured as changes in: (1) all six probe drugs by absolute bioavailability area under the curve (AUCoral/AUCiv) of midazolam (CYP3A4 probe), systemic exposure (AUCoral) of digoxin and rosuvastatin and drug:metabolite ratios for omeprazole, losartan and caffeine, levels of endogenous CYP3A biomarkers and genotypic variation, changes in the expression and activity data of the drug-metabolising, drug transport and drug regulatory proteins in biopsies from various organs and (2) body composition, cardiometabolic risk factors and metabolic biomarkers. Ethics and dissemination The COCKTAIL protocol was reviewed and approved by the Regional Committee for Medical and Health Research Ethics (Ref: 2013/2379/REK sørøst A). The results will be disseminated to academic and health professional audiences and the public via presentations at conferences, publications in peer-reviewed journals and press releases and provided to all participants. Trial registration number NCT02386917. PMID:29844102

Predicting transporter-mediated drug interactions: Commentary on: "Pharmacokinetic evaluation of a drug transporter cocktail consisting of digoxin, furosemide, metformin and rosuvastatin" and "Validation of a microdose probe drug cocktail for clinical drug interaction assessments for drug transporters and CYP3A".

PubMed

Zhang, L; Sparreboom, A

2017-04-01

Transporters, expressed in various tissues, govern the absorption, distribution, metabolism, and excretion of drugs, and consequently their inherent safety and efficacy profiles. Drugs may interact with a transporter as a substrate and/or an inhibitor. Understanding transporter-mediated drug-drug interactions (DDIs), in addition to enzyme-mediated DDIs, is an integral part of risk assessment in drug development and regulatory review because the concomitant use of more than one medication in patients is common. © 2016 ASCPT.

Synthesis, characterization and target protein binding of drug-conjugated quantum dots in vitro and in living cells

NASA Astrophysics Data System (ADS)

Choi, Youngseon; Kim, Minjung; Cho, Yoojin; Yun, Eunsuk; Song, Rita

2013-02-01

Elucidation of unknown target proteins of a drug is of great importance in understanding cell biology and drug discovery. There have been extensive studies to discover and identify target proteins in the cell. Visualization of targets using drug-conjugated probes has been an important approach to gathering mechanistic information of drug action at the cellular level. As quantum dot (QD) nanocrystals have attracted much attention as a fluorescent probe in the bioimaging area, we prepared drug-conjugated QD to explore the potential of target discovery. As a model drug, we selected a well-known anticancer drug, methotrexate (MTX), which has been known to target dihydrofolate reductase (DHFR) with high affinity binding (Kd = 0.54 nM). MTX molecules were covalently attached to amino-PEG-polymer-coated QDs. Specific interactions of MTX-conjugated QDs with DHFR were identified using agarose gel electrophoresis and fluorescence microscopy. Cellular uptake of the MTX-conjugated QDs in living CHO cells was investigated with regard to their localization and distribution pattern. MTX-QD was found to be internalized into the cells via caveolae-medicated endocytosis without significant sequestration in endosomes. A colocalization experiment of the MTX-QD conjugate with antiDHFR-TAT-QD also confirmed that MTX-QD binds to the target DHFR. This study showed the potential of the drug-QD conjugate to identify or visualize drug-target interactions in the cell, which is currently of great importance in the area of drug discovery and chemical biology.

Design, synthesis and DNA-binding study of some novel morpholine linked thiazolidinone derivatives

NASA Astrophysics Data System (ADS)

War, Javeed Ahmad; Srivastava, Santosh Kumar; Srivastava, Savitri Devi

2017-02-01

The emergence of multiple drug resistance amongst bacterial strains resulted in many clinical drugs to be ineffective. Being vulnerable to bacterial infections any lack in the development of new antimicrobial drugs could pose a serious threat to public health. Here we report design and synthesis of a novel class of morpholine linked thiazolidinone hybrid molecules. The compounds were characterized by FT-IR, NMR and HRMS techniques. Susceptibility tests showed that most of the synthesized molecules were highly active against multiple bacterial strains. Compound 3f displayed MIC values which were better than the standard drug for most of the tested strains. DNA being a well defined target for many antimicrobial drugs was probed as possible target for these synthetic molecules. DNA-binding study of 3f with sm-DNA was probed through UV-vis absorption, fluorescence quenching, gel electrophoresis and molecular docking techniques. The studies revealed that compound 3f has strong affinity towards DNA and binds at the minor groove. The docking studies revealed that the compound 3f shows preferential binding towards A/T residues.

Design, synthesis and DNA-binding study of some novel morpholine linked thiazolidinone derivatives.

PubMed

War, Javeed Ahmad; Srivastava, Santosh Kumar; Srivastava, Savitri Devi

2017-02-15

The emergence of multiple drug resistance amongst bacterial strains resulted in many clinical drugs to be ineffective. Being vulnerable to bacterial infections any lack in the development of new antimicrobial drugs could pose a serious threat to public health. Here we report design and synthesis of a novel class of morpholine linked thiazolidinone hybrid molecules. The compounds were characterized by FT-IR, NMR and HRMS techniques. Susceptibility tests showed that most of the synthesized molecules were highly active against multiple bacterial strains. Compound 3f displayed MIC values which were better than the standard drug for most of the tested strains. DNA being a well defined target for many antimicrobial drugs was probed as possible target for these synthetic molecules. DNA-binding study of 3f with sm-DNA was probed through UV-vis absorption, fluorescence quenching, gel electrophoresis and molecular docking techniques. The studies revealed that compound 3f has strong affinity towards DNA and binds at the minor groove. The docking studies revealed that the compound 3f shows preferential binding towards A/T residues. Copyright © 2016 Elsevier B.V. All rights reserved.

Pharmacokinetic Drug Interactions with Panax ginseng.

PubMed

Ramanathan, Meenakshi R; Penzak, Scott R

2017-08-01

Panax ginseng is widely used as an adaptogen throughout the world. The major active constituents of P. ginseng are ginsenosides. Most naturally occurring ginsenosides are deglycosylated by colonic bacteria to intestinal metabolites. Ginsenosides along with these metabolites are widely accepted as being responsible for the pharmacologic activity and drug interaction potential of ginseng. Numerous preclinical studies have assessed the influence of various ginseng components on cytochrome P450 (CYP), glucuronidation, and drug transport activity. Results from these investigations have been largely inconclusive due to the use of different ginseng products and variations in methodology between studies. Drug interaction studies in humans have been conflicting and have largely yielded negative results or results that suggest only a weak interaction. One study using a midazolam probe found weak CYP3A induction and another using a fexofenadine probe found weak P-gp inhibition. Despite several case reports indicating a drug interaction between warfarin and P. ginseng, pharmacokinetic studies involving these agents in combination have failed to find significant pharmacokinetic or pharmacodynamic interactions. To this end, drug interactions involving P. ginseng appear to be rare; however, close clinical monitoring is still suggested for patients taking warfarin or CYP3A or P-gp substrates with narrow therapeutic indices.

Organic synthesis toward small-molecule probes and drugs

PubMed Central

Schreiber, Stuart L.

2011-01-01

“Organic synthesis” is a compound-creating activity often focused on biologically active small molecules. This special issue of PNAS explores innovations and trends in the field that are enabling the synthesis of new types of small-molecule probes and drugs. This perspective article frames the research described in the special issue but also explores how these modern capabilities can both foster a new and more extensive view of basic research in the academy and promote the linkage of life-science research to the discovery of novel types of small-molecule therapeutics [Schreiber SL (2009) Chem Bio Chem 10:26–29]. This new view of basic research aims to bridge the chasm between basic scientific discoveries in life sciences and new drugs that treat the root cause of human disease—recently referred to as the “valley of death” for drug discovery. This perspective article describes new roles that modern organic chemistry will need to play in overcoming this challenge. PMID:21464328

Numerical simulation of magnetic nano drug targeting in patient-specific lower respiratory tract

NASA Astrophysics Data System (ADS)

Russo, Flavia; Boghi, Andrea; Gori, Fabio

2018-04-01

Magnetic nano drug targeting, with an external magnetic field, can potentially improve the drug absorption in specific locations of the body. However, the effectiveness of the procedure can be reduced due to the limitations of the magnetic field intensity. This work investigates this technique with the Computational Fluid Dynamics (CFD) approach. A single rectangular coil generates the external magnetic field. A patient-specific geometry of the Trachea, with its primary and secondary bronchi, is reconstructed from Digital Imaging and Communications in Medicine (DICOM) formatted images, throughout the Vascular Modelling Tool Kit (VMTK) software. A solver, coupling the Lagrangian dynamics of the magnetic nanoparticles with the Eulerian dynamics of the air, is used to perform the simulations. The resistive pressure, the pulsatile inlet velocity and the rectangular coil magnetic field are the boundary conditions. The dynamics of the injected particles is investigated without and with the magnetic probe. The flow field promotes particles adhesion to the tracheal wall. The particles volumetric flow rate in both cases has been calculated. The magnetic probe is shown to increase the particles flow in the target region, but at a limited extent. This behavior has been attributed to the small particle size and the probe configuration.

Understanding API-polymer proximities in amorphous stabilized composite drug products using fluorine-carbon 2D HETCOR solid-state NMR.

PubMed

Abraham, Anuji; Crull, George

2014-10-06

A simple and robust method for obtaining fluorine-carbon proximities was established using a (19)F-(13)C heteronuclear correlation (HETCOR) two-dimensional (2D) solid-state nuclear magnetic resonance (ssNMR) experiment under magic-angle spinning (MAS). The method was applied to study a crystalline active pharmaceutical ingredient (API), avagacestat, containing two types of fluorine atoms and its API-polymer composite drug product. These results provide insight into the molecular structure, aid with assigning the carbon resonances, and probe API-polymer proximities in amorphous spray dried dispersions (SDD). This method has an advantage over the commonly used (1)H-(13)C HETCOR because of the large chemical shift dispersion in the fluorine dimension. In the present study, fluorine-carbon distances up to 8 Å were probed, giving insight into the API structure, crystal packing, and assignments. Most importantly, the study demonstrates a method for probing an intimate molecular level contact between an amorphous API and a polymer in an SDD, giving insights into molecular association and understanding of the role of the polymer in API stability (such as recrystallization, degradation, etc.) in such novel composite drug products.

Seven novel probe systems for real-time PCR provide absolute single-base discrimination, higher signaling, and generic components.

PubMed

Murray, James L; Hu, Peixu; Shafer, David A

2014-11-01

We have developed novel probe systems for real-time PCR that provide higher specificity, greater sensitivity, and lower cost relative to dual-labeled probes. The seven DNA Detection Switch (DDS)-probe systems reported here employ two interacting polynucleotide components: a fluorescently labeled probe and a quencher antiprobe. High-fidelity detection is achieved with three DDS designs: two internal probes (internal DDS and Flip probes) and a primer probe (ZIPR probe), wherein each probe is combined with a carefully engineered, slightly mismatched, error-checking antiprobe. The antiprobe blocks off-target detection over a wide range of temperatures and facilitates multiplexing. Other designs (Universal probe, Half-Universal probe, and MacMan probe) use generic components that enable low-cost detection. Finally, single-molecule G-Force probes employ guanine-mediated fluorescent quenching by forming a hairpin between adjacent C-rich and G-rich sequences. Examples provided show how these probe technologies discriminate drug-resistant Mycobacterium tuberculosis mutants, Escherichia coli O157:H7, oncogenic EGFR deletion mutations, hepatitis B virus, influenza A/B strains, and single-nucleotide polymorphisms in the human VKORC1 gene. Copyright © 2014 American Society for Investigative Pathology and the Association for Molecular Pathology. Published by Elsevier Inc. All rights reserved.

Dose critical in-vivo detection of anti-cancer drug levels in blood

DOEpatents

Miller, Holly H.; Hirschfeld, deceased, Tomas B.

1991-01-01

A method and apparatus are disclosed for the in vivo and in vitro detection and measurement of dose critical levels of DNA-binding anti-cancer drug levels in biological fluids. The apparatus comprises a laser based fiber optic sensor (optrode) which utilizes the secondary interactions between the drug and an intercalating fluorochrome bound to a probe DNA, which in turn is attached to the fiber tip at one end thereof. The other end of the optical fiber is attached to an illumination source, detector and recorder. The fluorescence intensity is measured as a function of the drug concentration and its binding constant to the probe DNA. Anticancer drugs which lend themselves to analysis by the use of the method and the optrode of the present invention include doxorubicin, daunorubicin, carminomycin, aclacinomycin, chlorambucil, cyclophosphamide, methotrexate, 5-uracil, arabinosyl cytosine, mitomycin, cis-platinum 11 diamine dichloride procarbazine, vinblastine vincristine and the like. The present method and device are suitable for the continuous monitoring of the levels of these and other anticancer drugs in biological fluids such as blood, serum, urine and the like. The optrode of the instant invention also enables the measurement of the levels of these drugs from a remote location and from multiple samples.

In situ probing the interior of single bacterial cells at nanometer scale

NASA Astrophysics Data System (ADS)

Liu, Boyin; Hemayet Uddin, Md; Ng, Tuck Wah; Paterson, David L.; Velkov, Tony; Li, Jian; Fu, Jing

2014-10-01

We report a novel approach to probe the interior of single bacterial cells at nanometre resolution by combining focused ion beam (FIB) and atomic force microscopy (AFM). After removing layers of pre-defined thickness in the order of 100 nm on the target bacterial cells with FIB milling, AFM of different modes can be employed to probe the cellular interior under both ambient and aqueous environments. Our initial investigations focused on the surface topology induced by FIB milling and the hydration effects on AFM measurements, followed by assessment of the sample protocols. With fine-tuning of the process parameters, in situ AFM probing beneath the bacterial cell wall was achieved for the first time. We further demonstrate the proposed method by performing a spatial mapping of intracellular elasticity and chemistry of the multi-drug resistant strain Klebsiella pneumoniae cells prior to and after it was exposed to the ‘last-line’ antibiotic polymyxin B. Our results revealed increased stiffness occurring in both surface and interior regions of the treated cells, suggesting loss of integrity of the outer membrane from polymyxin treatments. In addition, the hydrophobicity measurement using a functionalized AFM tip was able to highlight the evident hydrophobic portion of the cell such as the regions containing cell membrane. We expect that the proposed FIB-AFM platform will help in gaining deeper insights of bacteria-drug interactions to develop potential strategies for combating multi-drug resistance.

Development of Si neural probe with piezoresistive force sensor for minimally invasive and precise monitoring of insertion forces

NASA Astrophysics Data System (ADS)

Harashima, Takuya; Morikawa, Takumi; Kino, Hisashi; Fukushima, Takafumi; Tanaka, Tetsu

2017-04-01

A Si neural probe is one of the most important tools for neurophysiology and brain science because of its various functions such as optical stimulation and drug delivery. However, the Si neural probe is not robust compared with a metal tetrode, and could be broken by mechanical stress caused by insertion to the brain. Therefore, the Si neural probe becomes more useful if it has a stress sensor that can measure mechanical forces applied to the probe so as not to be broken. In this paper, we proposed and fabricated the Si neural probe with a piezoresistive force sensor for minimally invasive and precise monitoring of insertion forces. The fabricated piezoresistive force sensor accurately measured forces and successfully detected insertion events without buckling or bending in the shank of the Si neural probe. This Si neural probe with a piezoresistive force sensor has become one of the most versatile tools for neurophysiology and brain science.

Silk and PEG as means to stiffen a parylene probe for insertion in the brain: toward a double time-scale tool for local drug delivery

NASA Astrophysics Data System (ADS)

Lecomte, A.; Castagnola, V.; Descamps, E.; Dahan, L.; Blatché, M. C.; Dinis, T. M.; Leclerc, E.; Egles, C.; Bergaud, C.

2015-12-01

The use of soft materials as substrate for neural probes aims at achieving better compliance with the surrounding neurons while maintaining minimal rejection. Many strategies have emerged to enable such probes to penetrate the cortex, among which the use of resorbable polymers. We performed several tests involving two resorbable polymers considered most promising: polyethylene glycol (PEG) and silk fibroin (SF) from Bombyx Mori silkworms. Our coating method provides a repeatable, uniform structure optimized for a stress-reduced insertion of a parylene-C neural probe. Standard compression tests as well as in vitro and in vivo insertion assessments show that both SF and PEG-coated probes are stiff enough to avoid the buckling effect during insertion in the cortex. However, with a buckling force of 300 mN and a mechanical holding in vitro of tens of minutes, we assess silk fibroin to be more reliable for practical handling. In vivo first try-outs in mouse brain showed neither buckling issues of the probe nor undesired alteration of the signal recording. Moreover, we evidenced two distinct time scales in the bioresorption of our polymer coatings: silk fibroin degrades itself in a matter of weeks and PEG dissolves itself within seconds in the presence of water. We then present a hybrid PEG and SF coating that could be used as a drug delivery system with different time scales to reduce both the acute and the chronic body reaction.

Design, synthesis, and biological evaluation of 6-methoxy-2-arylquinolines as potential P-glycoprotein inhibitors.

PubMed

Aboutorabzadeh, Sayyed Mohammad; Mosaffa, Fatemeh; Hadizadeh, Farzin; Ghodsi, Razieh

2018-01-01

In the present study, a new series of 6-methoxy-2-arylquinoline analogues was designed and synthesized as P-glycoprotein (P-gp) inhibitors using quinine and flavones as the lead compounds. The cytotoxic activity of the synthesized compounds was evaluated against two human cancer cell lines including EPG85-257RDB, multidrug-resistant gastric carcinoma cells (P-gp-positive gastric carcinoma cell line), and EPG85-257P, drug-sensitive gastric carcinoma cells. Compounds showing low to moderate toxicity in the MTT test were selected to investigate their P-gp inhibition activity. Moreover, trying to explain the results of biological experiments, docking studies of the selected compounds into the homology-modeled human P-gp, were carried out. The physicochemical and ADME properties of the compounds as drug candidate were also predicted. Most of our compounds exhibited negligible or much lower cytotoxic effect in both cancer cells. Among the series, 5a and 5b, alcoholic quinoline derivatives were found to inhibit the efflux of rhodamine 123 at the concentration of 10 μM significantly. Among the tested quinolines, 5a and 5b showed the most potent P-gp inhibitory activity in the series and were 1.3-fold and 2.1-fold stronger than verapamil, respectively. SAR data revealed that hydroxyl methyl in position 4 of quinolines has a key role in P-gp efflux inhibition of our compounds. ADME studies suggested that all of the compounds included in this study may have a good human intestinal absorption.

Selective breeding for magnitude of methamphetamine-induced sensitization alters methamphetamine consumption

PubMed Central

Scibelli, Angela C.; McKinnon, Carrie S.; Reed, Cheryl; Burkhart-Kasch, Sue; Li, Na; Baba, Harue; Wheeler, Jeanna M.

2012-01-01

Rationale Genetically determined differences in susceptibility to drug-induced sensitization could be related to risk for drug consumption. Objectives Studies were performed to determine whether selective breeding could be used to create lines of mice with different magnitudes of locomotor sensitization to methamphetamine (MA). MA sensitization (MASENS) lines were also examined for genetically correlated responses to MA. Methods Beginning with the F2 cross of C57BL/6J and DBA/2J strains, mice were tested for locomotor sensitization to repeated injections of 1 mg/kg MA and bred based on magnitude of sensitization. Five selected offspring generations were tested. All generations were also tested for MA consumption, and some were tested for dose-dependent locomotor-stimulant responses to MA, consumption of saccharin, quinine, and potassium chloride as a measure of taste sensitivity, and MA clearance after acute and repeated MA. Results Selective breeding resulted in creation of two lines [MA high sensitization (MAHSENS) and MA low sensitization (MALSENS)] that differed in magnitude of MA-induced sensitization. Initially, greater MA consumption in MAHSENS mice reversed over the course of selection so that MALSENS mice consumed more MA. MAHSENS mice exhibited greater sensitivity to the acute stimulant effects of MA, but there were no significant differences between the lines in MA clearance from blood. Conclusions Genetic factors influence magnitude of MA-induced locomotor sensitization and some of the genes involved in magnitude of this response also influence MA sensitivity and consumption. Genetic factors leading to greater MA-induced sensitization may serve a protective role against high levels of MA consumption. PMID:21088960

Habituation in non-neural organisms: evidence from slime moulds.

PubMed

Boisseau, Romain P; Vogel, David; Dussutour, Audrey

2016-04-27

Learning, defined as a change in behaviour evoked by experience, has hitherto been investigated almost exclusively in multicellular neural organisms. Evidence for learning in non-neural multicellular organisms is scant, and only a few unequivocal reports of learning have been described in single-celled organisms. Here we demonstrate habituation, an unmistakable form of learning, in the non-neural organism Physarum polycephalum In our experiment, using chemotaxis as the behavioural output and quinine or caffeine as the stimulus, we showed that P. polycephalum learnt to ignore quinine or caffeine when the stimuli were repeated, but responded again when the stimulus was withheld for a certain time. Our results meet the principle criteria that have been used to demonstrate habituation: responsiveness decline and spontaneous recovery. To distinguish habituation from sensory adaptation or motor fatigue, we also show stimulus specificity. Our results point to the diversity of organisms lacking neurons, which likely display a hitherto unrecognized capacity for learning, and suggest that slime moulds may be an ideal model system in which to investigate fundamental mechanisms underlying learning processes. Besides, documenting learning in non-neural organisms such as slime moulds is centrally important to a comprehensive, phylogenetic understanding of when and where in the tree of life the earliest manifestations of learning evolved. © 2016 The Author(s).

Bumblebees are not deterred by ecologically relevant concentrations of nectar toxins.

PubMed

Tiedeken, Erin Jo; Stout, Jane C; Stevenson, Philip C; Wright, Geraldine A

2014-05-01

Bees visit flowers to collect nectar and pollen that contain nutrients and simultaneously facilitate plant sexual reproduction. Paradoxically, nectar produced to attract pollinators often contains deterrent or toxic plant compounds associated with herbivore defence. The functional significance of these nectar toxins is not fully understood, but they may have a negative impact on pollinator behaviour and health, and, ultimately, plant pollination. This study investigates whether a generalist bumblebee, Bombus terrestris, can detect naturally occurring concentrations of nectar toxins. Using paired-choice experiments, we identified deterrence thresholds for five compounds found in the nectar of bee-pollinated plants: quinine, caffeine, nicotine, amygdalin and grayanotoxin. The deterrence threshold was determined when bumblebees significantly preferred a sucrose solution over a sucrose solution containing the compound. Bumblebees had the lowest deterrence threshold for the alkaloid quinine (0.01 mmol l(-1)); all other compounds had higher deterrence thresholds, above the natural concentration range in floral nectar. Our data, combined with previous work using honeybees, suggest that generalist bee species have poor acuity for the detection of nectar toxins. The fact that bees do not avoid nectar-relevant concentrations of these compounds likely indicates that it is difficult for them to learn to associate floral traits with the presence of toxins, thus maintaining this trait in plant populations.

Bumblebees are not deterred by ecologically relevant concentrations of nectar toxins

PubMed Central

Tiedeken, Erin Jo; Stout, Jane C.; Stevenson, Philip C.; Wright, Geraldine A.

2014-01-01

Bees visit flowers to collect nectar and pollen that contain nutrients and simultaneously facilitate plant sexual reproduction. Paradoxically, nectar produced to attract pollinators often contains deterrent or toxic plant compounds associated with herbivore defence. The functional significance of these nectar toxins is not fully understood, but they may have a negative impact on pollinator behaviour and health, and, ultimately, plant pollination. This study investigates whether a generalist bumblebee, Bombus terrestris, can detect naturally occurring concentrations of nectar toxins. Using paired-choice experiments, we identified deterrence thresholds for five compounds found in the nectar of bee-pollinated plants: quinine, caffeine, nicotine, amygdalin and grayanotoxin. The deterrence threshold was determined when bumblebees significantly preferred a sucrose solution over a sucrose solution containing the compound. Bumblebees had the lowest deterrence threshold for the alkaloid quinine (0.01 mmol l−1); all other compounds had higher deterrence thresholds, above the natural concentration range in floral nectar. Our data, combined with previous work using honeybees, suggest that generalist bee species have poor acuity for the detection of nectar toxins. The fact that bees do not avoid nectar-relevant concentrations of these compounds likely indicates that it is difficult for them to learn to associate floral traits with the presence of toxins, thus maintaining this trait in plant populations. PMID:24526720

Phytochemical screening, total phenolic, total flavonoids contents and antioxidant activity of cinchona ledgeriana leaves ethanol extract

NASA Astrophysics Data System (ADS)

Sundowo, Andini; Artanti, Nina; Hanafi, M.; Minarti, Primahana, Gian

2017-11-01

C ledgeriana is a medicinal plant that contains alkaloids, especially on the barks for commercial production of quinine as antimalarial. The main alkaloids in this plant are cinchonine, cinchonidine, quinine and quinidine. Besides for antiamalarial this plant is also commonly used to treat whooping cough, influenza and dysentery. Compare to other medicinal plants, nowadays only very few studies were conducted in Cinchona species. Our current study aims to determine the content of phytochemical, total phenol and total flavonoids from C. ledgeriana leaves 70% ethanol extract. The extraction was performed by maceration method using 70% ethanol solvent and then fractionated into hexane, ethylacetate and butanol. Phytochemical screening was performed to determine the content of alkaloids, flavonoids, terpenoids, tannins and saponins. Total phenol and flavonoid contents of the extract were determined by Folin-Ciocalteu and alumunium chloride colorimetric methods using gallic acid and quercetin as standards. The antioxidant activity was determined by using 2, 2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activity. The results of phytochemical screening showed that the 70% ethanol extract of C. ledgeriana leaves contained alkaloids, flavonoids, terpenoids, tannins and saponins. The total phenol and total flavonoids analysis showed that ethyl acetate fraction had the highest total phenol (40.23%) and total flavonoids (65.34%).

Habituation in non-neural organisms: evidence from slime moulds

PubMed Central

Boisseau, Romain P.; Vogel, David; Dussutour, Audrey

2016-01-01

Learning, defined as a change in behaviour evoked by experience, has hitherto been investigated almost exclusively in multicellular neural organisms. Evidence for learning in non-neural multicellular organisms is scant, and only a few unequivocal reports of learning have been described in single-celled organisms. Here we demonstrate habituation, an unmistakable form of learning, in the non-neural organism Physarum polycephalum. In our experiment, using chemotaxis as the behavioural output and quinine or caffeine as the stimulus, we showed that P. polycephalum learnt to ignore quinine or caffeine when the stimuli were repeated, but responded again when the stimulus was withheld for a certain time. Our results meet the principle criteria that have been used to demonstrate habituation: responsiveness decline and spontaneous recovery. To distinguish habituation from sensory adaptation or motor fatigue, we also show stimulus specificity. Our results point to the diversity of organisms lacking neurons, which likely display a hitherto unrecognized capacity for learning, and suggest that slime moulds may be an ideal model system in which to investigate fundamental mechanisms underlying learning processes. Besides, documenting learning in non-neural organisms such as slime moulds is centrally important to a comprehensive, phylogenetic understanding of when and where in the tree of life the earliest manifestations of learning evolved. PMID:27122563

Women's Access and Provider Practices for the Case Management of Malaria during Pregnancy: A Systematic Review and Meta-Analysis

PubMed Central

Hill, Jenny; D'Mello-Guyett, Lauren; Hoyt, Jenna; van Eijk, Anna M.; ter Kuile, Feiko O.; Webster, Jayne

2014-01-01

Background WHO recommends prompt diagnosis and quinine plus clindamycin for treatment of uncomplicated malaria in the first trimester and artemisinin-based combination therapies in subsequent trimesters. We undertook a systematic review of women's access to and healthcare provider adherence to WHO case management policy for malaria in pregnant women. Methods and Findings We searched the Malaria in Pregnancy Library, the Global Health Database, and the International Network for the Rational Use of Drugs Bibliography from 1 January 2006 to 3 April 2014, without language restriction. Data were appraised for quality and content. Frequencies of women's and healthcare providers' practices were explored using narrative synthesis and random effect meta-analysis. Barriers to women's access and providers' adherence to policy were explored by content analysis using NVivo. Determinants of women's access and providers' case management practices were extracted and compared across studies. We did not perform a meta-ethnography. Thirty-seven studies were included, conducted in Africa (30), Asia (4), Yemen (1), and Brazil (2). One- to three-quarters of women reported malaria episodes during pregnancy, of whom treatment was sought by >85%. Barriers to access among women included poor knowledge of drug safety, prohibitive costs, and self-treatment practices, used by 5%–40% of women. Determinants of women's treatment-seeking behaviour were education and previous experience of miscarriage and antenatal care. Healthcare provider reliance on clinical diagnosis and poor adherence to treatment policy, especially in first versus other trimesters (28%, 95% CI 14%–47%, versus 72%, 95% CI 39%–91%, p = 0.02), was consistently reported. Prescribing practices were driven by concerns over side effects and drug safety, patient preference, drug availability, and cost. Determinants of provider practices were access to training and facility type (public versus private). Findings were limited by the availability, quality, scope, and methodological inconsistencies of the included studies. Conclusions A systematic assessment of the extent of substandard case management practices of malaria in pregnancy is required, as well as quality improvement interventions that reach all providers administering antimalarial drugs in the community. Pregnant women need access to information on which anti-malarial drugs are safe to use at different stages of pregnancy. Please see later in the article for the Editors' Summary PMID:25093720

Women's access and provider practices for the case management of malaria during pregnancy: a systematic review and meta-analysis.

PubMed

Hill, Jenny; D'Mello-Guyett, Lauren; Hoyt, Jenna; van Eijk, Anna M; ter Kuile, Feiko O; Webster, Jayne

2014-08-01

WHO recommends prompt diagnosis and quinine plus clindamycin for treatment of uncomplicated malaria in the first trimester and artemisinin-based combination therapies in subsequent trimesters. We undertook a systematic review of women's access to and healthcare provider adherence to WHO case management policy for malaria in pregnant women. We searched the Malaria in Pregnancy Library, the Global Health Database, and the International Network for the Rational Use of Drugs Bibliography from 1 January 2006 to 3 April 2014, without language restriction. Data were appraised for quality and content. Frequencies of women's and healthcare providers' practices were explored using narrative synthesis and random effect meta-analysis. Barriers to women's access and providers' adherence to policy were explored by content analysis using NVivo. Determinants of women's access and providers' case management practices were extracted and compared across studies. We did not perform a meta-ethnography. Thirty-seven studies were included, conducted in Africa (30), Asia (4), Yemen (1), and Brazil (2). One- to three-quarters of women reported malaria episodes during pregnancy, of whom treatment was sought by >85%. Barriers to access among women included poor knowledge of drug safety, prohibitive costs, and self-treatment practices, used by 5%-40% of women. Determinants of women's treatment-seeking behaviour were education and previous experience of miscarriage and antenatal care. Healthcare provider reliance on clinical diagnosis and poor adherence to treatment policy, especially in first versus other trimesters (28%, 95% CI 14%-47%, versus 72%, 95% CI 39%-91%, p = 0.02), was consistently reported. Prescribing practices were driven by concerns over side effects and drug safety, patient preference, drug availability, and cost. Determinants of provider practices were access to training and facility type (public versus private). Findings were limited by the availability, quality, scope, and methodological inconsistencies of the included studies. A systematic assessment of the extent of substandard case management practices of malaria in pregnancy is required, as well as quality improvement interventions that reach all providers administering antimalarial drugs in the community. Pregnant women need access to information on which anti-malarial drugs are safe to use at different stages of pregnancy. Please see later in the article for the Editors' Summary.

Prevalence of Gene Mutations profiles by GenoType MTBDRplus/sl to First Line Antituberculosis Drugs and Clinical Characteristics in Drug Resistant Tuberculosis Patients Referred to the National Institute of Respiratory Diseases in Mexico City

PubMed Central

Martinez-Orozco, Jose Arturo; Nuñez-Luna, Blanca A; Narváez-Diaz, Luis A; Pilar, Mariela Segura-Del; Mujica-Sanchez, Mario; Salazar-Lezama, Miguel Angel; Mireles-Davalos, Christian D

2017-01-01

Abstract Background Drug resistance tuberculosis, specially MDR and XDR are a big challenge for diagnosis and treatment. In Mexico the prevalence of MDR is between 3–5%, a number probably underestimated due to lack of diagnostic tests for susceptibility. The National Institute of Respiratory Diseases in Mexico City is the national referral center for MDR/XDR tuberculosis. In our country there is no data about the gene mutations involved in drug resistance to first line antituberculosis treatment nor the clinical characteristics that accompany these findings. Objective: Evaluate the prevalence of genotyping profiles according to a line probe assay (LPA) in patients with drug resistance tuberculosis and their associated clinical characteristics Methods Retrospective cohort from 2010 to 2014 of M. tuberculosis isolates with any type of resistance to first line antituberculosis drugs identified by MGIT SIRE and in which GenoType MTBDRplus/sl were performed, we evaluate prevalence of genotyping profiles according to the LPA within the isolates and gather data from those with complete medical records to asses clinical characteristics. Results In 52 and 33 isolates phenotyping and genotyping MTBDRplus/sl respectively were performed, 41 resistant to Isoniazid INH with 75% genotypic concordance, 33 resistant to rifampicin RIF with 75.6% concordance, 14 to streptomycin SM with 23% concordance and 10 to ethambutol EMB with 100% concordance, 54% MDR tuberculosis. The genotyping profile for RIF was absence of probes rpoB Wild Type 8 (WT) 57.7%, WT 7 30.8% and presence of rpoB mutation 3 (MUT) 19.2%. For INH absence of InhA WT2 48.1% and InhA WT1 19.2%. For EMB absence of embB WT1 30.8% and for SM absence of rrs WT1 (19%). Absence of InhA WT1 was associated with female (P = 0.01) and DM2 (P = 0.032) patients, other clinical/biochemical characteristics and mortality was not different in patients with o without the genotypic profile for each drug. Cavitary disease by CT was more frequent in patients with WT probe absence in RIF and INH than those who did not have a LPA suggestive of resistance for this drugs. Conclusion Wild Type probe absense is the frequent finding in our isolates according to LPA in RIF, INH, EMB and SM, intrisic host factors and clinical characteristics seem not to be related to a particular resistant gene profile. Disclosures All authors: No reported disclosures.

Noradrenergic facilitation of shock-probe defensive burying in lateral septum of rats, and modulation by chronic treatment with desipramine.

PubMed

Bondi, Corina O; Barrera, Gabriel; Lapiz, M Danet S; Bedard, Tania; Mahan, Amy; Morilak, David A

2007-03-30

We have previously shown that acute stress-induced release of norepinephrine (NE) facilitates anxiety-like behavioral responses to stress, such as reduction in open-arm exploration on the elevated-plus maze and in social behavior on the social interaction test. Since these responses represent inhibition of ongoing behavior, it is important to also address whether NE facilitates a response that represents an activation of behavior. Correspondingly, it is unknown how a chronic elevation in tonic steady-state noradrenergic (NA) neurotransmission induced by NE reuptake blockade might alter this acute modulatory function, a regulatory process that may be pertinent to the anxiolytic effects of NE reuptake blockers such as desipramine (DMI). Therefore, in this study, we investigated noradrenergic modulation of the shock-probe defensive burying response in the lateral septum (LS). In experiment 1, shock-probe exposure induced an acute 3-fold increase in NE levels measured in LS of male Sprague-Dawley rats by microdialysis. Shock-probe exposure also induced a modest rise in plasma ACTH, taken as an indicator of perceived stress, that returned to baseline more rapidly in rats that were allowed to bury the probe compared to rats prevented from burying by providing them with minimal bedding, indicating that the active defensive burying behavior is an effective coping strategy that reduces the impact of acute shock probe-induced stress. In experiment 2, blockade of either alpha(1)- or beta-adrenergic receptors in LS by local antagonist microinjection immediately before testing reduced defensive burying and increased immobility. In the next experiment, chronic DMI treatment increased basal extracellular NE levels in LS, and attenuated the acute shock probe-induced increase in NE release in LS relative to baseline. Chronic DMI treatment decreased shock-probe defensive burying behavior in a time-dependent manner, apparent only after 2 weeks or more of drug treatment. Moreover, rats treated chronically with DMI showed no significant rise of plasma ACTH in response to shock-probe exposure. Thus, acute stress-induced release of NE in LS facilitated defensive burying, an active, adaptive behavioral coping response. Chronic treatment with the NE reuptake blocker and antidepressant drug DMI attenuated acute noradrenergic facilitation of the active burying response, and also attenuated the level of perceived stress driving that response. These results suggest that long-term regulation of the acute modulatory function of NE by chronic treatment with reuptake blockers may contribute to the mechanisms by which such drugs exert their anxiolytic effects in the treatment of stress-related psychiatric conditions, including depression and anxiety.

Drug Crisis: Schools Fight Back with Innovative Programs. Education U.S.A. Special Report.

ERIC Educational Resources Information Center

Jones, J. William

An indepth study of the drug issue and problem in American schools is presented in this Education U.S.A. Special Report by the National School Public Relations Association. Dealing with what is and what is not being accomplished, the report probes the extent of the drug problem; reasons for its existence; the scare tactics of overkill versus the…

Target-catalyzed hairpin assembly and metal-organic frameworks mediated nonenzymatic co-reaction for multiple signal amplification detection of miR-122 in human serum.

PubMed

Li, Yuliang; Yu, Chao; Yang, Bo; Liu, Zhirui; Xia, Peiyuan; Wang, Qian

2018-04-15

Herein, a new type of multifunctional iron based metal-organic frameworks (PdNPs@Fe-MOFs) has been synthesized by assembly palladium nanoparticles on the surface of Fe-MIL-88NH 2 MOFs microcrystals, and first applied in electrochemical biosensor for ultrasensitive detection of microRNA-122 (miR-122, a biomarker of drug-induced liver injury). The nanohybrids have not only been utilized as ideal nanocarriers for immobilization of signal probes, but also used as redox probes and electrocatalysts. In this biosensor, two hairpin probes were designed as capture probes and signal probes, respectively. The nanohybrids conjugated with streptavidin and biotinylated signal probes were used as the tracer labels, target miR-122 was sandwiched between the tracer labels and thiol-terminated capture probes inserted in MCH monolayer on the gold nanoparticles-functionalized nitrogen-doped graphene sheets (AuNPs@N-G) modified electrode. Based on target-catalyzed hairpin assembly, target miR-122 could trigger the hybridization of capture probes and signal probes to further be released to initiate the next reaction process resulted in numerous tracer indicators anchored onto the sensing interfaces. Thus, the detection signal could be dramatically enhanced towards the electrocatalytic oxidation of 3,3',5,5'-tetramethylbenzidine in the presence of H 2 O 2 owing to the intrinsic and intriguing peroxidase-like activity of the nanohybrids. With the assist of target-catalyzed hairpin assembly and PdNPs@Fe-MOFs mimetic co-reaction for signal amplification, a wide detection range from 0.01fM to 10pM was achieved with a low detection limit of 0.003fM (S/N =3). Furthermore, the proposed biosensor exhibited excellent specificity and recovery in spiked serum samples, and was successfully used for detecting miR-122 in real biological samples, which provided a rapid and efficient method for detecting drug-induced liver injury at an early stage. Copyright © 2017. Published by Elsevier B.V.

A cross-sectional study of the availability and price of anti-malarial medicines and malaria rapid diagnostic tests in private sector retail drug outlets in rural Western Kenya, 2013.

PubMed

Kioko, Urbanus; Riley, Christina; Dellicour, Stephanie; Were, Vincent; Ouma, Peter; Gutman, Julie; Kariuki, Simon; Omar, Ahmeddin; Desai, Meghna; Buff, Ann M

2016-07-12

Although anti-malarial medicines are free in Kenyan public health facilities, patients often seek treatment from private sector retail drug outlets. In mid-2010, the Affordable Medicines Facility-malaria (AMFm) was introduced to make quality-assured artemisinin-based combination therapy (ACT) accessible and affordable in private and public sectors. Private sector retail drug outlets stocking anti-malarial medications within a surveillance area of approximately 220,000 people in a malaria perennial high-transmission area in rural western Kenya were identified via a census in September 2013. A cross-sectional study was conducted in September-October 2013 to determine availability and price of anti-malarial medicines and malaria rapid diagnostic tests (RDTs) in drug outlets. A standardized questionnaire was administered to collect drug outlet and personnel characteristics and availability and price of anti-malarials and RDTs. Of 181 drug outlets identified, 179 (99 %) participated in the survey. Thirteen percent were registered pharmacies, 25 % informal drug shops, 46 % general shops, 13 % homesteads and 2 % other. One hundred sixty-five (92 %) had at least one ACT type: 162 (91 %) had recommended first-line artemether-lumefantrine (AL), 22 (12 %) had recommended second-line dihydroartemisinin-piperaquine (DHA-PPQ), 85 (48 %) had sulfadoxine-pyrimethamine (SP), 60 (34 %) had any quinine (QN) formulation, and 14 (8 %) had amodiaquine (AQ) monotherapy. The mean price (range) of an adult treatment course for AL was $1.01 ($0.35-4.71); DHA-PPQ was $4.39 ($0.71-7.06); QN tablets were $2.24 ($0.12-4.71); SP was $0.62 ($0.24-2.35); AQ monotherapy was $0.42 ($0.24-1.06). The mean AL price with or without the AMFm logo did not differ significantly ($1.01 and 1.07, respectively; p = 0.45). Only 17 (10 %) drug outlets had RDTs; 149 (84 %) never stocked RDTs. The mean RDT price was $0.92 ($0.24-2.35). Most outlets never stocked RDTs; therefore, testing prior to treatment was unlikely for customers seeking treatment in the private retail sector. The recommended first-line treatment, AL, was widely available. Although SP and AQ monotherapy are not recommended for treatment, both were less expensive than AL, which might have caused preferential use by customers. Interventions that create community demand for malaria diagnostic testing prior to treatment and that increase RDT availability should be encouraged.

Genetic Determinants of Drug Resistance in Mycobacterium tuberculosis and Their Diagnostic Value.

PubMed

Farhat, Maha R; Sultana, Razvan; Iartchouk, Oleg; Bozeman, Sam; Galagan, James; Sisk, Peter; Stolte, Christian; Nebenzahl-Guimaraes, Hanna; Jacobson, Karen; Sloutsky, Alexander; Kaur, Devinder; Posey, James; Kreiswirth, Barry N; Kurepina, Natalia; Rigouts, Leen; Streicher, Elizabeth M; Victor, Tommie C; Warren, Robin M; van Soolingen, Dick; Murray, Megan

2016-09-01

The development of molecular diagnostics that detect both the presence of Mycobacterium tuberculosis in clinical samples and drug resistance-conferring mutations promises to revolutionize patient care and interrupt transmission by ensuring early diagnosis. However, these tools require the identification of genetic determinants of resistance to the full range of antituberculosis drugs. To determine the optimal molecular approach needed, we sought to create a comprehensive catalog of resistance mutations and assess their sensitivity and specificity in diagnosing drug resistance. We developed and validated molecular inversion probes for DNA capture and deep sequencing of 28 drug-resistance loci in M. tuberculosis. We used the probes for targeted sequencing of a geographically diverse set of 1,397 clinical M. tuberculosis isolates with known drug resistance phenotypes. We identified a minimal set of mutations to predict resistance to first- and second-line antituberculosis drugs and validated our predictions in an independent dataset. We constructed and piloted a web-based database that provides public access to the sequence data and prediction tool. The predicted resistance to rifampicin and isoniazid exceeded 90% sensitivity and specificity but was lower for other drugs. The number of mutations needed to diagnose resistance is large, and for the 13 drugs studied it was 238 across 18 genetic loci. These data suggest that a comprehensive M. tuberculosis drug resistance diagnostic will need to allow for a high dimension of mutation detection. They also support the hypothesis that currently unknown genetic determinants, potentially discoverable by whole-genome sequencing, encode resistance to second-line tuberculosis drugs.

Genetic Determinants of Drug Resistance in Mycobacterium tuberculosis and Their Diagnostic Value

PubMed Central

Sultana, Razvan; Iartchouk, Oleg; Bozeman, Sam; Galagan, James; Sisk, Peter; Stolte, Christian; Nebenzahl-Guimaraes, Hanna; Jacobson, Karen; Sloutsky, Alexander; Kaur, Devinder; Posey, James; Kreiswirth, Barry N.; Kurepina, Natalia; Rigouts, Leen; Streicher, Elizabeth M.; Victor, Tommie C.; Warren, Robin M.; van Soolingen, Dick; Murray, Megan

2016-01-01

Rationale: The development of molecular diagnostics that detect both the presence of Mycobacterium tuberculosis in clinical samples and drug resistance–conferring mutations promises to revolutionize patient care and interrupt transmission by ensuring early diagnosis. However, these tools require the identification of genetic determinants of resistance to the full range of antituberculosis drugs. Objectives: To determine the optimal molecular approach needed, we sought to create a comprehensive catalog of resistance mutations and assess their sensitivity and specificity in diagnosing drug resistance. Methods: We developed and validated molecular inversion probes for DNA capture and deep sequencing of 28 drug-resistance loci in M. tuberculosis. We used the probes for targeted sequencing of a geographically diverse set of 1,397 clinical M. tuberculosis isolates with known drug resistance phenotypes. We identified a minimal set of mutations to predict resistance to first- and second-line antituberculosis drugs and validated our predictions in an independent dataset. We constructed and piloted a web-based database that provides public access to the sequence data and prediction tool. Measurements and Main Results: The predicted resistance to rifampicin and isoniazid exceeded 90% sensitivity and specificity but was lower for other drugs. The number of mutations needed to diagnose resistance is large, and for the 13 drugs studied it was 238 across 18 genetic loci. Conclusions: These data suggest that a comprehensive M. tuberculosis drug resistance diagnostic will need to allow for a high dimension of mutation detection. They also support the hypothesis that currently unknown genetic determinants, potentially discoverable by whole-genome sequencing, encode resistance to second-line tuberculosis drugs. PMID:26910495

An Introduction to Drug Discovery by Probing Protein-Substrate Interactions Using Saturation Transfer Difference-Nuclear Magnetic Resonance (STD-NMR)

ERIC Educational Resources Information Center

Guegan, Jean-Paul; Daniellou, Richard

2012-01-01

NMR spectroscopy is a powerful tool for characterizing and identifying molecules and nowadays is even used to characterize complex systems in biology. In the experiment presented here, students learned how to apply this modern technique to probe interactions between small molecules and proteins. With the use of simple organic synthesis, students…

The genomic response of skeletal muscle to methylprednisolone using microarrays: tailoring data mining to the structure of the pharmacogenomic time series

PubMed Central

DuBois, Debra C; Piel, William H; Jusko, William J

2008-01-01

High-throughput data collection using gene microarrays has great potential as a method for addressing the pharmacogenomics of complex biological systems. Similarly, mechanism-based pharmacokinetic/pharmacodynamic modeling provides a tool for formulating quantitative testable hypotheses concerning the responses of complex biological systems. As the response of such systems to drugs generally entails cascades of molecular events in time, a time series design provides the best approach to capturing the full scope of drug effects. A major problem in using microarrays for high-throughput data collection is sorting through the massive amount of data in order to identify probe sets and genes of interest. Due to its inherent redundancy, a rich time series containing many time points and multiple samples per time point allows for the use of less stringent criteria of expression, expression change and data quality for initial filtering of unwanted probe sets. The remaining probe sets can then become the focus of more intense scrutiny by other methods, including temporal clustering, functional clustering and pharmacokinetic/pharmacodynamic modeling, which provide additional ways of identifying the probes and genes of pharmacological interest. PMID:15212590

NMR Relaxometry to Characterize the Drug Structural Phase in a Porous Construct.

PubMed

Thrane, Linn W; Berglund, Emily A; Wilking, James N; Vodak, David; Seymour, Joseph D

2018-06-14

Nuclear magnetic resonance (NMR) frequency spectra and T 2 relaxation time measurements, using a high-power radio frequency probe, are shown to characterize the presence of an amorphous drug in a porous silica construct. The results indicate the ability of non-solid-state NMR methods to characterize crystalline and amorphous solid structural phases in drugs. Two-dimensional T 1 - T 2 magnetic relaxation time correlation experiments are shown to monitor the impact of relative humidity on the drug in a porous silica tablet.

A Course in Air Force Logistics History Since 1940

DTIC Science & Technology

1984-09-01

malarial procedures: long pants and sleeve-, repellents , sleeping under mosquito nets, takirg quinine or atabrine 48 --- Medical services heavily tasked...logistics forms a coequal triumvirate with strategy and tactics, recommend that students be given an overview course in strategic and tactical...Lesson 2: Overview of AF logistics history before WW II and beginning WW II. Lesson 3: WW II. Lesson 4: WW II. Lesson 5: WW II. 18 Lesson 6: Between WW

[Malaria prophylaxis; advice for the individual traveller. The Working Group for Malaria Prophylaxis].

PubMed

1998-04-18

Recently, the Dutch Working Group on Malaria Prophylaxis produced new national guidelines. The new approach takes the risk of malaria and of serious morbidity or mortality for the individual traveller as its point of departure. In large areas in the tropics, there is no malaria risk. In some areas with limited risk, proguanil is still an effective chemoprophylactic (mainly in Central America, the Near East, Central Asia and parts of Indonesia). However, multiple-drug resistant Plasmodium falciparum necessitates the use of mefloquine, despite disturbing side effects in some people, in Sub-Saharan Africa, major parts of South East Asia and the Amazone basin of South America. If mefloquine is contraindicated, alternatives advised are the combination of proguanil and chloroquine or (in South East Asia) doxycycline. For visits to transmission areas lasting 7 days or less, alternative prophylactic measures may be acceptable, but only if the traveller after the visit has easy access to adequate medical facilities. When exposure lasts not more than two nights, use of a mosquito net, repellents and protective clothing without chemoprophylaxis is acceptable, provided the traveller is well informed. To take along pocket treatment is only advised for some journeys lasting more than one month to areas with multiple-drug resistant falciparum malaria. When mefloquine prophylaxis is used, such stand-by treatment is only advocated for a few countries in South East Asia; when mefloquine cannot be given, also for other areas. The type of pocket treatment recommended depends on the chemoprophylaxis used and on whether contraindications exist. Drugs that can be used are: halofantrine (if no contraindications exist and an ECG shows no prolongation of the QT interval) or quinine, either alone (in pregnancy) or combined with doxycycline or clindamycine (the latter for children < 8 years). With the new individual approach advice may differ for different persons visiting similar tropical areas. It is the physician's task to explain the risks of a particular journey and the measures advised.

Screening of a library of traditional Chinese medicines to identify anti-malarial compounds and extracts.

PubMed

Nonaka, Motohiro; Murata, Yuho; Takano, Ryo; Han, Yongmei; Bin Kabir, Md Hazzaz; Kato, Kentaro

2018-06-25

Malaria is a major infectious disease in the world. In 2015, approximately 212 million people were infected and 429,000 people were killed by this disease. Plasmodium falciparum, which causes falciparum malaria, is becoming resistant to artemisinin (ART) in Southeast Asia; therefore, new anti-malarial drugs are urgently needed. Some excellent anti-malarial drugs, such as quinine or ART, were originally obtained from natural plants. Hence, the authors screened a natural product library comprising traditional Chinese medicines (TCMs) to identify compounds/extracts with anti-malarial effects. The authors performed three assays: a malaria growth inhibition assay (GIA), a cytotoxicity assay, and a malaria stage-specific GIA. The malaria GIA revealed the anti-malarial ability and half-maximal inhibitory concentrations (IC 50 ) of the natural products, whereas the malaria stage-specific GIA revealed the point in the malaria life cycle where the products exerted their anti-malarial effects. The toxicity of the products to the host cells was evaluated with the cytotoxicity assay. Four natural compounds (berberine chloride, coptisine chloride, palmatine chloride, and dehydrocorydaline nitrate) showed strong anti-malarial effects (IC 50  < 50 nM), and low cytotoxicity (cell viability > 90%) using P. falciparum 3D7 strain. Two natural extracts (Phellodendri cortex and Coptidis rhizoma) also showed strong antiplasmodial effects (IC 50  < 1 µg/ml), and low cytotoxicity (cell viability > 80%). These natural products also demonstrated anti-malarial capability during the trophozoite and schizont stages of the malaria life cycle. The authors identified four compounds (berberine chloride, coptisine chloride, palmatine chloride, and dehydrocorydaline nitrate) and two extracts (Phellodendri cortex and Coptidis rhizoma) with anti-malarial activity, neither of which had previously been described. The IC 50 values of the compounds were comparable to that of chloroquine and better than that of pyrimethamine. These compounds and extracts derived from TCMs thus show promise as potential future anti-malarial drugs.

Ex vivo activity of Proveblue, a methylene blue, against field isolates of Plasmodium falciparum in Dakar, Senegal from 2013-2015.

PubMed

Fall, Bécaye; Madamet, Marylin; Diawara, Silman; Briolant, Sébastien; Wade, Khalifa Ababacar; Lo, Gora; Nakoulima, Aminata; Fall, Mansour; Bercion, Raymond; Kounta, Mame Bou; Amalvict, Rémi; Benoit, Nicolas; Gueye, Mamadou Wague; Diatta, Bakary; Wade, Boubacar; Pradines, Bruno

2017-08-01

Resistance to most antimalarial drugs has spread from Southeast Asia to Africa. Accordingly, new therapies to use with artemisinin-based combination therapy (triple ACT) are urgently needed. Proveblue, a methylene blue preparation, was found to exhibit antimalarial activity against Plasmodium falciparum strains in vitro. Proveblue has synergistic effects when used in combination with dihydroartemisinin, and has been shown to significantly reduce or prevent cerebral malaria in mice. The objectives of the current study were to evaluate the in vitro baseline susceptibility of clinical field isolates to Proveblue, compare its activity with that of other standard antimalarial drugs and define the patterns of cross-susceptibility between Proveblue and conventional antimalarial drugs. The Proveblue IC 50 of 76 P. falciparum isolates ranged from 0.5 nM to 135.1 nM, with a mean of 8.1 nM [95% confidence interval, 6.4-10.3]. Proveblue was found to be more active against P. falciparum parasites than chloroquine, quinine, monodesethylamodiaquine, mefloquine, piperaquine, doxycycline (P <0.001) and lumefantrine (P = 0.014). Proveblue was as active as pyronaridine (P = 0.927), but was less active than dihydroartemisinin and artesunate (P <0.001). The only significant cross-susceptibilities found were between Proveblue and dihydroartemisinin (r 2  = 0.195, P = 0.0001), artesunate (r 2  = 0.187, P = 0.0002) and piperaquine (r 2  = 0.063, P = 0.029). The present study clearly demonstrates the potential of Proveblue as an effective therapeutic agent against P. falciparum. In this context, the use of Proveblue as part of the triple ACT treatment for multidrug-resistant malaria warrants further investigation. Copyright © 2017 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.

Polymorphism of antimalaria drug metabolizing, nuclear receptor, and drug transport genes among malaria patients in Zanzibar, East Africa.

PubMed

Ferreira, Pedro Eduardo; Veiga, Maria Isabel; Cavaco, Isa; Martins, J Paulo; Andersson, Björn; Mushin, Shaliya; Ali, Abullah S; Bhattarai, Achuyt; Ribeiro, Vera; Björkman, Anders; Gil, José Pedro

2008-02-01

Artemisinin-based combination therapy is a main strategy for malaria control in Africa. Zanzibar introduced this new treatment policy in 2003. The authors have studied the prevalence of a number of functional single nucleotide polymorphisms (SNPs) in genes associated with the elimination of the artemisinin-based combination therapy compounds in use in Zanzibar to investigate the frequencies of subgroups potentially at higher drug exposure and therefore possible higher risk of toxicity. One hundred three unrelated children with uncomplicated malaria from the Unguja and Pemba islands of Zanzibar were enrolled. With use of polymerase chain reaction (PCR)-restriction fragment length polymorphism and real-time PCR-based allele discrimination methods, the CYP2B6 (G15631T), CYP3A4 (A-392G), CYP3A5 (A6986G, G14690A, 27131-132 insT, C3699T) SNPs and MDR1 SNPs C3435T, G2677T/A, and T-129C were analyzed. PCR product sequencing was applied to regulatory regions of MDR1, the CYP3A4 proximal promoter, and to exons 2 and 5 of PXR, a gene coding for a nuclear factor activated by artemisinin antimalarials and associated with the transcription induction of most of the studied genes. Homozygous subjects for alleles coding for low activity proteins were found at the following frequencies: 1) MDR1: 2.9%; 2) CYP2B6: 9.7%; 3) CYP3A5: 14.1%; and 4) CYP3A4: 49.5%. No functionally relevant allele was found in the analyzed regions of PXR. A new MDR1 SNP was found (T-158C), located in a putative antigen recognition element. Ten (10.1%) subjects were predicted to be low metabolizers simultaneously for CYP3A4 and CYP3A5. This fraction of the population is suggested to be under higher exposure to certain antimalarials, including lumefantrine and quinine.

Malaria policies versus practices, a reality check from Kinshasa, the capital of the Democratic Republic of Congo.

PubMed

Muhindo Mavoko, Hypolite; Ilombe, Gillon; Inocêncio da Luz, Raquel; Kutekemeni, Albert; Van geertruyden, Jean-Pierre; Lutumba, Pascal

2015-04-10

Artemisinin-based combination therapy (ACT) following a confirmed parasitological diagnosis is recommended by the World Health Organization (WHO) and the Congolese National Malaria Control Program (NMCP). However, commitment and competence of all stakeholders (patients, medical professionals, governments and funders) is required to achieve effective case management and secure the "useful therapeutic life" of the recommended drugs. The health seeking behaviour of patients and health care professionals' practices for malaria management were assessed. This was an observational study embedded in a two-stage cluster randomized survey conducted in one health centre (HC) in each of the 12 selected health zones in Kinshasa city. All patients with clinical malaria diagnosis were eligible. Their health seeking behaviour was recorded on a specific questionnaire, as well as the health care practitioners' practices. The last were not aware that their practices would be assessed. Six hundred and twenty four patients were assessed, of whom 136 (21.8%) were under five years. Three hundred and thirty five (55%) had taken medication prior to the current consultation (self -medication with any product or visiting another HC) of whom 47(14%) took an antimalarial drug, and 56 (9%) were treated presumptively. Among those, 53.6% received monotherapy either with quinine, artesunate, phytomedicines, sulfadoxine-pyrimethamine or amodiaquine. On the other side, when clinicians were informed about laboratory results, monotherapy was prescribed in 39.9% of the confirmed malaria cases. Only 285 patients (45.7%) were managed in line with WHO and NMCP guidelines, of whom 120 (19.2%) were prescribed an ACT after positive blood smear and 165 (26.4%) received no antimalarial after a negative result. This study shows the discrepancy between malaria policies and the reality on the field in Kinshasa, regarding patients' health seeking behaviour and health professionals' practices. Consequently, the poor compliance to the policies may contribute to the genesis and spread of antimalarial drug resistance and also have a negative impact on the burden of the disease.

Marine actinomycetes: a new source of compounds against the human malaria parasite.

PubMed

Prudhomme, Jacques; McDaniel, Eric; Ponts, Nadia; Bertani, Stéphane; Fenical, William; Jensen, Paul; Le Roch, Karine

2008-06-04

Malaria continues to be a devastating parasitic disease that causes the death of 2 million individuals annually. The increase in multi-drug resistance together with the absence of an efficient vaccine hastens the need for speedy and comprehensive antimalarial drug discovery and development. Throughout history, traditional herbal remedies or natural products have been a reliable source of antimalarial agents, e.g. quinine and artemisinin. Today, one emerging source of small molecule drug leads is the world's oceans. Included among the source of marine natural products are marine microorganisms such as the recently described actinomycete. Members of the genus Salinispora have yielded a wealth of new secondary metabolites including salinosporamide A, a molecule currently advancing through clinical trials as an anticancer agent. Because of the biological activity of metabolites being isolated from marine microorganisms, our group became interested in exploring the potential efficacy of these compounds against the malaria parasite. We screened 80 bacterial crude extracts for their activity against malaria growth. We established that the pure compound, salinosporamide A, produced by the marine actinomycete, Salinispora tropica, shows strong inhibitory activity against the erythrocytic stages of the parasite cycle. Biochemical experiments support the likely inhibition of the parasite 20S proteasome. Crystal structure modeling of salinosporamide A and the parasite catalytic 20S subunit further confirm this hypothesis. Ultimately we showed that salinosporamide A protected mice against deadly malaria infection when administered at an extremely low dosage. These findings underline the potential of secondary metabolites, derived from marine microorganisms, to inhibit Plasmodium growth. More specifically, we highlight the effect of proteasome inhibitors such as salinosporamide A on in vitro and in vivo parasite development. Salinosporamide A (NPI-0052) now being advanced to phase I trials for the treatment of refractory multiple myeloma will need to be further explored to evaluate the safety profile for its use against malaria.

Impact of body weight, low energy diet and gastric bypass on drug bioavailability, cardiovascular risk factors and metabolic biomarkers: protocol for an open, non-randomised, three-armed single centre study (COCKTAIL).

PubMed

Hjelmesæth, Jøran; Åsberg, Anders; Andersson, Shalini; Sandbu, Rune; Robertsen, Ida; Johnson, Line Kristin; Angeles, Philip Carlo; Hertel, Jens Kristoffer; Skovlund, Eva; Heijer, Maria; Ek, Anna-Lena; Krogstad, Veronica; Karlsen, Tor-Ivar; Christensen, Hege; Andersson, Tommy B; Karlsson, Cecilia

2018-05-29

Roux-en-Y gastric bypass (GBP) is associated with changes in cardiometabolic risk factors and bioavailability of drugs, but whether these changes are induced by calorie restriction, the weight loss or surgery per se, remains uncertain. The COCKTAIL study was designed to disentangle the short-term (6 weeks) metabolic and pharmacokinetic effects of GBP and a very low energy diet (VLED) by inducing a similar weight loss in the two groups. This open, non-randomised, three-armed, single-centre study is performed at a tertiary care centre in Norway. It aims to compare the short-term (6 weeks) and long-term (2 years) effects of GBP and VLED on, first, bioavailability and pharmacokinetics (24 hours) of probe drugs and biomarkers and, second, their effects on metabolism, cardiometabolic risk factors and biomarkers. The primary outcomes will be measured as changes in: (1) all six probe drugs by absolute bioavailability area under the curve (AUC oral /AUC iv ) of midazolam (CYP3A4 probe), systemic exposure (AUC oral ) of digoxin and rosuvastatin and drug:metabolite ratios for omeprazole, losartan and caffeine, levels of endogenous CYP3A biomarkers and genotypic variation, changes in the expression and activity data of the drug-metabolising, drug transport and drug regulatory proteins in biopsies from various organs and (2) body composition, cardiometabolic risk factors and metabolic biomarkers. The COCKTAIL protocol was reviewed and approved by the Regional Committee for Medical and Health Research Ethics (Ref: 2013/2379/REK sørøst A). The results will be disseminated to academic and health professional audiences and the public via presentations at conferences, publications in peer-reviewed journals and press releases and provided to all participants. NCT02386917. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Diffusion and cellular uptake of drugs in live cells studied with surface-enhanced Raman scattering probes

NASA Astrophysics Data System (ADS)

Bálint, Štefan; Rao, Satish; Sánchez, Mónica Marro; Huntošová, Veronika; Miškovský, Pavol; Petrov, Dmitri

2010-03-01

An understanding of the mechanisms of drug diffusion and uptake through cellular membranes is critical for elucidating drug action and in the development of effective drug delivery systems. We study these processes for emodin, a potential anticancer drug, in live cancer cells using surface-enhanced Raman scattering. Micrometer-sized silica beads covered by nanosized silver colloids are passively embedded into the cell and used as sensors of the drug. We demonstrate that the technique offers distinct advantages: the possibility to study the kinetics of drug diffusion through the cellular membrane toward specific cell organelles, the detection of lower drug concentrations compared to fluorescence techniques, and less damage imparted on the cell.

Principles of Chemical Biology: From Sexy Fatty Acids and EBV probes to Anti-Acid Antibiotic via Post-Biotics and Host-Microbe Metabolic Complementarity.

PubMed

2017-06-22

This month: The role of fatty acids in sex determination; a probe to monitor and inhibit EBNA1 at the same time; a biological role for post-biotics; what happens when you mix microbes, hosts, and drugs; and an antibiotic that cross-protects with acid. Copyright © 2017. Published by Elsevier Ltd.

Intracellular probes for imaging oxygen concentration: how good are they?

NASA Astrophysics Data System (ADS)

Dmitriev, Ruslan I.; Papkovsky, Dmitri B.

2015-09-01

In the last decade a number of cell-permeable phosphorescence based probes for imaging of (intra)cellular oxygen (icO2) have been described. These small molecule, supramolecular and nanoparticle structures, although allowing analysis of hypoxia, local gradients and fluctuations in O2, responses to stimulation and drug treatment at sub-cellular level with high spatial and temporal resolution, differ significantly in their operational performance and applicability to different cell and tissue models. Here we discuss and compare these probes with respect to their staining efficiency, brightness, photostability, toxicity, cell specificity, compatibility with different cell and tissue models, and analytical performance. Merits and limitations of particular probes are highlighted and strategies for development of new high-performance O2 imaging probes defined. Key application areas in hypoxia research, stem cells, cancer biology and tissue physiology are also discussed.

Modulation of the Foreign Body Reaction for Implants in the Subcutaneous Space: Microdialysis Probes as Localized Drug Delivery/Sampling Devices

PubMed Central

Mou, Xiaodun; Lennartz, Michelle R; Loegering, Daniel J; Stenken, Julie A

2011-01-01

Modulation of the foreign body reaction is considered to be an important step toward creation of implanted sensors with reliable long-term performance. In this work, microdialysis probes were implanted into the subcutaneous space of Sprague-Dawley rats. The probe performance was evaluated by comparing collected endogenous glucose concentrations with internal standard calibration (2-deoxyglucose, antipyrine, and vitamin B12). Probes were tested until failure, which for this work was defined as loss of fluid flow. In order to determine the effect of fibrous capsule formation on probe function, monocyte chemoattractant protein-1/CC chemokine ligand 2 (MCP-1/CCL2) was delivered locally via the probe to increase capsule thickness and dexamethasone 21-phosphate was delivered to reduce capsule thickness. Probes delivering MCP-1 had a capsule that was twice the thickness (500–600 μm) of control probes (200–225 μm) and typically failed 2 days earlier than control probes. Probes delivering dexamethasone 21-phosphate had more fragile capsules and the probes typically failed 2 days later than controls. Unexpectedly, extraction efficiency and collected glucose concentrations exhibited minor differences between groups. This is an interesting result in that the foreign body capsule formation was related to the duration of probe function but did not consistently relate to probe calibration. PMID:21722577

Paper Test Cards for Presumptive Testing of Very Low Quality Antimalarial Medications

PubMed Central

Weaver, Abigail A.; Lieberman, Marya

2015-01-01

Carrying out chemical analysis of antimalarials to detect low-quality medications before they reach a patient is a costly venture. Here, we show that a library of chemical color tests embedded on a paper card can presumptively identify formulations corresponding to very low quality antimalarial drugs. The presence or absence of chloroquine (CQ), doxycycline (DOX), quinine, sulfadoxine, pyrimethamine, and primaquine antimalarial medications, in addition to fillers used in low-quality pharmaceuticals, are indicated by patterns of colors that are generated on the test cards. Test card sensitivity for detection of these pure components ranges from 90% to 100% with no false positives in the absence of pharmaceutical. The color intensities from reactions characteristic of CQ or DOX allowed visual detection of formulations of these medications cut with 60% or 100% filler, although samples cut with 30% filler could not be reliably detected colorimetrically. However, the addition of unexpected fillers, even in 30% quantities, or substitute pharmaceuticals, could sometimes be detected by other color reactions on the test cards. Tests are simple and inexpensive enough to be carried out in clinics, pharmacies, and ports of entry and could provide a screening method to presumptively indicate very low quality medicines throughout the supply chain. PMID:25897064

In vitro sensitivity of Plasmodium falciparum to artesunate in Thailand.

PubMed Central

Wongsrichanalai, C.; Wimonwattrawatee, T.; Sookto, P.; Laoboonchai, A.; Heppner, D. G.; Kyle, D. E.; Wernsdorfer, W. H.

1999-01-01

Reported are the in vitro susceptibilities of Plasmodium falciparum to artesunate, mefloquine, quinine and chloroquine of 86 isolates and to dihydroartemisinin of 45 isolates collected from areas of high resistance to mefloquine within Thailand near the borders with Myanmar and Cambodia, and from southern Thailand where P. falciparum is generally still sensitive to mefloquine. All the isolates were highly sensitive to artesunate, but the geometric mean IC50S were higher in isolates from the Thai-Myanmar and Thai-Cambodian borders than in those from southern Thailand. The IC50S for mefloquine and artesunate were strongly correlated (Pearson r = 0.605; n = 86; P < 0.00001). As expected, the in vitro sensitivities to dihydroartemisinin and artesunate were similar and strongly correlated (at IC50, Pearson r = 0.695; n = 45; P < 0.00002). The correlation between the activity of mefloquine and artesunate requires further investigation in order to determine the potential for development of cross-resistance in nature. Our results suggest that combination with mefloquine is not the ideal way of protecting the usefulness of artemisinin and its derivatives. A search for more suitable partner drugs to these compounds and careful regulation of their use are necessary in the interest of ensuring their long therapeutic life span. PMID:10361756

Molecular Dynamics Simulations of Supramolecular Anticancer Nanotubes.

PubMed

Kang, Myungshim; Chakraborty, Kaushik; Loverde, Sharon M

2018-06-25

We report here on long-time all-atomistic molecular dynamics simulations of functional supramolecular nanotubes composed by the self-assembly of peptide-drug amphiphiles (DAs). These DAs have been shown to possess an inherently high drug loading of the hydrophobic anticancer drug camptothecin. We probe the self-assembly mechanism from random with ∼0.4 μs molecular dynamics simulations. Furthermore, we also computationally characterize the interfacial structure, directionality of π-π stacking, and water dynamics within several peptide-drug nanotubes with diameters consistent with the reported experimental nanotube diameter. Insight gained should inform the future design of these novel anticancer drug delivery systems.

Activatable Fluorescence Probe via Self-Immolative Intramolecular Cyclization for Histone Deacetylase Imaging in Live Cells and Tissues.

PubMed

Liu, Xianjun; Xiang, Meihao; Tong, Zongxuan; Luo, Fengyan; Chen, Wen; Liu, Feng; Wang, Fenglin; Yu, Ru-Qin; Jiang, Jian-Hui

2018-05-01

Histone deacetylases (HDACs) play essential roles in transcription regulation and are valuable theranostic targets. However, there are no activatable fluorescent probes for imaging of HDAC activity in live cells. Here, we develop for the first time a novel activatable two-photon fluorescence probe that enables in situ imaging of HDAC activity in living cells and tissues. The probe is designed by conjugating an acetyl-lysine mimic substrate to a masked aldehyde-containing fluorophore via a cyanoester linker. Upon deacetylation by HDAC, the probe undergoes a rapid self-immolative intramolecular cyclization reaction, producing a cyanohydrin intermediate that is spontaneously rapidly decomposed into the highly fluorescent aldehyde-containing two-photon fluorophore. The probe is shown to exhibit high sensitivity, high specificity, and fast response for HDAC detection in vitro. Imaging studies reveal that the probe is able to directly visualize and monitor HDAC activity in living cells. Moreover, the probe is demonstrated to have the capability of two-photon imaging of HDAC activity in deep tissue slices up to 130 μm. This activatable fluorescent probe affords a useful tool for evaluating HDAC activity and screening HDAC-targeting drugs in both live cell and tissue assays.

Optogenetic Approaches to Drug Discovery in Neuroscience and Beyond.

PubMed

Zhang, Hongkang; Cohen, Adam E

2017-07-01

Recent advances in optogenetics have opened new routes to drug discovery, particularly in neuroscience. Physiological cellular assays probe functional phenotypes that connect genomic data to patient health. Optogenetic tools, in particular tools for all-optical electrophysiology, now provide a means to probe cellular disease models with unprecedented throughput and information content. These techniques promise to identify functional phenotypes associated with disease states and to identify compounds that improve cellular function regardless of whether the compound acts directly on a target or through a bypass mechanism. This review discusses opportunities and unresolved challenges in applying optogenetic techniques throughout the discovery pipeline - from target identification and validation, to target-based and phenotypic screens, to clinical trials. Copyright © 2017 Elsevier Ltd. All rights reserved.

Adenylyl cyclase-5 in the dorsal striatum function as a molecular switch for the generation of behavioral preferences for cue-directed food choices.

PubMed

Kim, Hannah; Kim, Tae-Kyung; Kim, Ji-Eun; Park, Jin-Young; Lee, Yunjin; Kang, Minkyung; Kim, Kyoung-Shim; Han, Pyung-Lim

2014-11-07

Behavioral choices in habits and innate behaviors occur automatically in the absence of conscious selection. These behaviors are not easily modified by learning. Similar types of behaviors also occur in various mental illnesses including drug addiction, obsessive-compulsive disorder, schizophrenia, and autism. However, underlying mechanisms are not clearly understood. In the present study, we investigated the molecular mechanisms regulating unconditioned preferred behaviors in food-choices. Mice lacking adenylyl cyclase-5 (AC5 KO mice), which is preferentially expressed in the dorsal striatum, consumed food pellets nearly one after another in cages. AC5 KO mice showed aversive behaviors to bitter tasting quinine, but they compulsively chose quinine-containing AC5 KO-pellets over fresh pellets. The unusual food-choice behaviors in AC5 KO mice were due to the gain of behavioral preferences for food pellets containing an olfactory cue, which wild-type mice normally ignored. Such food-choice behaviors in AC5 KO mice disappeared when whiskers were trimmed. Conversely, whisker trimming in wildtype mice induced behavioral preferences for AC5 KO food pellets, indicating that preferred food-choices were not learned through prior experience. Both AC5 KO mice and wildtype mice with trimmed whiskers had increased glutamatergic input from the barrel cortex into the dorsal striatum, resulting in an increase in the mGluR1-dependent signaling cascade. The siRNA-mediated inhibition of mGluR1 in the dorsal striatum in AC5 KO mice and wildtype mice with trimmed whiskers abolished preferred choices for AC5 KO food pellets, whereas siRNA-mediated inhibition of mGluR3 glutamate receptors in the dorsal striatum in wildtype mice induced behavioral preferences for AC5 KO food pellets, thus mimicking AC5 KO phenotypes. Our results show that the gain and loss of behavioral preferences for a specific cue-directed option were regulated by specific cellular factors in the dorsal striatum, such that the preferred food choices were switched on when either the mGluR3-AC5 pathway was inactive or the mGluR1 pathway was active, whereas the preferred food-choices were switched off when mGluR1 or its downstream pathway was suppressed. These results identify the AC5 and mGluR system in the dorsal striatum as molecular on/off switches to direct decisions on behavioral preferences for cue-oriented options.

A novel quantified bitterness evaluation model for traditional Chinese herbs based on an animal ethology principle.

PubMed

Han, Xue; Jiang, Hong; Han, Li; Xiong, Xi; He, Yanan; Fu, Chaomei; Xu, Runchun; Zhang, Dingkun; Lin, Junzhi; Yang, Ming

2018-03-01

Traditional Chinese herbs (TCH) are currently gaining attention in disease prevention and health care plans. However, their general bitter taste hinders their use. Despite the development of a variety of taste evaluation methods, it is still a major challenge to establish a quantitative detection technique that is objective, authentic and sensitive. Based on the two-bottle preference test (TBP), we proposed a novel quantitative strategy using a standardized animal test and a unified quantitative benchmark. To reduce the difference of results, the methodology of TBP was optimized. The relationship between the concentration of quinine and animal preference index (PI) was obtained. Then the PI of TCH was measured through TBP, and bitterness results were converted into a unified numerical system using the relationship of concentration and PI. To verify the authenticity and sensitivity of quantified results, human sensory testing and electronic tongue testing were applied. The quantified results showed a good discrimination ability. For example, the bitterness of Coptidis Rhizoma was equal to 0.0579 mg/mL quinine, and Nelumbinis Folium was equal to 0.0001 mg/mL. The validation results proved that the new assessment method for TCH was objective and reliable. In conclusion, this study provides an option for the quantification of bitterness and the evaluation of taste masking effects.

Combined use of [TBA][L-ASP] and hydroxypropyl-β-cyclodextrin as selectors for separation of Cinchona alkaloids by capillary electrophoresis.

PubMed

Zhang, Yu; Yu, Haixia; Wu, Yujiao; Zhao, Wenyan; Yang, Min; Jing, Huanwang; Chen, Anjia

2014-10-01

In this paper, a new capillary electrophoresis (CE) separation and detection method was developed for the chiral separation of the four major Cinchona alkaloids (quinine/quinidine and cinchonine/cinchonidine) using hydroxypropyl-β-cyclodextrin (HP-β-CD) and chiral ionic liquid ([TBA][L-ASP]) as selectors. Separation parameters such as buffer concentrations, pH, HP-β-CD and chiral ionic liquid concentrations, capillary temperature, and separation voltage were investigated. After optimization of separation conditions, baseline separation of the three analytes (cinchonidine, quinine, cinchonine) was achieved in fewer than 7 min in ammonium acetate background electrolyte (pH 5.0) with the addition of HP-β-CD in a concentration of 40 mM and [TBA][L-ASP] of 14 mM, while the baseline separation of cinchonine and quinidine was not obtained. Therefore, the first-order derivative electropherogram was applied for resolving overlapping peaks. Regression equations revealed a good linear relationship between peak areas in first-order derivative electropherograms and concentrations of the two diastereomer pairs. The results not only indicated that the first-order derivative electropherogram was effective in determination of a low content component and of those not fully separated from adjacent ones, but also showed that the ionic liquid appeared to be a very promising chiral selector in CE. Copyright © 2014 Elsevier Inc. All rights reserved.

Behavioural differentiation induced by environmental variation when crossing a toxic zone in an amoeba

NASA Astrophysics Data System (ADS)

Kunita, Itsuki; Ueda, Kei-Ichi; Akita, Dai; Kuroda, Shigeru; Nakagaki, Toshiyuki

2017-09-01

Organisms choose from among various courses of action in response to a wide variety of environmental conditions and the mechanism by which various behaviours are induced is an open question. Interesting behaviour was recently reported: that a unicellular organism of slime mold Physarum polycephalum known as an amoeba had multiple responses (crossing, returning, etc) when the amoeba encounters a zone with toxic levels of quinine, even under carefully controlled conditions. We here examined this elegant example in more detail to obtain insight into behavioural differentiation. We found that the statistical distribution of passage times across a quinine zone switch from unimodal to bimodal (with peaks corresponding to fast crossing and no crossing) when a periodic light stimulation to modulate a biorhythm in amoeba is applied homogeneously across the space, even under the same level of chemical stimuli. Based on a mathematical model for cell movement in amoeba, we successfully reproduced the stimulation-induced differentiation, which was observed experimentally. These dynamics may be explained by a saddle structure around a canard solution. Our results imply that the differentiation of behavioural types in amoeba is modified step-by-step via the compounding of stimulation inputs. The complex behaviour like the differentiation in amoeba may provide a basis for understanding the mechanism of behaviour selection in higher animals from an ethological perspective.

The history of the Greek Anti-Malaria League and the influence of the Italian School of Malariology.

PubMed

Tsiamis, Costas; Piperaki, Evangelia Theophano; Tsakris, Athanassios

2013-03-01

In 1905, a group of eminent Greek physicians led by Professor of Hygiene and Microbiology Constantinos Savvas and the pediatrician Dr. Ioannis Kardamatis founded the Greek Anti-Malaria League. The League assumed a role that the State would not, and for the next 25 years organized the country's anti-malaria campaign. During its first steps, the Greek Anti-Malaria League adopted the principles of Professor Angelo Celli's Italian Anti-Malaria League. The League's accomplishments include a decrease in malarial prevalence, due to mass treatment with quinine, new legislation ensuring the provision of quinine, State monopoly and the collection of epidemiologic data. However, defeat in the Greek-Turkish War (1922) and the massive influx of one million Greek refugees that ensued, led to a change in malarial epidemiology. In 1928, following a visit to Italy, the Greek League adopted the organization and knowledge of the Italian Malaria Schools in Rome and in Nettuno, and this experience served as the basis of their proposal to the State for the development of the anti-malaria services infrastructure. The State adopted many of Professor Savvas' proposals and modified his plan according to Greek needs. The League's experience, accumulated during its 25 years of struggle against malaria, was its legacy to the campaigns that eventually accomplished the eradication of malaria from Greece after World War II.

Mechanisms and roles of muscarinic activation in guinea-pig adrenal medullary cells.

PubMed

Inoue, Masumi; Harada, Keita; Matsuoka, Hidetada; Nakamura, Jun; Warashina, Akira

2012-09-15

Muscarinic receptors are expressed in the adrenal medullary (AM) cells of various mammals, but their physiological roles are controversial. Therefore, the ionic mechanism for muscarinic receptor-mediated depolarization and the role of muscarinic receptors in neuronal transmission were investigated in dissociated guinea-pig AM cells and in the perfused guinea-pig adrenal gland. Bath application of muscarine induced an inward current at -60 mV. This inward current was partially suppressed by quinine with an IC(50) of 6.1 μM. The quinine-insensitive component of muscarine-induced currents changed the polarity at -78 mV and was inhibited by bupivacaine, a TWIK-related acid-sensitive K(+) (TASK) channel inhibitor. Conversely, the current-voltage relationship for the bupivacaine-insensitive component of muscarine currents showed a reversal potential of -5 mV and a negative slope below -40 mV. External application of La(3+) had a double action on muscarine currents of both enhancement and suppression. Immunoblotting and immunocytochemistry revealed expression of TASK1 channels and cononical transient receptor potential channels 1, 4, 5, and 7 in guinea-pig AM cells. Retrograde application of atropine reversibly suppressed transsynaptically evoked catecholamine secretion from the adrenal gland. The results indicate that muscarinic receptor stimulation in guinea-pig AM cells induces depolarization through inhibition of TASK channels and activation of nonselective cation channels and that muscarinic receptors are involved in neuronal transmission from the splanchnic nerve.

Open Probe fast GC-MS - combining ambient sampling ultra-fast separation and in-vacuum ionization for real-time analysis.

PubMed

Keshet, U; Alon, T; Fialkov, A B; Amirav, A

2017-07-01

An Open Probe inlet was combined with a low thermal mass ultra-fast gas chromatograph (GC), in-vacuum electron ionization ion source and a mass spectrometer (MS) of GC-MS for obtaining real-time analysis with separation. The Open Probe enables ambient sampling via sample vaporization in an oven that is open to room air, and the ultra-fast GC provides ~30-s separation, while if no separation is required, it can act as a transfer line with 2 to 3-s sample transfer time. Sample analysis is as simple as touching the sample, pushing the sample holder into the Open Probe oven and obtaining the results in 30 s. The Open Probe fast GC was mounted on a standard Agilent 7890 GC that was coupled with an Agilent 5977A MS. Open Probe fast GC-MS provides real-time analysis combined with GC separation and library identification, and it uses the low-cost MS of GC-MS. The operation of Open Probe fast GC-MS is demonstrated in the 30-s separation and 50-s full analysis cycle time of tetrahydrocannabinol and cannabinol in Cannabis flower, sub 1-min analysis of trace trinitrotoluene transferred from a finger onto a glass surface, vitamin E in canola oil, sterols in olive oil, polybrominated flame retardants in plastics, alprazolam in Xanax drug pill and free fatty acids and cholesterol in human blood. The extrapolated limit of detection for pyrene is <1 fg, but the concentration is too high and the software noise calculation is untrustworthy. The broad range of compounds amenable for analysis is demonstrated in the analysis of reserpine. The possible use with alternate standard GC-MS and Open Probe fast GC-MS is demonstrated in the analysis of heroin in its street drug powder. The use of Open Probe with the fast GC acting as a transfer line is demonstrated in <10-s analysis without separation of ibuprofen and estradiol. Copyright © 2017 John Wiley & Sons, Ltd. Copyright © 2017 John Wiley & Sons, Ltd.

Multifunctional Nanoparticles as Biocompatible Targeted Probes for Human Cancer Diagnosis and Therapy

PubMed Central

Yong, Ken-Tye; Roy, Indrajit; Swihart, Mark T.; Prasad, Paras N.

2009-01-01

The use of nanoparticles in biological application has been rapidly advancing toward practical applications in human cancer diagnosis and therapy. Upon linking the nanoparticles with biomolecules, they can be used to locate cancerous area as well as for traceable drug delivery with high affinity and specificity. In this review, we discuss the engineering of multifunctional nanoparticle probes and their use in bioimaging and nanomedicine. PMID:20305738

Caspase-responsive smart gadolinium-based contrast agent for magnetic resonance imaging of drug-induced apoptosis.

PubMed

Ye, Deju; Shuhendler, Adam J; Pandit, Prachi; Brewer, Kimberly D; Tee, Sui Seng; Cui, Lina; Tikhomirov, Grigory; Rutt, Brian; Rao, Jianghong

2014-10-01

Non-invasive detection of caspase-3/7 activity in vivo has provided invaluable predictive information regarding tumor therapeutic efficacy and anti-tumor drug selection. Although a number of caspase-3/7 targeted fluorescence and positron emission tomography (PET) imaging probes have been developed, there is still a lack of gadolinium (Gd)-based magnetic resonance imaging (MRI) probes that enable high spatial resolution detection of caspase-3/7 activity in vivo . Here we employ a self-assembly approach and develop a caspase-3/7 activatable Gd-based MRI probe for monitoring tumor apoptosis in mice. Upon reduction and caspase-3/7 activation, the caspase-sensitive nano-aggregation MR probe (C-SNAM: 1 ) undergoes biocompatible intramolecular cyclization and subsequent self-assembly into Gd-nanoparticles (GdNPs). This results in enhanced r 1 relaxivity-19.0 (post-activation) vs. 10.2 mM -1 s -1 (pre-activation) at 1 T in solution-and prolonged accumulation in chemotherapy-induced apoptotic cells and tumors that express active caspase-3/7. We demonstrate that C-SNAM reports caspase-3/7 activity by generating a significantly brighter T 1 -weighted MR signal compared to non-treated tumors following intravenous administration of C-SNAM, providing great potential for high-resolution imaging of tumor apoptosis in vivo .

Quinoline Fluorescent Probes for Zinc - from Diagnostic to Therapeutic Molecules in Treating Neurodegenerative Diseases.

PubMed

Czaplinska, Barbara; Spaczynska, Ewelina; Musiol, Robert

2018-01-01

Fluorescent compounds had gained strong attention due to their wide and appealing applications. Microscopic techniques and visualization are good examples among others. Introduction of fluorescent dyes into microbiology opens the possibility to observe tissues, organisms or organelle with exceptional sensitivity and resolution. Probes for detection of biologically relevant metals as zinc, iron or copper seems to be particularly important for drug design and pharmaceutical sciences. Quinoline derivatives are well known for their good metal affinity and wide spectrum of biological activity. In this regard, molecular sensors built on this scaffold may be useful not only as analytical but also as therapeutic agents. In the present review, application of quinoline moiety in designing of novel fluorescent probes for zinc is presented and discussed. Zinc cations are relevant for vast majority of processes and recently attract a great deal of attention for their role in neurodegenerative diseases. Compounds interacting with Zn2+ may be used for early diagnosis of such disorders, for example the Alzheimer disease. Quinoline-based zinc probes may exert some beneficial role in organism acting as theranostic agents. First preliminary drugs for Alzheimer therapy that are based on quinoline moiety are good example of this trend. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Prediction of Relative In Vivo Metabolite Exposure from In Vitro Data Using Two Model Drugs: Dextromethorphan and Omeprazole

PubMed Central

Lutz, Justin D.

2012-01-01

Metabolites can have pharmacological or toxicological effects, inhibit metabolic enzymes, and be used as probes of drug-drug interactions or specific cytochrome P450 (P450) phenotypes. Thus, better understanding and prediction methods are needed to characterize metabolite exposures in vivo. This study aimed to test whether in vitro data could be used to predict and rationalize in vivo metabolite exposures using two model drugs and P450 probes: dextromethorphan and omeprazole with their primary metabolites dextrorphan, 5-hydroxyomeprazole (5OH-omeprazole), and omeprazole sulfone. Relative metabolite exposures were predicted using metabolite formation and elimination clearances. For dextrorphan, the formation clearances of dextrorphan glucuronide and 3-hydroxymorphinan from dextrorphan in human liver microsomes were used to predict metabolite (dextrorphan) clearance. For 5OH-omeprazole and omeprazole sulfone, the depletion rates of the metabolites in human hepatocytes were used to predict metabolite clearance. Dextrorphan/dextromethorphan in vivo metabolite/parent area under the plasma concentration versus time curve ratio (AUCm/AUCp) was overpredicted by 2.1-fold, whereas 5OH-omeprazole/omeprazole and omeprazole sulfone/omeprazole were predicted within 0.75- and 1.1-fold, respectively. The effect of inhibition or induction of the metabolite's formation and elimination on the AUCm/AUCp ratio was simulated. The simulations showed that unless metabolite clearance pathways are characterized, interpretation of the metabolic ratios is exceedingly difficult. This study shows that relative in vivo metabolite exposure can be predicted from in vitro data and characterization of secondary metabolism of probe metabolites is critical for interpretation of phenotypic data. PMID:22010218

Integrated microfluidic card with TaqMan probes and high-resolution melt analysis to detect tuberculosis drug resistance mutations across 10 genes.

PubMed

Pholwat, Suporn; Liu, Jie; Stroup, Suzanne; Gratz, Jean; Banu, Sayera; Rahman, S M Mazidur; Ferdous, Sara Sabrina; Foongladda, Suporn; Boonlert, Duangjai; Ogarkov, Oleg; Zhdanova, Svetlana; Kibiki, Gibson; Heysell, Scott; Houpt, Eric

2015-02-24

Genotypic methods for drug susceptibility testing of Mycobacterium tuberculosis are desirable to speed the diagnosis and proper therapy of tuberculosis (TB). However, the numbers of genes and polymorphisms implicated in resistance have proliferated, challenging diagnostic design. We developed a microfluidic TaqMan array card (TAC) that utilizes both sequence-specific probes and high-resolution melt analysis (HRM), providing two layers of detection of mutations. Twenty-seven primer pairs and 40 probes were designed to interrogate 3,200 base pairs of critical regions of the inhA, katG, rpoB, embB, rpsL, rrs, eis, gyrA, gyrB, and pncA genes. The method was evaluated on 230 clinical M. tuberculosis isolates from around the world, and it yielded 96.1% accuracy (2,431/2,530) in comparison to that of Sanger sequencing and 87% accuracy in comparison to that of the slow culture-based susceptibility testing. This TAC-HRM method integrates assays for 10 genes to yield fast, comprehensive, and accurate drug susceptibility results for the 9 major antibiotics used to treat TB and could be deployed to improve treatment outcomes. Multidrug-resistant tuberculosis threatens global tuberculosis control efforts. Optimal therapy utilizes susceptibility test results to guide individualized treatment regimens; however, the susceptibility testing methods in use are technically difficult and slow. We developed an integrated TaqMan array card method with high-resolution melt analysis that interrogates 10 genes to yield a fast, comprehensive, and accurate drug susceptibility result for the 9 major antituberculosis antibiotics. Copyright © 2015 Pholwat et al.

[From the plant to chemistry--the early history of "rheumatic medication"].

PubMed

Kaiser, H

2008-05-01

The empirical administration of medication of plant, animal and even mineral origin goes back thousands of years. It was only in the 19th century that such therapy gained a scientific basis by means of the possibility to extract the active substances and analyze them chemically, and ultimately create them synthetically and modify them chemically.Meadow saffron was used from the 2nd century BC for the treatment of joint disease and gout; the active ingredient colchicine was discovered in 1819. For 4000 years willow bark has also been considered a remedy against fever, pain and gout. The active ingredient salicin was isolated in 1829, followed by salicyl acid in 1838, while the better tolerated acetylsalicylic acid was synthesized in 1897. Although the antipyretic agent cinchona was never a rheumatic remedy, it was initially considered an important antiinflammatory medication. In 1844, during the search for an alternative to quinin, antipyrin was developed, from which many antiphlogistic, antipyretic and analgetic active substances were later derived. Following the Second World War, the strongest antiinflammatory drug, cortisone, was discovered, derivates of which are still indispensable today for the treatment of inflammatory rheumatic diseases. At about the same time, there was a new wave of research which lead to the development of a large number of so-called non-steroidal antiinflammatory drugs. Following the discovery of proinflammatory cytokines in the 1970s, it became possible in the 1990s to produce antibodies against these substances, which gave rheumatic therapy new perspectives in the form of "biologicals". The sap from poppy seed capsules was already considered to have analgesic properties in the time of Hippocrates. The active ingredient morphine was isolated at the beginning of the 19th century. Today, only synthetically produced"opioids" are used, if at all, for the treatment of rheumatic disease.

Parasite-based malaria diagnosis: Are Health Systems in Uganda equipped enough to implement the policy?

PubMed Central

2012-01-01

Background Malaria case management is a key strategy for malaria control. Effective coverage of parasite-based malaria diagnosis (PMD) remains limited in malaria endemic countries. This study assessed the health system's capacity to absorb PMD at primary health care facilities in Uganda. Methods In a cross sectional survey, using multi-stage cluster sampling, lower level health facilities (LLHF) in 11 districts in Uganda were assessed for 1) tools, 2) skills, 3) staff and infrastructure, and 4) structures, systems and roles necessary for the implementing of PMD. Results Tools for PMD (microscopy and/or RDTs) were available at 30 (24%) of the 125 LLHF. All LLHF had patient registers and 15% had functional in-patient facilities. Three months’ long stock-out periods were reported for oral and parenteral quinine at 39% and 47% of LLHF respectively. Out of 131 health workers interviewed, 86 (66%) were nursing assistants; 56 (43%) had received on-job training on malaria case management and 47 (36%) had adequate knowledge in malaria case management. Overall, only 18% (131/730) Ministry of Health approved staff positions were filled by qualified personnel and 12% were recruited or transferred within six months preceding the survey. Of 186 patients that received referrals from LLHF, 130(70%) had received pre-referral anti-malarial drugs, none received pre-referral rectal artesunate and 35% had been referred due to poor response to antimalarial drugs. Conclusion Primary health care facilities had inadequate human and infrastructural capacity to effectively implement universal parasite-based malaria diagnosis. The priority capacity building needs identified were: 1) recruitment and retention of qualified staff, 2) comprehensive training of health workers in fever management, 3) malaria diagnosis quality control systems and 4) strengthening of supply chain, stock management and referral systems. PMID:22920954

Antimalarial activity and safety assessment of Flueggea virosa leaves and its major constituent with special emphasis on their mode of action.

PubMed

Singh, Shiv Vardan; Manhas, Ashan; Kumar, Yogesh; Mishra, Sonali; Shanker, Karuna; Khan, Feroz; Srivastava, Kumkum; Pal, Anirban

2017-05-01

A clinical emergency stands due to the appearance of drug resistant Plasmodium strains necessitate novel and effective antimalarial chemotypes, where plants seem as the prime option, especially after the discovery of quinine and artemisinin. The present study was aimed towards bioprospecting leaves of Flueggea virosa for its antimalarial efficacy and active principles. Crude hydro-ethanolic extract along with solvent derived fractions were tested in vitro against Plasmodium falciparum CQ sensitive (3D7) and resistant (K1) strains, where all the fractions exhibited potential activity (IC 50 values <10μg/mL) against both the strains. Interestingly, under in vivo conditions against P. berghei in Swiss mice, preferential chemo-suppression was recorded for crude hydro-ethanolic extract (77.38%) and ethyl acetate fraction (86.09%) at the dose of 500mg/kg body weight. Additionally, ethyl acetate fraction was found to be capable of normalizing the host altered pharmacological parameters and enhanced oxidative stress augmented during the infection. The bioactivity guided fractionation lead to the isolation of bergenin as a major and active constituent (IC 50, 8.07±2.05μM) of ethyl acetate fraction with the inhibition of heme polymerization pathway of malaria parasite being one of the possible chemotherapeutic target. Furthermore, bergenin exhibited a moderate antimalarial activity against P. berghei and also ameliorated parasite induced systemic inflammation in host (mice). Safe toxicity profile elucidated through in vitro cytotoxicity and in silico ADME/T predications evidently suggest that bergenin possess drug like properties. Hence, the present study validates the traditional usage of F. indica as an antimalarial remedy and also insists for further chemical modifications of bergenin to obtain more effective antimalarial chemotypes. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

IDH1 R132H mutation regulates glioma chemosensitivity through Nrf2 pathway.

PubMed

Li, Kaishu; Ouyang, Leping; He, Mingliang; Luo, Ming; Cai, Wangqing; Tu, Yalin; Pi, Rongbiao; Liu, Anmin

2017-04-25

Numerous studies have reported that glioma patients with isocitrate dehydrogenase 1(IDH1) R132H mutation are sensitive to temozolomide treatment. However, the mechanism of IDH1 mutations on the chemosensitivity of glioma remains unclear. In this study, we investigated the role and the potential mechanism of Nrf2 in IDH1 R132H-mediated drug resistance. Wild type IDH1 (R132H-WT) and mutant IDH1 (R132H) plasmids were constructed. Stable U87 cells and U251 cells overexpressing IDH1 were generated. Phenotypic differences between IDH1-WT and IDH1 R132H overexpressing cells were evaluated using MTT, cell colony formation assay, scratch test assay and flow cytometry. Expression of IDH1 and its associated targets, nuclear factor-erythroid 2-related factor 2 (Nrf2), NAD(P)H quinine oxidoreductase 1 (NQO1), multidrug resistant protein 1 (MRP1) and p53 were analyzed. The IDH1 R132H overexpressing cells were more sensitive to temozolomide than WT and the control, and Nrf2 was significantly decreased in IDH1 R132H overexpressing cells. We found that knocking down Nrf2 could decrease resistance to temozolomide. The nuclear translocation of Nrf2 in IDH1 R132H overexpressing cells was lower than the WT and the control groups after temozolomide treatment. When compared with WT cells, NQO1 expression was reduced in IDH1 R132H cells, especially after temozolomide treatment. P53 was involved in the resistance mechanism of temozolomide mediated by Nrf2 and NQO1. Nrf2 played an important role in IDH1 R132H-mediated drug resistance. The present study provides new insight for glioma chemotherapy with temozolomide.

IDH1 R132H mutation regulates glioma chemosensitivity through Nrf2 pathway

PubMed Central

Luo, Ming; Cai, Wangqing; Tu, Yalin; Pi, Rongbiao; Liu, Anmin

2017-01-01

Purpose Numerous studies have reported that glioma patients with isocitrate dehydrogenase 1(IDH1) R132H mutation are sensitive to temozolomide treatment. However, the mechanism of IDH1 mutations on the chemosensitivity of glioma remains unclear. In this study, we investigated the role and the potential mechanism of Nrf2 in IDH1 R132H-mediated drug resistance. Methods Wild type IDH1 (R132H-WT) and mutant IDH1 (R132H) plasmids were constructed. Stable U87 cells and U251 cells overexpressing IDH1 were generated. Phenotypic differences between IDH1-WT and IDH1 R132H overexpressing cells were evaluated using MTT, cell colony formation assay, scratch test assay and flow cytometry. Expression of IDH1 and its associated targets, nuclear factor-erythroid 2-related factor 2 (Nrf2), NAD(P)H quinine oxidoreductase 1 (NQO1), multidrug resistant protein 1 (MRP1) and p53 were analyzed. Results The IDH1 R132H overexpressing cells were more sensitive to temozolomide than WT and the control, and Nrf2 was significantly decreased in IDH1 R132H overexpressing cells. We found that knocking down Nrf2 could decrease resistance to temozolomide. The nuclear translocation of Nrf2 in IDH1 R132H overexpressing cells was lower than the WT and the control groups after temozolomide treatment. When compared with WT cells, NQO1 expression was reduced in IDH1 R132H cells, especially after temozolomide treatment. P53 was involved in the resistance mechanism of temozolomide mediated by Nrf2 and NQO1. Conclusions Nrf2 played an important role in IDH1 R132H-mediated drug resistance. The present study provides new insight for glioma chemotherapy with temozolomide. PMID:28427200

Computational Prediction and Validation of an Expert's Evaluation of Chemical Probes

PubMed Central

Litterman, Nadia K.; Lipinski, Christopher A.; Bunin, Barry A.; Ekins, Sean

2016-01-01

In a decade with over half a billion dollars of investment, more than 300 chemical probes have been identified to have biological activity through NIH funded screening efforts. We have collected the evaluations of an experienced medicinal chemist on the likely chemistry quality of these probes based on a number of criteria including literature related to the probe and potential chemical reactivity. Over 20% of these probes were found to be undesirable. Analysis of the molecular properties of these compounds scored as desirable suggested higher pKa, molecular weight, heavy atom count and rotatable bond number. We were particularly interested whether the human evaluation aspect of medicinal chemistry due diligence could be computationally predicted. We used a process of sequential Bayesian model building and iterative testing as we included additional probes. Following external validation of these methods and comparing different machine learning methods we identified Bayesian models with accuracy comparable to other measures of drug-likeness and filtering rules created to date. PMID:25244007

Investigating local and long-range neuronal network dynamics by simultaneous optogenetics, reverse microdialysis and silicon probe recordings in vivo

PubMed Central

Taylor, Hannah; Schmiedt, Joscha T.; Çarçak, Nihan; Onat, Filiz; Di Giovanni, Giuseppe; Lambert, Régis; Leresche, Nathalie; Crunelli, Vincenzo; David, Francois

2014-01-01

Background The advent of optogenetics has given neuroscientists the opportunity to excite or inhibit neuronal population activity with high temporal resolution and cellular selectivity. Thus, when combined with recordings of neuronal ensemble activity in freely moving animals optogenetics can provide an unprecedented snapshot of the contribution of neuronal assemblies to (patho)physiological conditions in vivo. Still, the combination of optogenetic and silicone probe (or tetrode) recordings does not allow investigation of the role played by voltage- and transmitter-gated channels of the opsin-transfected neurons and/or other adjacent neurons in controlling neuronal activity. New method and results We demonstrate that optogenetics and silicone probe recordings can be combined with intracerebral reverse microdialysis for the long-term delivery of neuroactive drugs around the optic fiber and silicone probe. In particular, we show the effect of antagonists of T-type Ca2+ channels, hyperpolarization-activated cyclic nucleotide-gated channels and metabotropic glutamate receptors on silicone probe-recorded activity of the local opsin-transfected neurons in the ventrobasal thalamus, and demonstrate the changes that the block of these thalamic channels/receptors brings about in the network dynamics of distant somatotopic cortical neuronal ensembles. Comparison with existing methods This is the first demonstration of successfully combining optogenetics and neuronal ensemble recordings with reverse microdialysis. This combination of techniques overcomes some of the disadvantages that are associated with the use of intracerebral injection of a drug-containing solution at the site of laser activation. Conclusions The combination of reverse microdialysis, silicone probe recordings and optogenetics can unravel the short and long-term effects of specific transmitter- and voltage-gated channels on laser-modulated firing at the site of optogenetic stimulation and the actions that these manipulations exert on distant neuronal populations. PMID:25004203

Investigating local and long-range neuronal network dynamics by simultaneous optogenetics, reverse microdialysis and silicon probe recordings in vivo.

PubMed

Taylor, Hannah; Schmiedt, Joscha T; Carçak, Nihan; Onat, Filiz; Di Giovanni, Giuseppe; Lambert, Régis; Leresche, Nathalie; Crunelli, Vincenzo; David, Francois

2014-09-30

The advent of optogenetics has given neuroscientists the opportunity to excite or inhibit neuronal population activity with high temporal resolution and cellular selectivity. Thus, when combined with recordings of neuronal ensemble activity in freely moving animals optogenetics can provide an unprecedented snapshot of the contribution of neuronal assemblies to (patho)physiological conditions in vivo. Still, the combination of optogenetic and silicone probe (or tetrode) recordings does not allow investigation of the role played by voltage- and transmitter-gated channels of the opsin-transfected neurons and/or other adjacent neurons in controlling neuronal activity. We demonstrate that optogenetics and silicone probe recordings can be combined with intracerebral reverse microdialysis for the long-term delivery of neuroactive drugs around the optic fiber and silicone probe. In particular, we show the effect of antagonists of T-type Ca(2+) channels, hyperpolarization-activated cyclic nucleotide-gated channels and metabotropic glutamate receptors on silicone probe-recorded activity of the local opsin-transfected neurons in the ventrobasal thalamus, and demonstrate the changes that the block of these thalamic channels/receptors brings about in the network dynamics of distant somatotopic cortical neuronal ensembles. This is the first demonstration of successfully combining optogenetics and neuronal ensemble recordings with reverse microdialysis. This combination of techniques overcomes some of the disadvantages that are associated with the use of intracerebral injection of a drug-containing solution at the site of laser activation. The combination of reverse microdialysis, silicone probe recordings and optogenetics can unravel the short and long-term effects of specific transmitter- and voltage-gated channels on laser-modulated firing at the site of optogenetic stimulation and the actions that these manipulations exert on distant neuronal populations. Copyright © 2014. Published by Elsevier B.V.

Effect of Short-Term Fasting on Systemic Cytochrome P450-Mediated Drug Metabolism in Healthy Subjects: A Randomized, Controlled, Crossover Study Using a Cocktail Approach.

PubMed

Lammers, Laureen A; Achterbergh, Roos; van Schaik, Ron H N; Romijn, Johannes A; Mathôt, Ron A A

2017-10-01

Short-term fasting can alter drug exposure but it is unknown whether this is an effect of altered oral bioavailability and/or systemic clearance. Therefore, the aim of our study was to assess the effect of short-term fasting on oral bioavailability and systemic clearance of different drugs. In a randomized, controlled, crossover trial, 12 healthy subjects received a single administration of a cytochrome P450 (CYP) probe cocktail, consisting of caffeine (CYP1A2), metoprolol (CYP2D6), midazolam (CYP3A4), omeprazole (CYP2C19) and warfarin (CYP2C9), on four occasions: an oral (1) and intravenous (2) administration after an overnight fast (control) and an oral (3) and intravenous (4) administration after 36 h of fasting. Pharmacokinetic parameters of the probe drugs were analyzed using the nonlinear mixed-effects modeling software NONMEM. Short-term fasting increased systemic caffeine clearance by 17% (p = 0.04) and metoprolol clearance by 13% (p < 0.01), whereas S-warfarin clearance decreased by 19% (p < 0.01). Fasting did not affect bioavailability. The study demonstrates that short-term fasting alters CYP-mediated drug metabolism in a non-uniform pattern without affecting oral bioavailability.

Revealing chemical processes and kinetics of drug action within single living cells via plasmonic Raman probes.

PubMed

Li, Shan-Shan; Guan, Qi-Yuan; Meng, Gang; Chang, Xiao-Feng; Wei, Ji-Wu; Wang, Peng; Kang, Bin; Xu, Jing-Juan; Chen, Hong-Yuan

2017-05-23

Better understanding the drug action within cells may extend our knowledge on drug action mechanisms and promote new drugs discovery. Herein, we studied the processes of drug induced chemical changes on proteins and nucleic acids in human breast adenocarcinoma (MCF-7) cells via time-resolved plasmonic-enhanced Raman spectroscopy (PERS) in combination with principal component analysis (PCA). Using three popular chemotherapy drugs (fluorouracil, cisplatin and camptothecin) as models, chemical changes during drug action process were clearly discriminated. Reaction kinetics related to protein denaturation, conformational modification, DNA damage and their associated biomolecular events were calculated. Through rate constants and reaction delay times, the different action modes of these drugs could be distinguished. These results may provide vital insights into understanding the chemical reactions associated with drug-cell interactions.

Effect of a herbal extract containing curcumin and piperine on midazolam, flurbiprofen and paracetamol (acetaminophen) pharmacokinetics in healthy volunteers

PubMed Central

Volak, Laurie P; Hanley, Michael J; Masse, Gina; Hazarika, Suwagmani; Harmatz, Jerold S; Badmaev, Vladimir; Majeed, Muhammed; Greenblatt, David J; Court, Michael H

2013-01-01

Aims Turmeric extract derived curcuminoids (curcumin, demethoxycurcumin and bisdemethoxycurcumin) are currently being evaluated for the treatment of cancer and Alzheimer's dementia. Previous in vitro studies indicate that curcuminoids and piperine (a black pepper derivative that enhances curcuminoid bioavailability) could inhibit human CYP3A, CYP2C9, UGT and SULT dependent drug metabolism. The aim of this study was to determine whether a commercially available curcuminoid/piperine extract alters the pharmacokinetic disposition of probe drugs for these enzymes in human volunteers. Methods A randomized placebo-controlled six way crossover study was conducted in eight healthy volunteers. A standardized curcuminoid/piperine preparation (4 g curcuminoids plus 24 mg piperine) or matched placebo was given orally four times over 2 days before oral administration of midazolam (CYP3A probe), flurbiprofen (CYP2C9 probe) or paracetamol (acetaminophen) (dual UGT and SULT probe). Plasma and urine concentrations of drugs, metabolites and herbals were measured by HPLC. Subject sedation and electroencephalograph effects were also measured following midazolam dosing. Results Compared with placebo, the curcuminoid/piperine treatment produced no meaningful changes in plasma Cmax, AUC, clearance, elimination half-life or metabolite levels of midazolam, flurbiprofen or paracetamol (α = 0.05, paired t-tests). There was also no effect of curcuminoid/piperine treatment on the pharmacodynamics of midazolam. Although curcuminoid and piperine concentrations were readily measured in plasma following glucuronidase/sulfatase treatment, unconjugated concentrations were consistently below the assay thresholds (0.05–0.08 μm and 0.6 μm, respectively). Conclusion The results indicate that short term use of this piperine-enhanced curcuminoid preparation is unlikely to result in a clinically significant interaction involving CYP3A, CYP2C9 or the paracetamol conjugation enzymes. PMID:22725836

Calcium antagonists and deep gingival pockets in the population-based SHIP study

PubMed Central

Meisel, Peter; Schwahn, Christian; John, Ulrich; Kroemer, Heyo K; Kocher, Thomas

2005-01-01

Aim Gingival overgrowth is a common undesired side-effect in patients taking calcium channel blockers. Different reports have suggested that the drug-induced gingival hyperplasia may aggravate inflammatory periodontal disease. However, representative epidemiological data are lacking. We investigated the association between the intake of calcium antagonists and periodontitis in a population-based analysis including the most important risk factors of periodontitis. Methods In a cross-sectional epidemiological investigation involving 4290 subjects aged 20–80 years, we recorded periodontal risk factors and identified participants using calcium antagonists. Periodontal parameters, attachment loss, probing depth and number of teeth were assessed. In a subgroup analysis with matched pairs, 456 subjects using calcium antagonists and 456 without were compared for periodontal status. Results Subjects treated with calcium antagonistic drugs had significantly deeper gingival pockets than their drug-free counterparts. This was observed in the total population of 4290 and confirmed by logistic regression analyses (P < 0.001) controlled for the known risk factors of periodontitis (age, sex, smoking, education). In the matched-pair analysis only the probing depth was increased: extent probing depth ≥4 mm median 23.5 vs. 17.0% (P < 0.001); mean probing depth 3.0 ± 0.8 vs. 2.7 ± 0.9 mm (P < 0.001). No differences were found in extent and severity of clinical attachment loss and in the number of teeth. The risk of gingival overgrowth was aggravated in smokers. Conclusion In the general population, treatment with calcium antagonists leads to gingival overgrowth without an aggravation of periodontal disease. Interaction with smoking indicates the multifactorial background of the undesired effect of calcium antagonists. PMID:16236046