Cisplatin Tumor Biodistribution and Efficacy after Intratumoral Injection of a Biodegradable Extended Release Implant

Local delivery of chemotherapeutic drugs has long been recognized as a potential method for reaching high drug doses at the target site while minimizing systemic exposure. Cisplatin is one of the most effective chemotherapeutic agents for the treatment of various tumors; however, its systemic toxicity remains the primary dose-limiting factor. Here we report that incorporation of cisplatin into a fatty acid-based polymer carrier followed by a local injection into the solid tumor resulted in a successful tumor growth inhibition in heterotopic mouse bladder tumor model in mice. Platinum concentration in the tumor tissue surrounding the injected implant remained above the therapeutic level up to 14 days after the injection, while the plasma levels were several orders of magnitude lower comparing to systemic delivery. The reported delivery system increased the maximum tolerated dose of cisplatin 5 times compared to systemic delivery, thus potentially improving antitumor efficacy of cisplatin in solid tumor model

Endothelial Cells Potentiate Interferon-γ Production in a Novel Tripartite Culture Model of Human Cerebral Malaria

We have established a novel in vitro co-culture system of human brain endothelial cells (HBEC), Plasmodium falciparum parasitised red blood cells (iRBC) and peripheral blood mononuclear cells (PBMC), in order to simulate the chief pathophysiological lesion in cerebral malaria (CM). This approach has revealed a previously unsuspected pro-inflammatory role of the endothelial cell through potentiating the production of interferon (IFN)-γ by PBMC and concurrent reduction of interleukin (IL)-10. The IFN-γ increased the expression of CXCL10 and intercellular adhesion molecule (ICAM)-1, both of which have been shown to be crucial in the pathogenesis of CM. There was a shift in the ratio of IL-10:IFN-γ protein from >1 to <1 in the presence of HBEC, associated with the pro-inflammatory process in this model. For this to occur, a direct contact between PBMC and HBEC, but not PBMC and iRBC, was necessary. These results support HBEC playing an active role in the pathogenesis of CM. Thus, if these findings reflect the pathogenesis of CM, inhibition of HBEC and PBMC interactions might reduce the occurrence, or improve the prognosis, of the condition. © 2013 Khaw et al

Artemisone effective against murine cerebral malaria

<p>Abstract</p> <p>Background</p> <p>Artemisinins are the newest class of drug approved for malaria treatment. Due to their unique mechanism of action, rapid effect on Plasmodium, and high efficacy in vivo, artemisinins have become essential components of malaria treatment. Administration of artemisinin derivatives in combination with other anti-plasmodials has become the first-line treatment for uncomplicated falciparum malaria. However, their efficiency in cases of cerebral malaria (CM) remains to be determined.</p> <p>Methods</p> <p>The efficacy of several artemisinin derivatives for treatment of experimental CM was evaluated in ICR or C57BL/6 mice infected by <it>Plasmodium berghei </it>ANKA. Both mouse strains serve as murine models for CM.</p> <p>Results</p> <p>Artemisone was the most efficient drug tested, and could prevent death even when administered at relatively late stages of cerebral pathogenesis. No parasite resistance to artemisone was detected in recrudescence. Co-administration of artemisone together with chloroquine was more effective than monotherapy with either drug, and led to complete cure. Artemiside was even more effective than artemisone, but this substance has yet to be submitted to preclinical toxicological evaluation.</p> <p>Conclusions</p> <p>Altogether, the results support the use of artemisone for combined therapy of CM.</p

Recombinant Plasmodium falciparum glutathione reductase is inhibited by the antimalarial dye methylene blue

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/116326/1/feb2s0014579398000313.pd

A bioinspired hybrid silica–protein material with antimicrobial activity by iron uptake

A silica–protein hybrid material has been prepared by simultaneous covalent deposition of apoferritin and lactoferrin on functionalized silica. This material exhibits strong antibacterial activity against E. coli due to its high iron-uptake capacity.This work was supported by MINECO and FEDER (project CTQ2009-09344), Junta de Andalucía (project P07-FQM-02899) and BIOSEARCH SA (contract PostBIO)

Anti-plasmodial polyvalent interactions in Artemisia annua L. aqueous extract – possible synergistic and resistance mechanisms

Artemisia annua hot water infusion (tea) has been used in in vitro experiments against P. falciparum malaria parasites to test potency relative to equivalent pure artemisinin. High performance liquid chromatography (HPLC) and mass spectrometric analyses were employed to determine the metabolite profile of tea including the concentrations of artemisinin (47.5±0.8 mg L-1), dihydroartemisinic acid (70.0±0.3 mg L-1), arteannuin B (1.3±0.0 mg L-1), isovitexin (105.0±7.2 mg L-1) and a range of polyphenolic acids. The tea extract, purified compounds from the extract, and the combination of artemisinin with the purified compounds were tested against chloroquine sensitive and chloroquine resistant strains of P. falciparum using the DNA-intercalative SYBR Green I assay. The results of these in vitro tests and of isobologram analyses of combination effects showed mild to strong antagonistic interactions between artemisinin and the compounds (9-epi-artemisinin and artemisitene) extracted from A. annua with significant (IC50 <1 μM) anti-plasmodial activities for the combination range evaluated. Mono-caffeoylquinic acids, tri-caffeoylquinic acid, artemisinic acid and arteannuin B showed additive interaction while rosmarinic acid showed synergistic interaction with artemisinin in the chloroquine sensitive strain at a combination ratio of 1:3 (artemisinin to purified compound). In the chloroquine resistant parasite, using the same ratio, these compounds strongly antagonised artemisinin anti-plasmodial activity with the exception of arteannuin B, which was synergistic. This result would suggest a mechanism targeting parasite resistance defenses for arteannuin B’s potentiation of artemisinin

Coartem®: the journey to the clinic

Artemisinin, from which the artemether component of Coartem®(artemether/lumefantrine, AL) is derived, is obtained from the plant sweet wormwood (Artemisia annua) which has been used for over 2,000 years as a Chinese herbal remedy. Artemisinin was first identified by Chinese researchers as the active anti-malarial constituent of A. annua and its derivatives were found to be the most potent of all anti-malarial drugs. Artemether acts rapidly, reducing the infecting parasite biomass by approximately 10,000-fold per asexual life cycle. Lumefantrine, the other active constituent of AL, acts over a longer period to eliminate the residual 100-100,000 parasites that remain after artemether is cleared from the body and thus minimizes the risk of recrudescence. The two agents have different modes of action and act at different points in the parasite life cycle and show a synergistic action against Plasmodium falciparum in vitro. The combination of artemether and lumefantrine reduces the risk of resistance developing to either agent, and to date there are no reports of resistance to AL combined therapy in the malaria parasite that infects humans. Following a unique partnership agreement between Chinese authorities and Novartis, the manufacturer of AL, over 20 sponsored clinical studies have been undertaken in various malaria endemic regions and in travellers. These trials have involved more than 3,500 patients (including over 2,000 children), and led to identification of a six-dose, three-day regimen as the optimal dosing strategy for AL in uncomplicated falciparum malaria. AL has consistently shown 28-day polymerase chain (PCR)-corrected cure rates greater than 95% in the evaluable population, meeting WHO recommendations. More recently, Novartis and the Medicines for Malaria Venture have worked in partnership to develop Coartem® Dispersible, a new formulation designed specifically to meet the specific needs of children with malaria. The dispersible tablets have shown similar high response rates to those observed with crushed standard tablets of AL. A partnership agreement between Novartis and WHO has seen over 250 million AL (Coartem®) treatments (75% for children) being distributed to malaria patients in developing countries without profit, supported by training programmes and educational resources

Intravenous pharmacokinetics, oral bioavailability, dose proportionality and in situ permeability of anti-malarial lumefantrine in rats

<p>Abstract</p> <p>Background</p> <p>Despite the wide spread use of lumefantrine, there is no study reporting the detailed preclinical pharmacokinetics of lumefantrine. For the development of newer anti-malarial combination(s) and selection of better partner drugs, it is long felt need to understand the detailed preclinical pharmacokinetics of lumefantrine in preclinical experimental animal species. The focus of present study is to report bioavailability, pharmacokinetics, dose linearity and permeability of lumefantrine in rats.</p> <p>Methods</p> <p>A single dose of 10, 20 or 40 mg/kg of lumefantrine was given orally to male rats (N = 5 per dose level) to evaluate dose proportionality. In another study, a single intravenous bolus dose of lumefantrine was given to rats (N = 4) at 0.5 mg/kg dose following administration through the lateral tail vein in order to obtain the absolute oral bioavailability and clearance parameters. Blood samples were drawn at predetermined intervals and the concentration of lumefantrine and its metabolite desbutyl-lumefantrine in plasma were determined by partially validated LC-MS/MS method. <it>In-situ </it>permeability study was carried in anaesthetized rats. The concentration of lumefantrine in permeability samples was determined using RP-HPLC.</p> <p>Results</p> <p>For nominal doses increasing in a 1:2:4 proportion, the C_maxand AUC_0-∞values increased in the proportions of 1:0.6:1.5 and 1:0.8:1.8, respectively. For lumefantrine nominal doses increasing in a 1:2:4 proportion, the C_maxand the AUC_0-tvalues for desbutyl-lumefantrine increased in the proportions of 1:1.45:2.57 and 1:1.08:1.87, respectively. After intravenous administration the clearance (Cl) and volume of distribution (Vd) of lumefantrine in rats were 0.03 (± 0.02) L/h/kg and 2.40 (± 0.67) L/kg, respectively. Absolute oral bioavailability of lumefantrine across the tested doses ranged between 4.97% and 11.98%. Lumefantrine showed high permeability (4.37 × 10^-5cm/s) in permeability study.</p> <p>Conclusions</p> <p>The pharmacokinetic parameters of lumefantrine and its metabolite desbutyl-lumefantrine were successfully determined in rats for the first time. Lumefantrine displayed similar pharmacokinetics in the rat as in humans, with multiphasic disposition, low clearance, and a large volume of distribution resulting in a long terminal elimination half-life. The absolute oral bioavailability of lumefantrine was found to be dose dependent. Lumefantrine displayed high permeability in the <it>in-situ </it>permeability study.</p