/HUMAN EXPOSURE STUDIES/ ...Three combination regimens containing an average adult lumefantrine dose of 1,920 mg over 3 days (four doses) (regimen A) or 2,780 mg over 3 or 5 days (six doses) (regimen B or C, respectively) were given to 266 Thai patients. Detailed observations were obtained for 51 hospitalized adults, and sparse data were collected for 215 patients of all ages in a community setting. The population absorption half-life of lumefantrine was 4.5 hr. The model-based median (5th and 95th percentiles) peak plasma lumefantrine concentrations were 6.2 (0.25 and 14.8) ug/mL after regimen A, 9. 0 (1.1 and 19.8) ug/mL after regimen B, and 8 (1.4 and 17.4) ug/mL after regimen C. During acute malaria, there was marked variability in the fraction of drug absorbed by patients (coefficient of variation, 150%). The fraction increased considerably and variability fell with clinical recovery, largely because food intake was resumed; taking a normal meal close to drug administration increased oral bioavailability by 108% (90% confidence interval, 64 to 164) (P, 0.0001). The higher-dose regimens (B and C) gave 60 and 100% higher areas under the concentration-time curves (AUC), respectively, and thus longer durations for which plasma lumefantrine concentrations exceeded the putative in vivo MIC of 280 ug/mL (median for regimen B, 252 hr; that for regimen C, 298 hr; that for regimen A, 204 hr [P, 0.0001]) and higher cure rates. Lumefantrine oral bioavailability is very dependent on food and is consequently poor in acute malaria but improves markedly with recovery. The high cure rates with the two six-dose regimens resulted from increased AUC and increased time at which lumefantrine concentrations were above the in vivo MIC.
/ALTERNATIVE IN VITRO TESTS/ Using a continuous in vitro culture system, the sensitivity of Plasmodium falciparum to artemether and a new antimalarial drug, benflumetol (lumefantrine), alone and in combination, was investigated with a multiresistant strain (T-996) from Thailand and a chloroquine-resistant strain (LS-21) from India. Both strains showed similar 50% inhibitory concentration (IC50) levels with artemether alone or benflumetol alone, but the IC90 was higher in strain T-996 compared with strain LS-21: for artemether, 34.45 and 7.11 nmol/L (10.28 and 2.12 ng/mL of erythrocyte-medium mixture [EMM]), and for benflumetol, 293.03 and 95.61 nmol/L (154.69 and 50.47 ng/mL of EMM). When tested in association at artemether:benflumetol (mol: mol) ratios between 100:1 and 1:100, substantial synergism was seen in both strains, especially at the IC90 and IC99 levels.
The combination of artemether and lumefantrine (benflumetol) is a new and very well tolerated oral antimalarial drug effective even against multidrug-resistant falciparum malaria. ... The lumefantrine component is absorbed variably in malaria, and is eliminated more slowly (half-life of 3 to 6 days). Absorption is very dependent on coadministration with fat, and so improves markedly with recovery from malaria.
The pharmacokinetics of benflumetol as a fixed combination, artemether-benflumetol (CGP 56697), following three regimens (regimen A: four tablets at 0, 8, 24 and 48 hr (320 mg artemether, 1,920 mg benflumetol); regimen B: two tablets at 0, 8, 24 and 48 hr (160 mg artemether, 960 mg benflumetol); regimen C: four tablets at 0, 8 and 24 hr (240 mg artemether, 1,440 mg benflumetol)) were investigated in 39 patients with acute uncomplicated falciparum malaria. All patients showed a rapid initial response with a median parasite clearance time of 40, 41 and 39.5 hr and a fever clearance time of 27.8, 32 and 24.5 hr for regimens A, B and C, respectively. In nine patients (two, four and three patients in regimens A, B and C, respectively), however, parasitemia reappeared in the peripheral blood smear between days 9 and 23. The pharmacokinetics of benflumetol were highly variable, with coefficients of variation in pharmacokinetic parameters ranging from 14.9% to 144%. Absorption and elimination of benflumetol were relatively slow. Median Cmax per dose (first dose) was significantly higher in regimen B (6.29 ng/ml/mg dose) than in regimen A (2.6 ng/ml/mg dose) and regimen C (3.06 ng/ml/mg dose). Mean T1/2z in regimen C (2.65 hr) was significantly shorter than in regimen A (4.5 hr) and regimen B (3.89 hr). In patients on regimens A and B who showed a sensitive response, plasma concentrations of benflumetol were significantly higher than in those with treatment failure.
...Three combination regimens containing an average adult lumefantrine dose of 1,920 mg over 3 days (four doses) (regimen A) or 2,780 mg over 3 or 5 days (six doses) (regimen B or C, respectively) were given to 266 Thai patients. Detailed observations were obtained for 51 hospitalized adults, and sparse data were collected for 215 patients of all ages in a community setting. The population absorption half-life of lumefantrine was 4.5 hr. The model-based median (5th and 95th percentiles) peak plasma lumefantrine concentrations were 6.2 (0.25 and 14.8) ug/mL after regimen A, 9. 0 (1.1 and 19.8) ug/mL after regimen B, and 8 (1.4 and 17.4) ug/mL after regimen C. During acute malaria, there was marked variability in the fraction of drug absorbed by patients (coefficient of variation, 150%). The fraction increased considerably and variability fell with clinical recovery, largely because food intake was resumed; taking a normal meal close to drug administration increased oral bioavailability by 108% (90% confidence interval, 64 to 164) (P, 0.0001). The higher-dose regimens (B and C) gave 60 and 100% higher areas under the concentration-time curves (AUC), respectively, and thus longer durations for which plasma lumefantrine concentrations exceeded the putative in vivo MIC of 280 ug/mL (median for regimen B, 252 hr; that for regimen C, 298 hr; that for regimen A, 204 hr [P, 0.0001]) and higher cure rates. Lumefantrine oral bioavailability is very dependent on food and is consequently poor in acute malaria but improves markedly with recovery. The high cure rates with the two six-dose regimens resulted from increased AUC and increased time at which lumefantrine concentrations were above the in vivo MIC.
[EN] AZEPANYL-DERIVATIVES AND PHARMACEUTICAL COMPOSITIONS COMPRISING THE SAME WITH ANTIPARASITIC ACTIVITY<br/>[FR] DÉRIVÉS D'AZÉPANYLE ET COMPOSITIONS PHARMACEUTIQUES À ACTIVITÉ ANTI-PARASITAIRE LES CONTENANT
申请人：MERCK PATENT GMBH
公开号：WO2016000827A1
公开（公告）日：2016-01-07
The present invention provides compounds of Formula (i). Furthermore, pharmaceutical compositions are provided comprising at least one compound of Formula (i), for the treatment of parasitic diseases including malaria, as well as neurodegenerative diseases.
SUBSTITUTED 2,4 DIAMINO-QUINOLINE AS NEW MEDICAMENT FOR FIBROSIS, AUTOPHAGY AND CATHEPSINS B (CTSB), L (CTSL) AND D (CTSD) RELATED DISEASES
申请人：Genoscience Pharma SAS
公开号：EP3620164A1
公开（公告）日：2020-03-11
The present invention relates to novel 2-primary amino-4-secondary amino-quinoline derivatives, their manufacture, pharmaceutical compositions comprising them and their use as medicaments. The active compounds of the present invention can be useful as a medicament in the treatment and/or the decreasing and/or the prevention of fibrosis and/or fibrosis related diseases, or for use as a medicament in the treatment and/or the decreasing and/or the prevention of the autophagy and/or autophagy related diseases and for the inhibition of the autophagy flux, or for use in the inhibition of cathepsins B (CTSB), L (CTSL) and/or D (CTSD) and/or cathepsins B (CTSB), L (CTSL) and/or D (CTSD) related diseases; with the proviso that said compounds are not to be used for the treatment of any forms of cancers.
[EN] SUBSTITUTED HETEROARYL COMPOUNDS AND METHODS OF USE<br/>[FR] COMPOSÉS HÉTÉROARYLE SUBSTITUÉS ET LEURS MÉTHODES D'UTILISATION
申请人：CALITOR SCIENCES LLC
公开号：WO2015148868A1
公开（公告）日：2015-10-01
The present invention provides novel heteroaryl compounds, pharmaceutical acceptable salts and formulations thereof useful in preventing, treating or lessening the severity of a protein-mediated disease. The invention also provides pharmaceutically acceptable compositions comprising such compounds and methods of using the compositions in the treatment of protein kinase-mediated disease.
[EN] HETEROCYCLIC COMPOUNDS AND USES THEREOF<br/>[FR] COMPOSÉS HÉTÉROCYCLIQUES ET LEURS UTILISATIONS
申请人：INFINITY PHARMACEUTICALS INC
公开号：WO2015051241A1
公开（公告）日：2015-04-09
Compounds and pharmaceutical compositions that modulate kinase activity, including PI3 kinase activity, and compounds, pharmaceutical compositions, and methods of treatment of diseases and conditions associated with kinase activity, including PI3 kinase activity, are described herein.
Use of Inhibitors of the Activity or Function of PI3K
申请人：NOVARTIS AG
公开号：US20150342951A1
公开（公告）日：2015-12-03
The invention relates to new uses of PI3K inhibitors, wherein said inhibitors have an inhibitory action on the PI3K isoform delta for the treatment of immunopathology in a subject suffering from a disease or disorder selected from malaria, leishmaniasis, trypanosomiasis, toxoplasmosis and/or neurocysticercosis, via functional inhibition of TLR9 of the infected subject.
