- Replacing the chlorophenyl group of WR 194,965 with pyridines or pyrimidines improved antimalarial activity. Optimization of the pyridine series afforded JPC-3210 which displayed potent in vitro activity against chloroquine-sensitive and chloroquine-resistant parasites. JPC-3210 showed exceptional in vivo antimalarial activity in a mouse model and overcame the hERG liability of the lead compound with a favorable pharmacokinetic profile.
Zidovudine (AZT) is a nucleoside analog, a reverse transcriptase inhibitor (NRTI) and a type of antiretroviral drug used for the treatment of HIV/AIDS. The administration of zidovudine to the wistar albino rats showed an increase in erythrocyte fragility as can be seen from figure 1. There were significant (p<0.05)>0.05) decrease in serum ALP activity, significant (p<0.05) decrease in Fe2+/Fe3+ ratio and NADH methaemoglobin reductase activity. Findings from this study have revealed that zidovudine is hepatotoxic, increases the concentraton of ferric iron in the body thus imparing oxygen transport and also affects the erythrocyte membrane proteins adversely.
Zidovudine (AZT) is a nucleoside analog, a reverse transcriptase inhibitor (NRTI) and a type of antiretroviral drug used for the treatment of HIV/AIDS. The administration of zidovudine to the wistar albino rats showed an increase in erythrocyte fragility as can be seen from figure 1. There were significant (p<0.05)>0.05) decrease in serum ALP activity, significant (p<0.05) decrease in Fe2+/Fe3+ ratio and NADH methaemoglobin reductase activity. Findings from this study have revealed that zidovudine is hepatotoxic, increases the concentraton of ferric iron in the body thus imparing oxygen transport and also affects the erythrocyte membrane proteins adversely.
ABSTRACT- Multiple Drug resistance (MDR) tuberculosis timely diagnose is of utmost clinical relevance and needs to be diagnose at initial stages for the proper treatment. The current study was done to detect the several genes for MDR tuberculosis (TB) in clinical isolates by molecular tools. 60 clinical isolates were collected and subjected for AFB smear preparation, Nested PCR (IS6110) for mycobacterium tuberculosis complex detection and MDR TB PCR targeting rpoB, kat G, mab A promoter. 12 came positive for AFB smears, out of which 08 were pulmonary and 04 were extra pulmonary. Nested PCR targeting IS6110 gene was amplified at 123 base pairs with 340 base pairs as IC (internal control) was seen in 25 cases which include 19 pulmonary and 6 extra pulmonary. The Positive TB PCR specimens were subjected for MDRTB PCR Only 06 cases yielded, an amplicon of 315 bp confirming the rpoB gene resistance for resistance for rifampcin drug. In any of the 06 positives none of the other resistance gene other than rpoB was amplified. Targeting multiple genes at once, additional information will be gained from a single test run that otherwise would require several times the reagents and more time to perform. Current study signifies the usage of quick, cost effective, DNA sequences based method for MDR TB detection where disease will be diagnosed earlier and hence treatment would be started at an early stage.
Keywords: Multiple drug resistance, amplicon, Polymerase chain reaction, Nested PCR, Rifampicin.
Applying new techniques to blood assays in cats has enabled researchers to reduce the amount of blood needed nutrition study sample collection studies by 80%, with concomitant benefits for animal welfare. Presented at the Waltham InternationaI Nutrition Science Symposium, October 2016, Chicago
Atherosclerosis: New Insights on Foamy Macrophage Induction and PersistenceDr. Marian Laderoute
It is commonly assumed high cholesterol contributes to atherosclerosis which initiates with foamy macrophages. Here it is suggested the induction of foam in human macrophages relates instead to the induction of a newly described foamy virus, human endogenous retrovirus K102 (HERV-K102) in response to high cortisol and/or viruses, other intracellular pathogens, or tumors. HERV-K102 is a newly described human host protection mechanism and the particles are replication competent in vitro and in vivo. In healthy or younger adults, the foamy macrophages lyse on day 7 and release the protective HERV-K102 particles. When immunosenescence is evident (associated with low DHEA and high cortisol) the lysis and release of the HERV-K102 particles is blocked by alpha-fetoprotein (AFP). The dysfunctional and partly activated macrophages promote immunosenescence including atherosclerosis. See Laderoute MP, Discovery Medicine article published December 2015 for more details.
iDiffIR: Identifying differential intron retention from RNA-seqAraport
iDiffIR is a method for identifying differential intron retention from RNA-seq. For more information, please visit http://combi.cs.colostate.edu/idiffir/
Objective: To investigate the changes in the retina due to deltamethrin toxicity and the process in cell inflammation and apoptosis.
Study Design: Sixteen Wistar albino rats were randomly divided into two groups as control (n=8) and deltamethrin (n=8) groups. Saline was given to the control group, and 0.5 mL of 5 mg/kg deltamethrin was given to the deltamethrin group for 14 days each. Blood was collected for biochemical analysis. Retinal tissue was processed for histological examination.
Results: Compared to the control group, MDA levels were high while GSH and CAT levels were low in the deltamethrin group. Histopathological analysis showed spaces between the pigment epithelium, irregularity in the delimiting membrane, degenerated ganglion, cone and bacillus cell, pyknotic nuclei, thinned inner limitation membrane, and thickened vascular wall. The control group showed FAS expression in the pigment layer limiting membranes, in the nuclei of many cone and bacillus cells, and ganglion cells in the control group sections. In the deltamethrin group, FAS expression was observed in the inner and outer limiting membranes of the pigment epithelium, cone and bacillus cells, and ganglion cell nuclei. In the control group, negative NOS expression in the pigment epithelium and outer limiting membranes, internal limitation membrane, and ganglion cells in the cone and bacillus cell nuclei were observed. In the deltamethrin group, NOS expression was positive in the pigment epithelium, cone and bacillus, and ganglion cell nuclei.
Conclusion: We suggest that deltamethrin toxicity induced apoptotic process due to increased inflammation in the retina and may cause visual impairment as a result of neural damage.
Keywords: deltamethrin, FAS, insecticides, NOS, nitric oxide synthase, retina
ABSTRACT- Multiple Drug resistance (MDR) tuberculosis timely diagnose is of utmost clinical relevance and needs to be diagnose at initial stages for the proper treatment. The current study was done to detect the several genes for MDR tuberculosis (TB) in clinical isolates by molecular tools. 60 clinical isolates were collected and subjected for AFB smear preparation, Nested PCR (IS6110) for mycobacterium tuberculosis complex detection and MDR TB PCR targeting rpoB, kat G, mab A promoter. 12 came positive for AFB smears, out of which 08 were pulmonary and 04 were extra pulmonary. Nested PCR targeting IS6110 gene was amplified at 123 base pairs with 340 base pairs as IC (internal control) was seen in 25 cases which include 19 pulmonary and 6 extra pulmonary. The Positive TB PCR specimens were subjected for MDRTB PCR Only 06 cases yielded, an amplicon of 315 bp confirming the rpoB gene resistance for resistance for rifampcin drug. In any of the 06 positives none of the other resistance gene other than rpoB was amplified. Targeting multiple genes at once, additional information will be gained from a single test run that otherwise would require several times the reagents and more time to perform. Current study signifies the usage of quick, cost effective, DNA sequences based method for MDR TB detection where disease will be diagnosed earlier and hence treatment would be started at an early stage.
Keywords: Multiple drug resistance, amplicon, Polymerase chain reaction, Nested PCR, Rifampicin.
Applying new techniques to blood assays in cats has enabled researchers to reduce the amount of blood needed nutrition study sample collection studies by 80%, with concomitant benefits for animal welfare. Presented at the Waltham InternationaI Nutrition Science Symposium, October 2016, Chicago
Atherosclerosis: New Insights on Foamy Macrophage Induction and PersistenceDr. Marian Laderoute
It is commonly assumed high cholesterol contributes to atherosclerosis which initiates with foamy macrophages. Here it is suggested the induction of foam in human macrophages relates instead to the induction of a newly described foamy virus, human endogenous retrovirus K102 (HERV-K102) in response to high cortisol and/or viruses, other intracellular pathogens, or tumors. HERV-K102 is a newly described human host protection mechanism and the particles are replication competent in vitro and in vivo. In healthy or younger adults, the foamy macrophages lyse on day 7 and release the protective HERV-K102 particles. When immunosenescence is evident (associated with low DHEA and high cortisol) the lysis and release of the HERV-K102 particles is blocked by alpha-fetoprotein (AFP). The dysfunctional and partly activated macrophages promote immunosenescence including atherosclerosis. See Laderoute MP, Discovery Medicine article published December 2015 for more details.
iDiffIR: Identifying differential intron retention from RNA-seqAraport
iDiffIR is a method for identifying differential intron retention from RNA-seq. For more information, please visit http://combi.cs.colostate.edu/idiffir/
Objective: To investigate the changes in the retina due to deltamethrin toxicity and the process in cell inflammation and apoptosis.
Study Design: Sixteen Wistar albino rats were randomly divided into two groups as control (n=8) and deltamethrin (n=8) groups. Saline was given to the control group, and 0.5 mL of 5 mg/kg deltamethrin was given to the deltamethrin group for 14 days each. Blood was collected for biochemical analysis. Retinal tissue was processed for histological examination.
Results: Compared to the control group, MDA levels were high while GSH and CAT levels were low in the deltamethrin group. Histopathological analysis showed spaces between the pigment epithelium, irregularity in the delimiting membrane, degenerated ganglion, cone and bacillus cell, pyknotic nuclei, thinned inner limitation membrane, and thickened vascular wall. The control group showed FAS expression in the pigment layer limiting membranes, in the nuclei of many cone and bacillus cells, and ganglion cells in the control group sections. In the deltamethrin group, FAS expression was observed in the inner and outer limiting membranes of the pigment epithelium, cone and bacillus cells, and ganglion cell nuclei. In the control group, negative NOS expression in the pigment epithelium and outer limiting membranes, internal limitation membrane, and ganglion cells in the cone and bacillus cell nuclei were observed. In the deltamethrin group, NOS expression was positive in the pigment epithelium, cone and bacillus, and ganglion cell nuclei.
Conclusion: We suggest that deltamethrin toxicity induced apoptotic process due to increased inflammation in the retina and may cause visual impairment as a result of neural damage.
Keywords: deltamethrin, FAS, insecticides, NOS, nitric oxide synthase, retina
Natural compounds from the bark of the cinchona tree, most notably quinine was observed to exhibit antimalarial activity.
Until the development of synthetic derivatives (ie. 4-aminoquinoline antimalarials), quinine continued to be the first choice to treat malaria.
Quinine is associated with side effects such as diarrhœa.
4-aminoquinoline antimalarials such as amodiaquine and chloroquine largely replaced quinine because of reduced unpleasant side effects.
The life cycle of the parasite and the immunological defence mechanisms against the parasite are complex.
Part of the parasite’s life cycle involves invasion of red blood cells (erythrocytes).
The haemoglobin within the red blood cell is broken down by the parasite and is used as a source of amino acids.
The 4-aminoquinolines act at the erythrocytic stage of the parasite.
Doxycycline is a compound used in prophylaxis against plasmodial parasites.
Other compounds associated with treating malaria include halofantrine and lumefantrine, often used in combination with other drugs.
This presentation includes details about ADEPT(Antibody Directed Enzyme prodrug Therapy), various challenges that one should meet to design an ADEPT and various enzymes and prodrugs that are reported and also the data of clinical studies.
Science Behind The News: TAP(Triaminopyrimidine) discovered as a promising dr...Kiran Shaw
In a path breaking discovery, Scientists from Bengaluru and across the world have discovered triaminopyrimidine (TAP) as a promising drug candidate for malaria that kills the parasite rapidly over a long duration.This article published by Nature on the 31st of March dwells into the science behind this drug discovery.
International Journal of Engineering and Science Invention (IJESI)inventionjournals
International Journal of Engineering and Science Invention (IJESI) is an international journal intended for professionals and researchers in all fields of computer science and electronics. IJESI publishes research articles and reviews within the whole field Engineering Science and Technology, new teaching methods, assessment, validation and the impact of new technologies and it will continue to provide information on the latest trends and developments in this ever-expanding subject. The publications of papers are selected through double peer reviewed to ensure originality, relevance, and readability. The articles published in our journal can be accessed online.
Dr. Robert Langer - Simposio Internacional 'Terapias oncológicas avanzadas'Fundación Ramón Areces
Los días 15 y 16 de octubre de 2014, la Fundación Ramón Areces y la Real Academia Nacional de Farmacia, en colaboración con la Fundación de la Innovación Bankinter, reunieron en Madrid a algunos de los mayores expertos mundiales en nuevas terapias contra el cáncer. El Simposio Internacional, coordinado por la profesora y académica María José Alonso, analizó el momento actual de la lucha contra esta enfermedad. También fue un punto de encuentro para científicos de los más innovadores institutos de investigación en oncología, quienes debatieron sobre tres grandes temas: la Medicina Personalizada contra el cáncer, los nanomedicamentos en la terapia del cáncer y las terapias basadas en la inmunomodulación.
Total saponins in Rubus parvifolius L. induce lymphoma cells apoptosis throug...LucyPi1
Abstract Purpose: To investigate the effect of total saponins of Rubus parvifolius L. (TSRP) on lymphoma Raji cells and further discuss its mechanism. Methods: The model of nude mice bearing Raji cells was established, the volume, weight and inhibition rate of the transplanted tumor were analyzed and compared after different concentrations of TSRP treatment. Cell apoptosis and expression of Bcl-2, Bax, Fas proteins were detected by TUNEL and immunohistochemiscal method respectively. Effects of TSRP on cell proliferation were tested with MTT assay in vitro. Cell apoptosis and expression of Caspase-9, Caspase-3, Bcl-2, Bax and Fas proteins were tested with DAPI staining and Western blot. Results: TSRP significantly reduced the volume and tumor weight of Raji subcutaneous transplanted tumor and induced the apoptosis of Raji cells in vivo. The tumor inhibition rate of high-dose (100 mg/kg) TSRP is 90.84%. The TUNEL test results show that the fluorescence intensity of the tumor issue treated with TSRP is significantly improved. Compared with the control group, the fluorescence intensity of high-concentration TSRP is 82.43 ± 7.81, which is significantly different (P < 0.001). The results of immunohistochemistry test showed that the Bcl-2 expression of Raji cell treated with TSRP is obviously reduced, and Bax expression is obviously increased. Meanwhile, compared with that of control group, Fas expression is obviously reduced. MTT assay showed that TSRP can significantly inhibit proliferation of Raji cells with dose dependence. The inhibition rate of 400 μg/mL TSRP is 53.46 ± 4.90% (P < 0.001). DAPI staining results showed that TSRP can significantly induce cell apoptosis. According to Western blot results, it is found that TSRP can significantly inhibit activity of Bcl-2 and increase Bax expression, and TSRP can also inhibit Fas expression. Meanwhile, expression of Caspase-9 and Caspase-3 is also increased. Conclusion: TSRP could inhibit the proliferation of lymphoma via induction of apoptosis in a time and dose-dependent manner. Apoptotic signaling induced by TSRP was characterized by up-regulating Bax, Fas and Caspase-8 protein expression, and down-regulating of Bcl-2 protein expression.
1. Summary of Initial SAR Analysis
Initial SAR study focused on four areas of the molecule:
Hydroxyl group: Replacement with H or F abolished antimalarial activity.
tert-Butylamine: A variety of amines tolerated, but none better then tert-butyl.
tert-Butyl group: Substituted phenyl tolerated, but increased lipophilicity.
Reduced activity observed for small lipophilic or polar groups.
Chlorophenyl group: Heteroaromatic replacements improved activity.
SAR of Heteroaryl Analogs
Pyridine analogs chosen for further optimization studies.
Identification of 2-aminomethylphenol antimalarials with potent in vitro and in vivo activity against Plasmodium blood stages
Gavin D. Heffernan,1 David P. Jacobus,1 John W. Anderson,1 Peter Krasucki,1 Kurt W. Saionz,1 Guy Schiehser,1 Hong-Ming Shieh,1 Wenyi Zhao,1 Arba Ager,2
Marina Chavchich,3 Geoffrey Birrell,3 Dennis Shanks,3 Michael Edstein.3
1Jacobus Pharmaceutical, P.O. Box 5290, Princeton, NJ 08540, USA, 2University of Miami, Miller School of Medicine, Miami, FL 33136, USA
3Australian Army Malaria Institute, Weary Dunlop Drive, Gallipoli Barracks, Enoggera, QLD 4051, Australia.
.
Summary
Replacing the chlorophenyl group of WR 194,965 with pyridines or pyrimidines
improved antimalarial activity.
Optimization of the pyridine series afforded JPC-3210 which displayed potent in
vitro activity against chloroquine-sensitive and chloroquine-resistant parasites.
Exceptional in vivo antimalarial activity observed for JPC-3210.
JPC-3210 overcame the hERG liability present in the lead and exhibited a
favorable pharmacokinetic profile.
References
1. World Health Organization World Malaria Report 2014.
2. Peters, W. et al. Annals of Tropical Medicine and Parasitology 1984, 78, 567-579.
3. Desjardins, R. E. et al. Antimicrob. Agents Chemother. 1979, 16, 710–718.
4. Ager, A. L. Experimental models: rodent malaria models (in vivo). In Handbook of experimental pharmacology: antimalarial
drugs; Peters, W., Richards, W. H. G., Ed.; Springer Verlag, New York, NY, 1984; vol 68, pp 225-254.
5. ChanTest Corporation, Cleveland, OH 44128
Synthesis of Heteroaryl Analogs
Reagents and conditions: (a) Br2, CH2Cl2, 0oC to rt, 99% yield; (b) MEMCl, iPr2NEt, CH2Cl2, 0oC to rt,
99% yield; (c) nBuLi, B(OiPr)3, THF, -78 to -10oC, 99% yield; (d) HetArX, Pd(PPh3)4, K2CO3, H2O, DME,
80oC; (e) 1M aq. HCl, MeOH, 60oC; (f) (CH2O)n, tBuNH2, iPrOH, reflux; (g) 1M aq. HCl, EtOH, rt.
Introduction
Worldwide, more than 3 billion people are at risk of being infected with malaria and
in 2013 an estimated 584,000 deaths were attributed to the disease.1
New antimalarial drugs are urgently needed due to the development of resistance to
current treatments.
WR 194,9652 was selected as the starting point of a medicinal chemistry program.
Exhibited potent in vitro activity against two P. falciparum lines, the chloroquine-
sensitive D6 line, and the chloroquine-resistant W2 line.
Substantial hERG inhibition a major drawback of WR 194,965.
JACOBUS
PHARMACEUTICAL
WR 194,965
Pyridine Analogs Focused SAR Study
Trifluoromethylated analogs (1, 2 & 12) displayed excellent in vivo activity
Corresponding 2-pyridyl (13) and 2-pyrimidyl (14) isomers notably less active
Methods:
In vitro Antimalarial Testing:
Parasite susceptibility to test compounds was determined by measuring the inhibition of
[3H]Hypoxanthine uptake in a whole blood isotopic assay (1% starting parasitemia).3
In vivo Antimalarial Testing (Modified Thompson Test):
Survival and parasite clearance in male CD1 mice infected with P. berghei (1% parasitemia)
were measured for 31 days. Test compounds were administered twice daily by oral gavage on
days 3–5. Mice that survived for 31 days and were blood-film negative were considered cured.4
hERG Testing:
Drug interactions with the hERG potassium channel, responsible for the cardiac 'rapid' delayed
rectifier current (IKr), were determined using a manual patch clamp assay.5
Activity of Optimized Compounds
Mouse PK Data for JPC-3210a
High oral Cmax achieved (1,180 ng/mL, 2.96 mM), very long half-life (7 days).
Excellent bioavailability (86%).
Plasma levels of JPC-3210 exceed the P.f. D6 IC50 for >28 days after a single
16 mg/kg dose (data not shown).
aIn male CD1 mice. Results are the mean of n = 3
bIn 5% Tween in phosphate buffered saline. cIn.0.1% Tween80/0.5% hydroxyethylcellulose in water.
In vitro activity improved 3-fold over the lead WR 194,965.
JPC-3210 8-fold more active in vivo than WR 194,965.
No hERG liability observed for JPC-3186 and JPC-3210.
Compound 2 Compound 12
WR 194,965 JPC-3186 JPC-3210
P.f. D6 IC50 (nM) 31 10 9
P.f. W2 IC50 (nM) 28 9 8
Curative dose
(Thompson test)
32 mg/kg/day 8 mg/kg/day 4 mg/kg/day
hERG IC50 (mM) 1.1 >10 >10
Route of
Administration
/ Dose
Tmax (h)
Cmax
(ng/mL)
t1/2 (h)
AUC0-last
(h*ng/mL)
Clearance
(mL/h/kg)
Vol. of
Distribution
(mL/kg)
F (%)
IV
b
/ 2 mg/kg 0.083 847 139 16,100 116 23,200 NA
Oralc
/ 16 mg/kg 2 1,180 169 111,000 119 29,000 86
Compd. HetAr
P.f. D6
IC50 (nM)
Thompson test
survival at day 31
@ Dose/day
Compd. HetAr
P.f. D6
IC50 (nM)
Thompson test
survival at day 31
@ Dose/day
1 13
7/7 @
8 mg/kg
8 25
7/7 @
64 mg/kg
2 10
7/7 @
8 mg/kg
9 350
0/7 @
32 mg/kg
3 25
4/7 @
8 mg/kg
10 23
0/7 @
64 mg/kg
4 19
3/7 @
16 mg/kg
11 24
1/7 @
64 mg/kg
5 67
0/7 @
64 mg/kg
12 9
7/7 @
4 mg/kg
6 64
4/7 @
64 mg/kg
13 231
0/7 @
64 mg/kg
7 23
5/7 @
64 mg/kg
14 6,300 Not tested